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  • 1.
    Abdulmahdi, Rasha
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Statinanvändning hos äldre hypertonipatienter med nedsatt njurfunktion2013Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Statinanvändning hos äldre hypertonipatienter med nedsatt njurfunktion

    Rasha Abdulmahdi

    Handledare: Björn Wettermark, Docent, Apotekare, Utvecklingsavdelningen, SLL. Yvonne Freund-Levi, MD PhD Överläkare KI. Tero Shemiekka, överläkare Avdelningen för E-hälsa, SLL. Examinator: Margareta Hammarlund-Udenaes, Professor i farmakokinetik och farmakodynamik. Institutionen för farmaceutisk biovetenskap. Examensarbete i Farmakoterapi D, 30hp, Uppsala universitet.

     

    Introduktion: Äldre patienter löper större risk att utveckla läkemedelsbiverkningar p.g.a. avtagande njurfunktion. Flera publicerade studier tyder på att många patienter läggs in akut på sjukhus för att de använder läkemedel som inte anpassas efter deras njurfunktion. Syfte: Att kartlägga förskrivning av statiner hos äldre hypertonipatienter med avseende på njurfunktion i Skaraborg och sydvästra Stockholms Län. Material och metoder: En tvärsnittstudie baserad på data hämtade från SPCCD (Swedish Primary Care Cardiovascular Database). Patienter ≥ 65 år som hade minst ett registrerat S-kreatinin under år 2006-2008 inkluderades och andelen som hämtade ut statiner under perioden 2006-2009 analyserades. GFR (Glomerular Filtration Rate) beräknades med CKD-EPI-formeln (Chronic Kidney Disease Epidemiology Collaboration). Läkemedelssubstanserna lämplighet eller behov av dosjustering i relation till njurfunktion granskades enligt RenBase, en databas med dokumentation av läkemedel vid nedsatt njurfunktion. Resultat. Totalt identifierades 38 239 individer och av dessa hade 23,8 % behandlats med statiner. De mest förskrivna statinerna var simvastatin (84,2 %) och atorvastatin (10,5 %). Det var signifikant färre (95 % C.I.) som behandlades med de båda statinerna vid en jämförelse mellan GFR < 30 och >30. Det fanns ingen korrelation mellan snittdosering (mg/dag) och njurfunktion. Konklusion: Många äldre hypertonipatienter i primärvården med nedsatt njurfunktion får statinbehandling. Det förefaller dock som om simvastatin inte dosjusteras hos patienter med svårt nedsatt njurfunktion.

                 

  • 2.
    Akcan, Martina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Smärtstillande läkemedelsbehandling hosäldre i Uppsala län - en retrospektiv studie2014Självständigt arbete på grundnivå (yrkesexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Introduktion: Hos äldre är smärta relativt vanligt då det med ökad ålder uppkommerproblem i muskler, leder, senor och skelett, t.ex. artros, osteoporos och sarkopeni.Socialstyrelsen utformade 2004 en mall för god läkemedelsterapi hos äldre, s.k.kvalitetsindikatorer. T.ex. får paracetamol inte överstiga en dygnsdos på 4 g/dygn ochNSAID bör endast användas vid inflammatorisk smärta. När lätta analgetika inte hjälperrekommenderas behandling med starka opioider direkt utan att först använda lättaopioider lätta opioider då dessa anses olämpliga för äldre. Vid perifer neuropatisksmärta rekommenderas i första hand TCA (amitriptylin, nortriptylin) eller gabapentin.Syfte: Det övergripande syftet är att värdera kvaliteten i äldres smärtstillandeläkemedelsbehandling genom att relatera den till rekommenderad behandling för att ökakunskapen om hur behandling med smärtstillande läkemedel ser ut inom äldrevårdenidag. Material och metoder: Läkemedelslistor från 434 patienter från olikaäldreboenden i Uppsala län inkluderas i studien. Insamlade, avidentifierade data fördesin i Excel med information som student-ID, patient-ID, ålder, kön, substansnamn,stående dos, vidbehovsdos och stående + vidbehovsdos. Resultat: Gruppen bestod av299 kvinnor och 135 män med medelåldern 85,4 år. Totalt förskrevs 485 smärtstillandeläkemedel till de 434 patienterna. 75.8 % patienter förskrevs paracetamol, 27,2 %opioider, 3,45 % NSAID, 0,92 % amitriptylin respektive 1,61 % gabapentin.Rekommenderad dygnsdos av paracetamol överskreds hos 13 patienter, av diklofenakhos en patient medan 33 patienter inte hade maximal dygnsdos angiven. Förskrivning avett analgetikum var vanligast och förekom hos 179 patienter. Två analgetika förskrevstill 119 patienter medan två, en man och en kvinna, förskrevs 5 analgetika vardera.Totalt 94 personer, 21,4 %, använde inga smärtstillande läkemedel alls. Konklusion:Studien visar att smärtstillande läkemedelsbehandling hos äldre i Uppsala län inteskiljer sig markant från studier gjorda i övriga Sverige och Europa. Dock var det någrasom, enligt Socialstyrelsen kvalitetsindikatorer, överskred dygnsdosen och stod påläkemedel som anses vara olämpliga för äldre, vilket visar att det fortfarande finnsproblem med äldres läkemedelsterapi.

  • 3.
    Akin, Berivan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    En undersökning gällande val av antibiotika för behandling av nedre UVI hos kvinnor2016Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    En undersökning gällande val av antibiotika för behandling av nedre UVI hos kvinnor Berivan Akin Handledare: Margareta Hammarlund-Udenaes – Institution för farmaceutisk biovetenskap Examinator: Agneta Freijs – Institution för farmaceutisk biovetenskap

    Introduktion: Nedre UVI är en infektion som lokaliseras till urinröret och orsakas till mestadels av de primära patogenerna E. coli eller S. saprophyticus. Infektionen kan diagnostiseras endast baserad på symtomen eller med tillägg av tester som leukocytesterastest, nitrittest samt urinodling. Användning av de testerna ger en säkrare diagnos och förskrivaren kan därmed ge patienten en lämpligare behandling. Detta kan skilja sig om det är sporadisk eller recidiverande nedre UVI. Antibiotika som förskrivs för nedre UVI är huvudsakligen nitrofurantoin, pivmecillinam, trimetoprim och ciprofloxacin. Syfte: Huvudsyftet med arbetet var att klargöra hur förskrivaren resonerar kring valet av tester och antibiotika för att behandla en patient med misstänkt nedre UVI. Metod: Förskrivare med olika bakgrund och erfarenhet intervjuades för att undersöka bakomliggande motiv tillbehandlingsvalet. En litteraturstudie genomfördes för att erhålla information om resistensproblematiken samt miljövänligheten av preparaten. Förskrivningsstatistik togs fram via Socialstyrelsens databas för läkemedel. Resultat: Det konstaterades att labprov och teststickor inte nödvändigtvis behövs för att förskriva läkemedel mot nedre UVI. Förskrivningsstatistiken visade att antalet recept med nitrofurantoin och pivmecillinam har ökat markant från år 2006 och framåt, medan trimetoprim och ciprofloxacin har minskat. Slutsats: Pivmecillinam förskrivs mest och därefter nitrofurantoin. Förskrivarna resonerar olika vid valet av antibiotika beroende på erfarenheten. Resistensproblematiken tas hänsyn till, men miljöproblematiken prioriteras lågt.

  • 4.
    Alassaad, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Gillespie, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Bertilsson, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Prescription and transcription errors in multidose-dispensed medications on discharge from hospital: an observationaland interventional study2013Ingår i: Journal of Evaluation In Clinical Practice, ISSN 1356-1294, E-ISSN 1365-2753, Vol. 19, nr 1, s. 185-191Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background 

    Medication errors frequently occur when patients are transferred between health care settings. The main objective of this study was to investigate the frequency, type and severity of prescribing and transcribing errors for drugs dispensed in multidose plastic packs when patients are discharged from the hospital. The secondary objective was to correct identified errors and suggest measures to promote safe prescribing.

    Methods 

    The drugs on the patients' multidose drug dispensing (MDD) order sheets and the medication administration records were reconciled prior to the MDD orders being sent to the pharmacy for dispensing. Discrepancies were recorded and the prescribing physician was notified and given the opportunity to change the order. Discrepancies categorized as unintentional and related to the discharge process were subject to further analysis.

    Results 

    Seventy-two (25%) of the 290 reviewed MDD orders had at least one discharge error. In total, 120 discharge errors were identified, of which 49 (41%) were assessed as being of moderate and three (3%) of major severity. Orders with a higher number of medications and orders from the orthopaedic wards had a significantly higher error rate.

    Conclusion 

    The main purpose of the MDD system is to increase patient safety by reducing medication errors. However, this study shows that prescribing and transcribing errors frequently occur when patients are hospitalized. Because the population enrolled in the MDD system is an elderly, physically vulnerable group with a high number of prescribed drugs, preventive measures to ensure safe prescribing of MDD drugs are warranted.

  • 5.
    Alenius, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Treatment Response in Psychotic Patients in a Naturalistic Setting: Classification, Genes, Drugs, Insight and Social Networks2009Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Many patients with psychotic symptoms respond poorly to treatment. Various approaches have been made to classify these patients according to treatment response. However, existing classifications have been criticized for various reasons and a new classification system is needed. Further, no satisfactory explanation of the poor treatment response has been apparent. The general aim of this thesis was therefore to develop and validate a new classification method of functional remission in a naturalistic population of patients with psychosis and to utilize this classification to investigate the population from genetic, drug treatment, insight and social network points of view.

    Data for this cross-sectional study of patients (n=123) attending the Psychosis Outpatient Care clinic in the county of Jönköping, Sweden, were obtained from patient interviews, blood samples and information from patient files. The new classification method CANSEPT, which combines the CAN rating scale (CAN), the UKU side effect rating scale (SE) and the patient’s previous treatment history (PT), showed validity in discriminating the patients and was accepted well by the patients. CANSEPT was used to group the patients in the other studies in this thesis.

    The results indicated that the gene polymorphism ABCB1 3435T, was related to worse significant social and clinical needs for patients on olanzapine, while the polymorphism DRD2 Taq1 A1 was related to a greater risk of significant side effects; especially if male, or taking strong dopamine D2-receptor antagonistic drugs. Drug treatment factors were also related to treatment response; longer duration of untreated prodromal and early psychosis was seen for patients with current significant social and clinical needs and non-adherence to treatment was associated with worse significant side effects. Worse treatment outcomes also appeared to be associated with smaller social network groups, worse insight into illness, poorer knowledge of warning signs and worse coping strategies.

    In summary, CANSEPT was shown to be a useful valid, multidimensional tool for classification of treatment response. Gene polymorphisms, duration of untreated illness, non-adherence to treatment, social networks and knowledge should be taken into consideration when investigating inadequate treatment response.

    Delarbeten
    1. Treatmentresponse in psychotic patients classified according to social and clinical needs, drug side effects, and previous treatment; a method to identify functional remission
    Öppna denna publikation i ny flik eller fönster >>Treatmentresponse in psychotic patients classified according to social and clinical needs, drug side effects, and previous treatment; a method to identify functional remission
    Visa övriga...
    2009 (Engelska)Ingår i: Comprehensive Psychiatry, ISSN 0010-440X, E-ISSN 1532-8384, Vol. 50, nr 5, s. 453-462Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    BACKGROUND: Various approaches have been made over the years to classify psychotic patients according to inadequate treatment response, using terms such as treatment resistant or treatment refractory. Existing classifications have been criticized for overestimating positive symptoms; underestimating residual symptoms, negative symptoms, and side effects; or being to open for individual interpretation. The aim of this study was to present and evaluate a new method of classification according to treatment response and, thus, to identify patients in functional remission. METHOD: A naturalistic, cross-sectional study was performed using patient interviews and information from patient files. The new classification method CANSEPT, which combines the Camberwell Assessment of Need rating scale, the Udvalg for Kliniske Undersøgelser side effect rating scale (SE), and the patient's previous treatment history (PT), was used to group the patients according to treatment response. CANSEPT was evaluated by comparison of expected and observed results. RESULTS: In the patient population (n = 123), the patients in functional remission, as defined by CANSEPT, had higher quality of life, fewer hospitalizations, fewer psychotic symptoms, and higher rate of workers than those with the worst treatment outcome. CONCLUSION: In the evaluation, CANSEPT showed validity in discriminating the patients of interest and was well tolerated by the patients. CANSEPT could secure inclusion of correct patients in the clinic or in research.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-98078 (URN)10.1016/j.comppsych.2008.11.001 (DOI)000269251100009 ()19683616 (PubMedID)
    Tillgänglig från: 2009-02-11 Skapad: 2009-02-11 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    2. Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting
    Öppna denna publikation i ny flik eller fönster >>Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting
    Visa övriga...
    2008 (Engelska)Ingår i: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 42, nr 11, s. 884-893Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    RATIONALE: Many patients with psychotic symptoms respond poorly to treatment. Factors possibly affecting treatment response include the presence of polymorphisms in genes coding for various receptor populations, drug-metabolizing enzymes or transport proteins. OBJECTIVES: To investigate whether genetic polymorphisms could be indicators of treatment response to antipsychotic drugs. The genes of interest were the dopamine D2 receptor gene (DRD2), the serotonin 2A and 2C receptor genes (HTR2A and HTR2C), the P-glycoprotein gene (ABCB1 or MDR1) and the drug-metabolizing cytochrome P450 2D6 gene (CYP2D6). MATERIAL AND METHODS: Data for this naturalistic, cross-sectional study of patients requiring antipsychotic drugs and attending the Psychosis Outpatient Care clinic in Jönköping, Sweden were obtained from patient interviews, blood samples and information from patient files. Blood samples were genotyped for DRD2 Taq1 A, Ins/Del and Ser311Cys, HTR2A T102C, HTR2C Cys23Ser, ABCB1 1236C>T, 2677G>T/A, 3435C>T and genetic variants of CYP2D6. The patients (n=116) were grouped according to the CANSEPT method regarding significant social and clinical needs and significant side effects. RESULTS: Patients on olanzapine homozygous for ABCB1 3435T, had more significant social and clinical needs than others. Patients with one or two DRD2 Taq1 A1 alleles had a greater risk of significant side effects, particularly if they were male, Caucasian, had a schizophrenic or delusional disorder or were taking strong dopamine D2-receptor antagonistic drugs. CONCLUSION: If these results are confirmed, patients carrying the DRD2 Taq1 A1 allele would benefit from using drugs without strong dopamine D2 receptor antagonistic properties.

    Nyckelord
    DRD2, 5-HT2, ABCB1, Cytochrome P-450 CYP2D6, Antipsychotic agents, Schizophrenia
    Nationell ämneskategori
    Farmaceutiska vetenskaper Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-98079 (URN)10.1016/j.jpsychires.2007.10.007 (DOI)000258798300002 ()18086475 (PubMedID)
    Tillgänglig från: 2009-02-11 Skapad: 2009-02-11 Senast uppdaterad: 2018-01-13
    3. Current and retrospective antipsychotic drug use in relation to treatment response in a naturalistic setting of psychotic patients
    Öppna denna publikation i ny flik eller fönster >>Current and retrospective antipsychotic drug use in relation to treatment response in a naturalistic setting of psychotic patients
    2009 (Engelska)Artikel i tidskrift (Refereegranskat) Submitted
    Identifikatorer
    urn:nbn:se:uu:diva-98080 (URN)
    Tillgänglig från: 2009-02-11 Skapad: 2009-02-11 Senast uppdaterad: 2011-05-11Bibliografiskt granskad
    4. Knowledge and insight in relation to functional remission in patients with long-term psychotic disorders
    Öppna denna publikation i ny flik eller fönster >>Knowledge and insight in relation to functional remission in patients with long-term psychotic disorders
    2010 (Engelska)Ingår i: Social Psychiatry and Psychiatric Epidemiology, ISSN 0933-7954, E-ISSN 1433-9285, Vol. 45, nr 5, s. 523-529Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    BACKGROUND: Patients with psychotic symptoms often respond poorly to treatment. Outcomes can be affected by biological, physiological and psychological factors according to the vulnerability-stress model. The patient's coping strategies and beliefs have been correlated with outcomes. OBJECTIVES: To investigate the knowledge and insight in relation to treatment response. METHODS: A naturalistic study was performed using patient interviews and information gathered from patient drug charts. Apart from the rating scales used for classification of treatment response (CANSEPT method), the SPKS knowledge of illness and drugs rating scale was utilized. RESULTS: In the group of patients in functional remission (FR; n = 38), 37% had insight into their illness as compared to 10% among those not in functional remission (non-FR; n = 78; P < 0.01). As much as 23% of the non-FR group had no strategy for responding to warning signs versus 8% in the FR group (P < 0.05). CONCLUSIONS: Better treatment outcomes appear to be associated with better insight into illness, higher knowledge of warning signs and better coping strategies.

    Nyckelord
    Health knowledge, Treatment outcome, Schizophrenia, Psychotic disorders, Insight
    Nationell ämneskategori
    Psykiatri
    Identifikatorer
    urn:nbn:se:uu:diva-123011 (URN)10.1007/s00127-009-0096-3 (DOI)000275422700002 ()19626260 (PubMedID)
    Tillgänglig från: 2010-04-22 Skapad: 2010-04-22 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
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  • 6.
    Alenius, Malin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Dahl, Marja-Liisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Hartvig, Per
    Lindström, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting2008Ingår i: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 42, nr 11, s. 884-893Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    RATIONALE: Many patients with psychotic symptoms respond poorly to treatment. Factors possibly affecting treatment response include the presence of polymorphisms in genes coding for various receptor populations, drug-metabolizing enzymes or transport proteins. OBJECTIVES: To investigate whether genetic polymorphisms could be indicators of treatment response to antipsychotic drugs. The genes of interest were the dopamine D2 receptor gene (DRD2), the serotonin 2A and 2C receptor genes (HTR2A and HTR2C), the P-glycoprotein gene (ABCB1 or MDR1) and the drug-metabolizing cytochrome P450 2D6 gene (CYP2D6). MATERIAL AND METHODS: Data for this naturalistic, cross-sectional study of patients requiring antipsychotic drugs and attending the Psychosis Outpatient Care clinic in Jönköping, Sweden were obtained from patient interviews, blood samples and information from patient files. Blood samples were genotyped for DRD2 Taq1 A, Ins/Del and Ser311Cys, HTR2A T102C, HTR2C Cys23Ser, ABCB1 1236C>T, 2677G>T/A, 3435C>T and genetic variants of CYP2D6. The patients (n=116) were grouped according to the CANSEPT method regarding significant social and clinical needs and significant side effects. RESULTS: Patients on olanzapine homozygous for ABCB1 3435T, had more significant social and clinical needs than others. Patients with one or two DRD2 Taq1 A1 alleles had a greater risk of significant side effects, particularly if they were male, Caucasian, had a schizophrenic or delusional disorder or were taking strong dopamine D2-receptor antagonistic drugs. CONCLUSION: If these results are confirmed, patients carrying the DRD2 Taq1 A1 allele would benefit from using drugs without strong dopamine D2 receptor antagonistic properties.

  • 7.
    Ali, karzan Asi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Vilken evidens finns det för att ge peroral kortisonkur till KOL-patienter med exacerbation? – en litteraturstudie2019Självständigt arbete på grundnivå (högskoleexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Bakgrund: Kroniskt obstruktiv lungsjukdom (KOL) är en vanlig sjukdom som drabbar oftast äldre och rökare. Typiska symtom är andnöd, produktiv hosta, trötthet samt återkommande luftvägsinfektioner. Flera olika bidragande orsaker kan leda till att en KOL-patient utvecklar sjukdomen, bland annat rökning, luftföroreningar, socioekonomisk status, astma, genetik, luftvägsinfektioner och dålig kost. KOLpatienter drabbas oftast av försämringsperioder, så kallade KOL-exacerbationer. En KOL-exacerbation kan förekomma i olika grader: som mild, måttlig eller svår. Oavsett svårighetsgraden ges olika läkemedel för att minska frekvensen av exacerbationer och för att förbättra livskvaliteten hos en KOL-patient. Det finns olika tillgängliga läkemedel i dagsläget för att behandla både KOL och KOL-exacerbationer. I detta projektarbete granskades åtta tidigare studier för att undersöka effekten av peroral kortisonkur hos KOL-patienter med mild till måttlig KOL-exacerbation. Även undersöktes om peroral kortisonkur var en effektiv behandling för att minska exacerbationsfrekvens och därmed förbättra livskvaliteten samt hälsostatus hos KOLpatienter.

    Syfte: Syftet var att undersöka vilken evidens som finns för peroral kortisonkur enligt GOLD 2019s rekommendation vid mild-måttlig KOL-exacerbation hos KOL-patienter i GOLD stadium B.

    Metod: En systematisk litteraturgenomgång gjordes enligt Statens beredning för medicinsk och social utvärdering (SBU) metoden. Databaserna PubMed och Cochrane library användes för att hitta relevanta artiklar för projektarbetet. Både randomiserade studier och systematiska översikter inkluderades i projektarbetet. Bedömning av relevans och kvalitet av artiklarna gjordes med hjälp av mallar från SBU.

    Resultat: Åtta artiklar inkluderades, av vilka två av hög kvalitet och resterande sex av godtagbar kvalitet. Artiklarnas resultat visade att det fanns evidens för att ge peroral kortisonkur till KOL-patienter med mild till måttlig KOL-exacerbation. Dessutom ger peroral kortisonkur positiv effekt med avseende på excerbationsfrekvens, andfåddhet, hälsostatus och livskvalitet. Risken/biverkningarna av peroral kortisonkur har inte tagit med i detta arbete.

    Slutsats: Slutsatsen för projektarbetet var att peroralt prednisolon ger effekt vid mild till måttlig KOL-exacerbation i GOLD stadium B och minskar exacerbationsfrekvens, förbättrar lungfunktion samt livskvalitet. En mer nyanserande evidenssammanställning hade kunnat göras om även riskerna med kortisonbehandling hade beaktats.

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  • 8.
    Al-zaibari, Liza
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Visualization of metabotropic glutamate receptor 5 (mGluR5) expression and function during progression of Alzheimer’s disease2014Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
  • 9.
    Asfaw, Harnet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Undersökning av samtal om läkemedelsinteraktioner inkomna till Läkemedelsupplysningen på Läkemedelsverket.2019Självständigt arbete på avancerad nivå (magisterexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Introduktion: Läkemedelsinteraktion uppstår vid samtidig behandling med flera läkemedel som påverkar varandras effekter. Interaktioner uppkommer inte endast vid samtidig behandling av flera receptbelagda läkemedel. Även natur- och receptfria läkemedel, vissa födoämnen exempelvis grapefruktjuice och kalkhaltiga livsmedel som mjölkprodukter samt alkohol kan ge upphov till interaktioner. Läkemedel påverkar varandras effekter genom farmakokinetiska och farmakodynamiska processer. Läkemedelupplysningen är en upplysningstjänst på Läkemedelverket och har som uppdrag att förmedla information om läkemedelsanvändning till allmänheten. Frågorna varierar och handlar ofta om läkemedels möjliga säkerhetsrisker t.ex. interaktioner och biverkningar.

    Syfte: Syftet med denna studie var att sortera och analysera inkomna frågor till LMU för att ta reda på vilken information som efterfrågas om interaktioner.Metod: Undersökning genomfördes utifrån kvalitativa och kvantitativa perspektiv och Microsoft Excel-dokument innehållande all information om bland annat läkemedelsinteraktioner inkomma till LMU användes.

    Resultat: Undersökningen visade att 25% av alla frågor inkomna till LMU handlade om läkemedelsinteraktioner. Resultatet visade att de flesta frågor handlade om läkemedelsinteraktioner mellan läkemedel för nervsystemet blodtrycks- och blodförtunnade mediciner. Kategorisering för egenvårdsprodukter resulterade i att frågeställarna i de flesta fall frågar om deras receptbelagda läkemedel fungerar ihop med receptfria produkter som smärtstillande NSAID, paracetamol protonpumpshämmare samt vitaminkosttillkott. Validering av ett antal frågor visade i stort sett rätt kategorisering.

    Konklusion: Resultatet visar att allmänheten har stora behov av information om läkemedelsinteraktioner om läkemedel för nervsystemet, blodtrycks- och blodförtunnade mediciner och egenvårdsprodukter bl.a. smärtstillande läkemedel.

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    Harnet Dawit Asfaw
  • 10.
    Bengtsson, Jörgen
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Boström, Emma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    The use of a deuterated calibrator for in vivo recovery estimations in microdialysis studies2008Ingår i: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 97, nr 8, s. 3433-3441Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    One of the crucial issues in quantitative microdialysis is the reliability of recovery estimates to correctly estimate unbound drug tissue concentrations. If a deuterated calibrator is used for retrodialysis, the calibrator has the same properties as the study drug. However, recovery of the calibrator may be affected by the presence of the drug in the tissues. The aim of this study was to investigate the recovery of deuterated morphine with time in the absence and presence of morphine in rat tissues. Microdialysis probes were placed in the brain and blood of eight rats. Ringer's solution containing D3-morphine was perfused throughout the study and recovery was estimated. After a stabilization period of 3 h, an exponential infusion of morphine was administered over 4 h. The presence of morphine did not affect the recovery of D3-morphine from brain or blood. The average recovery values (SD) were 0.145 (0.039) and 0.131 (0.048) during the stabilization and infusion periods, respectively, for the brain probe and 0.792 (0.055) and 0.790 (0.084), respectively, for the blood probe. The recovery of deuterated morphine was stable over time in the brain and in blood, and was not affected by the presence of pharmacologically concentrations of morphine.

  • 11.
    Bengtsson, Jörgen
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Engwall, Ann-Cathrin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Kultima, Kim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Jergil, Måns
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Differences in gene expression in the developing rat brain using cDNA microarray and real-time PCRManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The blood-brain barrier (BBB) is formed by endothelial cells, connected by tight junction proteins restricting paracellular transport. Transport of substances into the brain may also be limited due to active efflux transporters. Not much is known about the development of tight junction proteins and active transporters in the BBB, and how this affects drug distribution to the brain at different ages. The aim of this study was to analyze possible differences in expression of tight junction proteins and active transporters in the BBB at different postnatal ages in the rat. Brain capillary-rich fractions (BCRF) were collected and gene expression levels were compared at three postnatal ages using microarray analysis. BCRF was also analyzed for the mRNA expression levels of P-gp Abcb1 (P-gp), Abcg2 (Bcrp), Slc22a8 (Oat3) and occludin using real-time PCR at 12 different postnatal ages between postnatal Day 1 and Adult. In the array analysis, 28 genes of interest were found to be differentially expressed. The mRNA levels of Abcg2 decreased to one seventh from postnatal Day 1 to Day 15. The levels of Slc22a8 increased from birth and reached a plateau at Day 3 - 12 followed by a decrease to Day 15. These findings show that active transporters are differentially expressed in the developing BBB, possibly affecting drug distribution to the brain. No change in the mRNA levels for Abcb1 or occludin was observed.

  • 12.
    Bengtsson, Jörgen
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Jansson, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    On-line desalting and determination of morphine, morphine-3-glucuronide and morphine-6-glucuronide in microdialysis and plasma samples using column switching and liquid chromatography/tandem mass spectrometry2005Ingår i: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 19, nr 15, s. 2116-2122Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A sensitive and reproducible method for the determination of morphine and the metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was developed. The method was validated for perfusion fluid used in microdialysis as well as for sheep and human plasma. A C18 guard column was used to desalt the samples before analytical separation on a ZIC HILIC (hydrophilic interaction chromatography) column and detection with tandem mass spectrometry (MS/MS). The mobile phases were 0.05% trifluoroacetic acid (TFA) for desalting and acetonitrile/5 mM ammonium acetate (70:30) for separation. Microdialysis samples (5 microL) were directly injected onto the system. The lower limits of quantification (LLOQ) for morphine, M3G and M6G were 0.50, 0.22 and 0.55 ng/mL, respectively, and the method was linear from LLOQ to 200 ng/mL. For plasma, a volume of 100 microL was precipitated with acetonitrile containing internal standards (deuterated morphine and metabolites). The supernatant was evaporated and reconstituted in 0.05% TFA before the desalting process. The LLOQs for sheep plasma were 2.0 and 3.1 ng/mL and the ranges were 2.0-2000 and 3.1-3100 ng/mL for morphine and M3G, respectively. For human plasma, the LLOQs were 0.78, 1.49 and 0.53 ng/mL and the ranges were 0.78-500, 1.49-1000 and 0.53-500 ng/mL for morphine, M3G and M6G, respectively.

  • 13.
    Bengtsson, Jörgen
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Mukai, Chisato
    Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan..
    Kitagaki, Shinji
    Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan..
    Miyakoshi, Naoki
    Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan..
    Terasaki, Tetsuya
    Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan..
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Bcrp does not influence transport of nitrofurantoin across the blood-brain barrier at different agesManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    In the blood-brain barrier (BBB), tight junction proteins together with active efflux transporters efficiently restrict access of many compounds to the brain. The contribution of breast cancer resistance protein (Bcrp, coded by Abcg2) for drug efflux in the BBB is not clear. The aim of this study was to investigate the contribution of Bcrp in the rat BBB and how development affects distribution of a Bcrp substrate with age. Nitrofurantoin (NTF) is a good substrate for Bcrp and was used as model substance. Brain-to-plasma concentration ratio (Kp) of NTF was measured at postnatal Day 1, Day 4, Day 11 and in adult rats. Microdialysis was used to measure concentration ratio of unbound NTF across the BBB (Kp,uu) with or without blockers for active transport (PSC833 and probenecid). To investigate the in vivo contribution of Bcrp, Kp was also measured in Bcrp-/- and wild-type control mice with or without the selective Bcrp blocker Ko143. The Kp decreased with age, but due to an increase in the protein binding. The Kp,uu was on average 0.047 and not affected by the presence of any blocker. Possible explanations for the low Kp,uu is intra-brain metabolism and/or efflux due to other transporter(s). No difference was observed in the Kp of NTF for Bcrp-/- compared to wild-type mice, independent of co-administration with Ko143. Thus, no in vivo contribution of Bcrp to the BBB brain transport of NTF was detected.

  • 14.
    Berg, Josefin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Transferrin receptor scFv ligands in mediation of therapeutics across the blood-brain barrier2016Självständigt arbete på avancerad nivå (yrkesexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
  • 15.
    Bergström, Mats
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Yates, Roger
    Wall, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Kågedal, Matts
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Syvänen, Stina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Långström, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Blood-brain barrier penetration of zolmitriptan--modelling of positron emission tomography data2006Ingår i: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 33, nr 1, s. 75-91Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Positron emission tomography (PET) with the drug radiolabelled allows a direct measurement of brain or other organ kinetics, information which can be essential in drug development. Usually, however, a PET-tracer is administered intravenously (i.v.), whereas the therapeutic drug is mostly given orally or by a different route to the PET-tracer. In such cases, a recalculation is needed to make the PET data representative for the alternative administration route. To investigate the blood-brain barrier penetration of a drug (zolmitriptan) using dynamic PET and by PK modelling quantify the brain concentration of the drug after the nasal administration of a therapeutic dose. [11C]Zolmitriptan at tracer dose was administered as a short i.v. infusion and the brain tissue and venous blood kinetics of [11C]zolmitriptan was measured by PET in 7 healthy volunteers. One PET study was performed before and one 30 min after the administration of 5 mg zolmitriptan as nasal spray. At each of the instances, the brain radioactivity concentration after subtraction of the vascular component was determined up to 90 min after administration and compared to venous plasma radioactivity concentration after correction for radiolabelled metabolites. Convolution methods were used to describe the relationship between arterial and venous tracer concentrations, respectively between brain and arterial tracer concentration. Finally, the impulse response functions derived from the PET studies were applied on plasma PK data to estimate the brain zolmitriptan concentration after a nasal administration of a therapeutic dose. The studies shows that the PET data on brain kinetics could well be described as the convolution of venous tracer kinetics with an impulse response including terms for arterial-to-venous plasma and arterial-to-brain impulse responses. Application of the PET derived impulse responses on the plasma PK from nasal administration demonstrated that brain PK of zolmitriptan increased with time, achieving about 0.5 mg/ml at 30 min and close to a maximum of 1.5 mg/ml after 2 hr. A significant brain concentration was observed already after 5 min. The data support the notation of a rapid brain availability of zolmitriptan after nasal administration.

  • 16.
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    A comment on the application of drug tissue-plasma partition coefficients Kp in eliminating organs to calculation of volume of distribution at steady state2005Ingår i: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 32, nr 5-6, s. 655-658Artikel i tidskrift (Refereegranskat)
  • 17.
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Prediction of cytochrome p450-mediated hepatic drug clearance in neonates, infants and children: how accurate are available scaling methods?2006Ingår i: Clinical Pharmacokinetics, ISSN 0312-5963, E-ISSN 1179-1926, Vol. 45, nr 1, s. 1-11Artikel, forskningsöversikt (Övrigt vetenskapligt)
    Abstract [en]

    Correct dosing of drugs in neonates, infants and children is hampered by a general lack of knowledge about drug disposition in this population. Suggested methods to improve our knowledge without performing conventional full-scale investigations include population pharmacokinetic studies, allometric scaling of drug disposition according to bodyweight and in silico prediction of pharmacokinetics. The last method entails scaling of pharmacokinetic parameters according to age-dependent changes in drug absorption and elimination capacity, plasma protein binding and physiological characteristics of the subjects. Maturation (or ontogeny) of the drug-metabolising part of the cytochrome P450 (CYP) enzyme system is thus an important factor in the calculations for most drugs. The aim of this commentary is to test and critically examine the proposed methods to estimate hepatic clearance (CL) as a function of age (0-20 years), with CYP3A-mediated metabolism as the case in point. Midazolam and alfentanil were used as model drugs.Allometric scaling failed to predict the CL of midazolam and alfentanil in neonates. Calculations using in vitro findings on CYP maturation gave better estimates for neonates but very divergent ones for older infants and children. This was chiefly due to very different data on CYP3A4/5 ontogeny in three published studies. In the age range where full adult CYP activity per gram of liver could be assumed, allometric scaling and in silico predictions gave similar results. These predictions were also in approximate agreement with clinical data.The findings with the two model drugs can very probably be generalised to most drugs cleared by CYP-dependent hepatic metabolism. Allometric scaling accounts for development of body size and function but not for the fact that the drug-metabolising capacity of the liver is generally low at birth. The crucial question in the prediction of CL is thus when the activity of the applicable CYP isoform(s) attains adult levels. There are still not enough data on this, particularly when different studies even on the same CYP isoform have given very divergent results. It may also be pointed out that CYP ontogeny is an area where we have at least some information. There are several other important developmental changes about which we know practically nothing. Thus, while allometric scaling is generally unreliable for prediction in neonates and infants, the alternative method of in silico prediction can at present be used only to obtain tentative initial estimates of drug CL. Neither of the methods can be used as a substitute for actual clinical studies.

  • 18.
    Björkman, Sven E.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Folkesson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Berntorp, E.
    In vivo recovery of factor VIII and factor IX: intra- and interindividual variance in a clinical setting2007Ingår i: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 13, nr 1, s. 2-8Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In vivo recovery (IVR) is traditionally used as a parameter to characterize the pharmacokinetic properties of coagulation factors. It has also been suggested that dosing of factor VIII (FVIII) and factor IX (FIX) can be adjusted according to the need of the individual patient, based on an individually determined IVR value. This approach, however, requires that the individual IVR value is more reliably representative for the patient than the mean value in the population, i.e. that there is less variance within than between the individuals. The aim of this investigation was to compare intra- and interindividual variance in IVR (as U dL−1 per U kg−1) for FVIII and plasma-derived FIX in a cohort of non-bleeding patients with haemophilia. The data were collected retrospectively from six clinical studies, yielding 297 IVR determinations in 50 patients with haemophilia A and 93 determinations in 13 patients with haemophilia B. For FVIII, the mean variance within patients exceeded the between-patient variance. Thus, an individually determined IVR value is apparently no more informative than an average, or population, value for the dosing of FVIII. There was no apparent relationship between IVR and age of the patient (1.5–67 years). For FIX, the mean variance within patients was lower than the between-patient variance, and there was a significant positive relationship between IVR and age (13–69 years). From these data, it seems probable that using an individual IVR confers little advantage in comparison to using an age-specific population mean value. Dose tailoring of coagulation factor treatment has been applied successfully after determination of the entire single-dose curve of FVIII:C or FIX:C in the patient and calculation of the relevant pharmacokinetic parameters. However, the findings presented here do not support the assumption that dosing of FVIII or FIX can be individualized on the basis of a clinically determined IVR value.

  • 19.
    Boström, Emma
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Pharmacokinetics and Pharmacodynamics of Oxycodone and Morphine with Emphasis on Blood-Brain Barrier Transport2007Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The pharmacokinetics and pharmacodynamics of oxycodone and morphine was investigated and related to the transport across the blood-brain barrier (BBB) in rats. The influence of a P-glycoprotein (P-gp) inhibitor on the plasma pharmacokinetics and pharmacodynamics of oxycodone was evaluated. Microdialysis experiments were conducted to evaluate the unbound pharmacokinetics, including the rate and extent of transport across the BBB, of oxycodone and morphine. Mathematical models were used to assess the pharmacokinetics and also the relationship between pharmacokinetics and pharmacodynamics of the drugs.

    Oxycodone clearance, volume of distribution at steady-state, half-life, total brain tissue concentrations and tail-flick latency were all unaffected when a P-gp inhibitor was co-administered with oxycodone as compared to a control group. The lack of differences between the groups indicates that oxycodone BBB transport is not affected by P-gp inhibition. Investigating the unbound concentrations of oxycodone in brain and blood using microdialysis revealed an exciting finding. At steady-state, the unbound concentration in brain was 3 times higher than in blood (i.e. a Kp,uu of 3), indicating that active influx is involved in the BBB transport of oxycodone. In contrast, the Kp,uu of morphine was estimated to 0.56, which is an indication that active efflux mechanisms are involved in the BBB transport of morphine. This means that based on the same unbound concentration in blood, an approximately 6-fold higher unbound concentration of oxycodone compared to morphine will be reached in the brain. Using pharmacokinetic-pharmacodynamic modelling, the unbound brain concentrations of oxycodone and morphine were correlated to the tail-flick latency in vivo. The relative potency of the drugs was found to be concentration dependent with an infliction point of 55 nM.

    In summary, this thesis emphasise the importance of taking the local brain pharmacokinetics into consideration when investigating the pharmacokinetics and the pharmacokinetic-pharmacodynamic relationships of centrally acting drugs.

    Delarbeten
    1. The Use of Liquid Chromatography/Mass Spectrometry for Quantitative Analysis of Oxycodone, Oxymorphone and Noroxycodone in Ringer Solution, Rat Plasma and Rat Brain Tissue
    Öppna denna publikation i ny flik eller fönster >>The Use of Liquid Chromatography/Mass Spectrometry for Quantitative Analysis of Oxycodone, Oxymorphone and Noroxycodone in Ringer Solution, Rat Plasma and Rat Brain Tissue
    2004 (Engelska)Ingår i: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 18, nr 21, s. 2565-2576Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Sensitive and reproducible methods for the determination of oxycodone, oxymorphone and noroxycodone in Ringer solution, rat plasma and rat brain tissue by liquid chromatography/mass spectrometry are described. Deuterated analogs of the substances were used as internal standards. Samples in Ringer solution were analyzed by direct injection of 10 microL Ringer solution diluted by an equal volume of water. The limit of quantification was 0.5 ng/mL and the method was linear in the range of 0.5-150 ng/mL for all substances. To analyze oxycodone and oxymorphone in rat plasma, 50 microL of plasma were precipitated with acetonitrile, and the supernatant was directly injected onto the column. To analyze oxycodone, oxymorphone and noroxycodone in rat plasma, 100 microL of rat plasma were subjected to a C18 solid-phase extraction (SPE) procedure, before reconstituting in mobile phase and injection onto the column. For both methods the limit of quantification in rat plasma was 0.5 ng/mL and the methods were linear in the range of 0.5-250 ng/mL for all substances. To analyze the content of oxycodone, oxymorphone and noroxycodone in rat brain tissue, 100 microL of the brain homogenate supernatant were subjected to a C18 SPE procedure. The limit of quantification of oxycodone was 20 ng/g brain, and for oxymorphone and noroxycodone 4 ng/g brain, and the method was linear in the range of 20-1000 ng/g brain for oxycodone and 4-1000 ng/g brain for oxymorphone and noroxycodone. All methods utilized a mobile phase of 5 mM ammonium acetate in 45% acetonitrile, and a SB-CN column was used for separation. The total run time of all methods was 9 min. The intra-day precision and accuracy were <11.3% and <+/-14.9%, respectively, and the inter-day precision and accuracy were <14.9% and <+/-6.5%, respectively, for all the concentrations and matrices described.

    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-95634 (URN)10.1002/rcm.1658 (DOI)000224872500007 ()15468158 (PubMedID)
    Tillgänglig från: 2007-03-30 Skapad: 2007-03-30 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
    2. Oxycodone Pharmacokinetics and Pharmacodynamics in the Rat in the Presence of the P-Glycoprotein Inhibitor PSC833
    Öppna denna publikation i ny flik eller fönster >>Oxycodone Pharmacokinetics and Pharmacodynamics in the Rat in the Presence of the P-Glycoprotein Inhibitor PSC833
    2005 (Engelska)Ingår i: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 94, nr 5, s. 1060-1066Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The objective of this study was to investigate the in vivo influence of the P-glycoprotein (P-gp) inhibitor PSC833 on the plasma pharmacokinetics, total brain concentrations and tail-flick latency of oxycodone in rats. Eight rats each received an infusion of PSC833 or vehicle without PSC833. One hour later, all animals received 0.3 mg/kg oxycodone as a 1-h infusion. Plasma samples were taken, and tail-flick latency was monitored during the infusion and for 2 h thereafter. The brains were collected at the end of the experiment. There were no differences between the two groups in area under the plasma oxycodone concentration-time curve from time zero to infinity, or oxycodone plasma clearance, volume of distribution at steady-state, or half-life. There were no differences in average total brain oxycodone concentrations at 180 min, nor were there any differences in average tail-flick latency for the PSC833 and control groups. In conclusion, coadministration of PSC833 did not alter the plasma pharmacokinetics, brain concentrations, or associated tail-flick latency of oxycodone, indicating that oxycodone is not a P-gp substrate in the rat. This has important clinical implications, as it indicates that oxycodone, unlike some other opioids, will not interact at the blood-brain barrier (BBB) with concomitantly administered P-gp substrates.

    Nyckelord
    P-glycoprotein, pharmacokineties/pharmacodynamics, blood-brain barrier, efflux pumps, active transports, transporters, CNS, clearance
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-95635 (URN)10.1002/jps.20327 (DOI)000228792200014 ()15799017 (PubMedID)
    Tillgänglig från: 2007-03-30 Skapad: 2007-03-30 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
    3. In Vivo Blood-Brain Barrier Transport of Oxycodone in the Rat: Indications for Active Influx and Implications for Pharmacokinetics/Pharmacodynamics
    Öppna denna publikation i ny flik eller fönster >>In Vivo Blood-Brain Barrier Transport of Oxycodone in the Rat: Indications for Active Influx and Implications for Pharmacokinetics/Pharmacodynamics
    2006 (Engelska)Ingår i: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 34, nr 9, s. 1624-1631Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The blood-brain barrier (BBB) transport of oxycodone was studied in rats. Microdialysis probes were inserted into the striatum and vena jugularis. Ten animals were given a bolus dose followed by a 120-min constant rate infusion to study the steady-state concepts of oxycodone BBB equilibration. Another 10 animals were given a 60-min constant rate infusion to study the rate of equilibration across the BBB. Oxycodone-D3 was used as a calibrator for the microdialysis experiments. The samples were analyzed with a liquid chromatography-tandem mass spectrometry method and a population pharmacokinetic model was used to simultaneously fit all the data using NONMEM. A two-compartment model which allowed for a delay between the venous and arterial compartments best described the pharmacokinetics for oxycodone in blood and plasma, whereas a one-compartment model was sufficient to describe the pharmacokinetics in the brain. The BBB transport of oxycodone was parameterized as CL(in) and K(p,uu). CL(in) describes the clearance of oxycodone across the BBB into the brain, whereas K(p,uu) describes the extent of drug equilibration across the BBB. CL(in) across the BBB was estimated to 1910 microl/min x g brain. K(p,uu) was estimated to 3.0, meaning that the unbound concentration of oxycodone in brain was 3 times higher than in blood, which is an indication of active influx of oxycodone at the BBB. This is the first evidence of an opioid having an unbound steady-state concentration in brain that is higher than unity, which can explain potency discrepancies between oxycodone and other opioids.

    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-95636 (URN)10.1124/dmd.106.009746 (DOI)000239938500025 ()16763013 (PubMedID)
    Tillgänglig från: 2007-03-30 Skapad: 2007-03-30 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
    4. Blood–Brain Barrier Transport Helps to Explain Discrepancies in In Vivo Potency between Oxycodone and Morphine
    Öppna denna publikation i ny flik eller fönster >>Blood–Brain Barrier Transport Helps to Explain Discrepancies in In Vivo Potency between Oxycodone and Morphine
    2008 (Engelska)Ingår i: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 108, nr 3, s. 495-505Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background The objective of this study was to evaluate the brain pharmacokinetic-pharmacodynamic relations of un-bound oxycodone and morphine to investigate the influence of blood-brain barrier transport on differences in potency between these drugs. Methods: Microdialysis was used to obtain unbound concentrations in brain and blood. The antinociceptive effect of each drug was assessed using the hot water tail-flick method. Population pharmacokinetic modeling was used to describe the bloodbrain barrier transport of morphine as the rate (Cl.) and extent (K-p,K-uu) of equilibration, where CLin is the influx clearance across the blood-brain barrier and Kp,,,, is the ratio of the unbound concentration in brain to that in blood at steady state. Results: The six-fold difference in K-p,K-uu between oxycodone and morphine implies that, for the same unbound concentration in blood, the concentrations of unbound oxycodone in brain will be six times higher than those of morphine. A joint pharmacokinetic-pharmacodynamic model of oxycodone and morphine based on unbound brain concentrations was developed and used as a statistical tool to evaluate differences in the pharmacodynamic parameters of the drugs. A power model using Effect = Baseline + Slope center dot C-gamma best described the data. Drug-specific slope and gamma parameters made the relative potency of the drugs concentration dependent. Conclusions: For centrally acting drugs such as opioids, pharmacokinetic-pharmacodynamic relations describing the interaction with the receptor are better obtained by correlating the effects to concentrations of unbound drug in the tissue of interest rather than to blood concentrations.

    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-95637 (URN)10.1097/ALN.0b013e318164cf9e (DOI)000253395800021 ()18292687 (PubMedID)
    Tillgänglig från: 2007-03-30 Skapad: 2007-03-30 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
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  • 20.
    Boström, Emma
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Simonsson, Ulrika S. H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Blood–Brain Barrier Transport Helps to Explain Discrepancies in In Vivo Potency between Oxycodone and Morphine2008Ingår i: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 108, nr 3, s. 495-505Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background The objective of this study was to evaluate the brain pharmacokinetic-pharmacodynamic relations of un-bound oxycodone and morphine to investigate the influence of blood-brain barrier transport on differences in potency between these drugs. Methods: Microdialysis was used to obtain unbound concentrations in brain and blood. The antinociceptive effect of each drug was assessed using the hot water tail-flick method. Population pharmacokinetic modeling was used to describe the bloodbrain barrier transport of morphine as the rate (Cl.) and extent (K-p,K-uu) of equilibration, where CLin is the influx clearance across the blood-brain barrier and Kp,,,, is the ratio of the unbound concentration in brain to that in blood at steady state. Results: The six-fold difference in K-p,K-uu between oxycodone and morphine implies that, for the same unbound concentration in blood, the concentrations of unbound oxycodone in brain will be six times higher than those of morphine. A joint pharmacokinetic-pharmacodynamic model of oxycodone and morphine based on unbound brain concentrations was developed and used as a statistical tool to evaluate differences in the pharmacodynamic parameters of the drugs. A power model using Effect = Baseline + Slope center dot C-gamma best described the data. Drug-specific slope and gamma parameters made the relative potency of the drugs concentration dependent. Conclusions: For centrally acting drugs such as opioids, pharmacokinetic-pharmacodynamic relations describing the interaction with the receptor are better obtained by correlating the effects to concentrations of unbound drug in the tissue of interest rather than to blood concentrations.

  • 21.
    Boström, Emma
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Jansson, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Simonsson, Ulrika S. H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    The Use of Liquid Chromatography/Mass Spectrometry for Quantitative Analysis of Oxycodone, Oxymorphone and Noroxycodone in Ringer Solution, Rat Plasma and Rat Brain Tissue2004Ingår i: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 18, nr 21, s. 2565-2576Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sensitive and reproducible methods for the determination of oxycodone, oxymorphone and noroxycodone in Ringer solution, rat plasma and rat brain tissue by liquid chromatography/mass spectrometry are described. Deuterated analogs of the substances were used as internal standards. Samples in Ringer solution were analyzed by direct injection of 10 microL Ringer solution diluted by an equal volume of water. The limit of quantification was 0.5 ng/mL and the method was linear in the range of 0.5-150 ng/mL for all substances. To analyze oxycodone and oxymorphone in rat plasma, 50 microL of plasma were precipitated with acetonitrile, and the supernatant was directly injected onto the column. To analyze oxycodone, oxymorphone and noroxycodone in rat plasma, 100 microL of rat plasma were subjected to a C18 solid-phase extraction (SPE) procedure, before reconstituting in mobile phase and injection onto the column. For both methods the limit of quantification in rat plasma was 0.5 ng/mL and the methods were linear in the range of 0.5-250 ng/mL for all substances. To analyze the content of oxycodone, oxymorphone and noroxycodone in rat brain tissue, 100 microL of the brain homogenate supernatant were subjected to a C18 SPE procedure. The limit of quantification of oxycodone was 20 ng/g brain, and for oxymorphone and noroxycodone 4 ng/g brain, and the method was linear in the range of 20-1000 ng/g brain for oxycodone and 4-1000 ng/g brain for oxymorphone and noroxycodone. All methods utilized a mobile phase of 5 mM ammonium acetate in 45% acetonitrile, and a SB-CN column was used for separation. The total run time of all methods was 9 min. The intra-day precision and accuracy were <11.3% and <+/-14.9%, respectively, and the inter-day precision and accuracy were <14.9% and <+/-6.5%, respectively, for all the concentrations and matrices described.

  • 22.
    Boström, Emma
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Simonsson, Ulrika S. H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    In Vivo Blood-Brain Barrier Transport of Oxycodone in the Rat: Indications for Active Influx and Implications for Pharmacokinetics/Pharmacodynamics2006Ingår i: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 34, nr 9, s. 1624-1631Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The blood-brain barrier (BBB) transport of oxycodone was studied in rats. Microdialysis probes were inserted into the striatum and vena jugularis. Ten animals were given a bolus dose followed by a 120-min constant rate infusion to study the steady-state concepts of oxycodone BBB equilibration. Another 10 animals were given a 60-min constant rate infusion to study the rate of equilibration across the BBB. Oxycodone-D3 was used as a calibrator for the microdialysis experiments. The samples were analyzed with a liquid chromatography-tandem mass spectrometry method and a population pharmacokinetic model was used to simultaneously fit all the data using NONMEM. A two-compartment model which allowed for a delay between the venous and arterial compartments best described the pharmacokinetics for oxycodone in blood and plasma, whereas a one-compartment model was sufficient to describe the pharmacokinetics in the brain. The BBB transport of oxycodone was parameterized as CL(in) and K(p,uu). CL(in) describes the clearance of oxycodone across the BBB into the brain, whereas K(p,uu) describes the extent of drug equilibration across the BBB. CL(in) across the BBB was estimated to 1910 microl/min x g brain. K(p,uu) was estimated to 3.0, meaning that the unbound concentration of oxycodone in brain was 3 times higher than in blood, which is an indication of active influx of oxycodone at the BBB. This is the first evidence of an opioid having an unbound steady-state concentration in brain that is higher than unity, which can explain potency discrepancies between oxycodone and other opioids.

  • 23.
    Boström, Emma
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Simonsson, Ulrika S. H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Oxycodone Pharmacokinetics and Pharmacodynamics in the Rat in the Presence of the P-Glycoprotein Inhibitor PSC8332005Ingår i: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 94, nr 5, s. 1060-1066Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The objective of this study was to investigate the in vivo influence of the P-glycoprotein (P-gp) inhibitor PSC833 on the plasma pharmacokinetics, total brain concentrations and tail-flick latency of oxycodone in rats. Eight rats each received an infusion of PSC833 or vehicle without PSC833. One hour later, all animals received 0.3 mg/kg oxycodone as a 1-h infusion. Plasma samples were taken, and tail-flick latency was monitored during the infusion and for 2 h thereafter. The brains were collected at the end of the experiment. There were no differences between the two groups in area under the plasma oxycodone concentration-time curve from time zero to infinity, or oxycodone plasma clearance, volume of distribution at steady-state, or half-life. There were no differences in average total brain oxycodone concentrations at 180 min, nor were there any differences in average tail-flick latency for the PSC833 and control groups. In conclusion, coadministration of PSC833 did not alter the plasma pharmacokinetics, brain concentrations, or associated tail-flick latency of oxycodone, indicating that oxycodone is not a P-gp substrate in the rat. This has important clinical implications, as it indicates that oxycodone, unlike some other opioids, will not interact at the blood-brain barrier (BBB) with concomitantly administered P-gp substrates.

  • 24.
    Bouw, M. René
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Xie, Rujia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Tunblad, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Blood-brain barrier transport and brain distribution of morphine-6-glucuronide in relation to the antinociceptive effect in rats: pharmacokinetic/pharmacodynamic modelling2001Ingår i: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 134, nr 8, s. 1796-1804Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    1. The objective of this study was to investigate the contribution of the blood-brain barrier (BBB) transport to the delay in antinociceptive effect of morphine-6-glucuronide (M6G), and to study the equilibration of M6G in vivo across the BBB with microdialysis measuring unbound concentrations. 2. On two consecutive days, rats received an exponential infusion of M6G for 4 h aiming at a target concentration of 3000 ng ml(-1) (6.5 microM) in blood. Concentrations of unbound M6G were determined in brain extracellular fluid (ECF) and venous blood using microdialysis and in arterial blood by regular sampling. MD probes were calibrated in vivo using retrodialysis by drug prior to drug administration. 3. The half-life of M6G was 23+/-5 min in arterial blood, 26+/-10 min in venous blood and 58+/-17 min in brain ECF (P<0.05; brain vs blood). The BBB equilibration, expressed as the unbound steady-state concentration ratio, was 0.22+/-0.09, indicating active efflux in the BBB transport of M6G. A two-compartment model best described the brain distribution of M6G. The unbound volume of distribution was 0.20+/-0.02 ml g brain(-1). The concentration-antinociceptive effect relationships exhibited a clear hysteresis, resulting in an effect delay half-life of 103 min in relation to blood concentrations and a remaining effect delay half-life of 53 min in relation to brain ECF concentrations. 4. Half the effect delay of M6G can be explained by transport across the BBB, suggesting that the remaining effect delay of 53 min is a result of drug distribution within the brain tissue or rate-limiting mechanisms at the receptor level.

  • 25.
    Callmar, Marika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    The impact of a pharmacy technician on medicines management and skill mix at the Emergency Department of Antrim Area Hospital2015Självständigt arbete på avancerad nivå (yrkesexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    På Antrim Area Hospital (Nordirland) arbetar farmaceuter tillsammans med läkare i egenskap av läkemedelsexperter. Farmaceuterna gör bl.a. läkemedelsgenomgångar, d.v.s. upprättar en korrekt lista över alla läkemedel patienten använder och identifierar eventuella problem. På akutmottagningen spenderar dock farmaceuterna mycket tid på uppgifter som skulle kunna utföras av en apotekstekniker istället.

    En apotekstekniker i Nordirland är expert på hantering av läkemedelslager och har genomgått en mer omfattande utbildning än svenska apotekstekniker. De kan även hjälpa till med läkemedelsgenomgångar, men då krävs en särskild utbildning. De hanterar också patientens egna läkemedel som patienterna tar med sig till akutmottagningen. Läkemedlen kan användas för att behandla patienten under sjukhusvistelsen, men det är viktigt att de förvaras på rätt sätt.

    Syftet med studien var att ta reda på om farmaceuternas arbetsbörda minskade av att anställa en apotekstekniker. En effektivare arbetsfördelning möjliggör bättre behandling av patienter och sparar pengar för sjukhuset. Tiden farmaceuterna spenderade på varje uppgift mättes och jämfördes före och efter apoteksteknikern. Det undersöktes också om hanteringen av patientens egna läkemedel förbättrades. Förvaringen av patienternas egna läkemedel i akutmottagningen och om de flyttades med patienten noterades och jämfördes.

    Med en apotekstekniker kunde tiden som spenderades på läkemedelslagret halveras. I övrigt påverkades inte farmaceutens arbete och resurserna skulle kunna utnyttjas bättre. En förbättring var att patientens egna läkemedel förvarades rätt i 37,9% av fallen med apoteksteknikern, jämfört med 0 % innan.

  • 26.
    Chammas, Nancy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Avvikelser mellan journalens läkemedelslista och sjuksköterskans underlag för läkemedelshanteringen hos yngre-äldre och äldre-äldre i särskilda boende2011Självständigt arbete på grundnivå (yrkesexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
  • 27.
    Cullberg, Marie
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Direct Thrombin Inhibitors in Treatment and Prevention of Venous Thromboembolism: Dose – Concentration – Response Relationships2006Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    For prevention and treatment of thrombotic diseases with an anticoagulant drug it is important that an adequate dose is given to avoid occurrence or recurrence of thrombosis, without increasing the risk of bleeding and other adverse events to unacceptable levels. The aim of this thesis was to develop mathematical models that describe the dose-concentration (pharmacokinetic) and concentration-response (pharmacodynamic) relationships of direct thrombin inhibitors, in order to estimate optimal dosages for treatment and long-term secondary prevention of venous thromboembolism (VTE).

    Population pharmacokinetic-pharmacodynamic models were developed, based on data from clinical investigations in healthy volunteers and patients receiving intravenous inogatran, subcutaneous melagatran and/or its oral prodrug ximelagatran. The benefit-risk profiles of different ximelagatran dosages were estimated using clinical utility functions. These functions were based on the probabilities and fatal consequences of thrombosis, bleeding and elevation of the hepatic enzyme alanine aminotransferase (ALAT).

    The studies demonstrate that the pharmacokinetics of melagatran and ximelagatran were predictable and well correlated to renal function. The coagulation marker, activated partial thromboplastin time (APTT), increased non-linearly with increasing thrombin inhibitor plasma concentration. Overall, the systemic melagatran exposure (AUC) and APTT were similarly predictive of thrombosis and bleedings. The identified relationship between the risk of ALAT-elevation and melagatran AUC suggests that the incidence approaches a maximum at high exposures. The estimated clinical utility was favourable compared to placebo in the overall study population and in special subgroups of patients following fixed dosing of ximelagatran for long-term secondary prevention of VTE. Individualized dosing was predicted to add limited clinical benefit in this indication.

    The models developed can be used to support the studied dosage and for selection of alternative dosing strategies that may improve the clinical outcome of ximelagatran treatment. In addition, the models may be extrapolated to aid the dose selection in clinical trials with other direct thrombin inhibitors.

    Delarbeten
    1. Population modelling of the effect of inogatran, at thrombin inhibitor, on ex vivo coagulation time (APTT) in healthy subjects and patients with coronary artery disease
    Öppna denna publikation i ny flik eller fönster >>Population modelling of the effect of inogatran, at thrombin inhibitor, on ex vivo coagulation time (APTT) in healthy subjects and patients with coronary artery disease
    2001 (Engelska)Ingår i: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 51, nr 1, s. 71-79Artikel i tidskrift (Refereegranskat) Published
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-94472 (URN)10.1046/j.1365-2125.2001.01326.x (DOI)
    Tillgänglig från: 2006-05-02 Skapad: 2006-05-02 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
    2. Utility of ecarin clotting time, an ex vivo coagulation test, for pharmacokinetic analysis of the direct thrombin inhibitor melagatran
    Öppna denna publikation i ny flik eller fönster >>Utility of ecarin clotting time, an ex vivo coagulation test, for pharmacokinetic analysis of the direct thrombin inhibitor melagatran
    (Engelska)Artikel i tidskrift (Refereegranskat) Submitted
    Identifikatorer
    urn:nbn:se:uu:diva-94473 (URN)
    Tillgänglig från: 2006-05-02 Skapad: 2006-05-02 Senast uppdaterad: 2011-06-21Bibliografiskt granskad
    3. Pharmacokinetics of ximelagatran and relationship to clinical response in acute vein thrombosis
    Öppna denna publikation i ny flik eller fönster >>Pharmacokinetics of ximelagatran and relationship to clinical response in acute vein thrombosis
    Visa övriga...
    2005 (Engelska)Ingår i: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 77, nr 4, s. 279-290Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    OBJECTIVE:

    Our objective was to characterize the pharmacokinetics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, and the relationship between melagatran exposure and clinical outcome in patients with acute deep vein thrombosis.

    METHODS:

    A population pharmacokinetic analysis was performed on samples from patients with deep vein thrombosis participating in a randomized dose-finding study (THRombin Inhibitor in Venous thrombo-Embolism [THRIVE I]). Patients received fixed doses of oral ximelagatran (24, 36, 48, or 60 mg twice daily) for 12 to 16 days. Thrombus size was evaluated by venography before and after treatment. Exposure-response curves were characterized for the probability of regression, no change, and progression of the thrombus extension and of having a bleeding-related event, by use of logistic regression models.

    RESULTS:

    The pharmacokinetics of melagatran (1836 samples in 264 patients) was predictable, without significant time or dose dependencies. Clearance after oral administration (population mean, 27.3 L/h) was correlated with creatinine clearance (P < 10(-6)), and volume of distribution (population mean, 176 L) was correlated with body weight (P = 2 x 10(-5)). Gender, age, or smoking did not significantly influence melagatran pharmacokinetics after the influence of renal function and body weight was accounted for. Unexplained interpatient variability values in total plasma clearance and bioavailability were 19% and 21%, respectively. The median area under the plasma melagatran concentration versus time curve across all patients and dose levels was 3.22 h x micromol/L (5th-95th percentiles, 1.35-7.69). There was no significant relationship between area under the plasma concentration versus time curve and change in thrombus extension (P = .59) or bleeding-related events (P = .77), and the estimated exposure-response curves were relatively flat.

    CONCLUSIONS:

    The pharmacokinetics of melagatran in patients with acute deep vein thrombosis was predictable after oral ximelagatran administration. Shallow exposure-response curves for efficacy and bleeding indicate that there is no need for individualized dosing or therapeutic drug monitoring in the patient population studied.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-94474 (URN)10.1016/j.clpt.2004.11.001 (DOI)15903126 (PubMedID)
    Tillgänglig från: 2006-05-02 Skapad: 2006-05-02 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    4. Ximelagatran in extended secondary prevention of venous thromboembolism: Pharmacokinetics, pharmacodynamics and relationships to clinical events
    Öppna denna publikation i ny flik eller fönster >>Ximelagatran in extended secondary prevention of venous thromboembolism: Pharmacokinetics, pharmacodynamics and relationships to clinical events
    Visa övriga...
    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:uu:diva-94475 (URN)
    Tillgänglig från: 2006-05-02 Skapad: 2006-05-02 Senast uppdaterad: 2011-03-01
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  • 28.
    Cullberg, Marie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Eriksson, Ulf G.
    Larsson, Marita
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Population modelling of the effect of inogatran, at thrombin inhibitor, on ex vivo coagulation time (APTT) in healthy subjects and patients with coronary artery disease2001Ingår i: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 51, nr 1, s. 71-79Artikel i tidskrift (Refereegranskat)
  • 29.
    Cullberg, Marie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Eriksson, Ulf G.
    Wåhlander, Karin
    Eriksson, Henry
    Schulman, Sam
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Pharmacokinetics of ximelagatran and relationship to clinical response in acute vein thrombosis2005Ingår i: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 77, nr 4, s. 279-290Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE:

    Our objective was to characterize the pharmacokinetics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, and the relationship between melagatran exposure and clinical outcome in patients with acute deep vein thrombosis.

    METHODS:

    A population pharmacokinetic analysis was performed on samples from patients with deep vein thrombosis participating in a randomized dose-finding study (THRombin Inhibitor in Venous thrombo-Embolism [THRIVE I]). Patients received fixed doses of oral ximelagatran (24, 36, 48, or 60 mg twice daily) for 12 to 16 days. Thrombus size was evaluated by venography before and after treatment. Exposure-response curves were characterized for the probability of regression, no change, and progression of the thrombus extension and of having a bleeding-related event, by use of logistic regression models.

    RESULTS:

    The pharmacokinetics of melagatran (1836 samples in 264 patients) was predictable, without significant time or dose dependencies. Clearance after oral administration (population mean, 27.3 L/h) was correlated with creatinine clearance (P < 10(-6)), and volume of distribution (population mean, 176 L) was correlated with body weight (P = 2 x 10(-5)). Gender, age, or smoking did not significantly influence melagatran pharmacokinetics after the influence of renal function and body weight was accounted for. Unexplained interpatient variability values in total plasma clearance and bioavailability were 19% and 21%, respectively. The median area under the plasma melagatran concentration versus time curve across all patients and dose levels was 3.22 h x micromol/L (5th-95th percentiles, 1.35-7.69). There was no significant relationship between area under the plasma concentration versus time curve and change in thrombus extension (P = .59) or bleeding-related events (P = .77), and the estimated exposure-response curves were relatively flat.

    CONCLUSIONS:

    The pharmacokinetics of melagatran in patients with acute deep vein thrombosis was predictable after oral ximelagatran administration. Shallow exposure-response curves for efficacy and bleeding indicate that there is no need for individualized dosing or therapeutic drug monitoring in the patient population studied.

  • 30.
    Cullberg, Marie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Wählby, Ulrika
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Eriksson, Ulf G.
    Utility of ecarin clotting time, an ex vivo coagulation test, for pharmacokinetic analysis of the direct thrombin inhibitor melagatranArtikel i tidskrift (Refereegranskat)
  • 31.
    Cullberg, Marie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Wåhlander, Karin
    Lundström, Torbjörn
    Wall, Ulrika
    Eriksson, Ulf G.
    Karlsson, Mats O.
    Ximelagatran in extended secondary prevention of venous thromboembolism: Pharmacokinetics, pharmacodynamics and relationships to clinical eventsManuskript (Övrigt vetenskapligt)
  • 32.
    Dansirikul, Chantaratsamon
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Silber, Hanna E
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Approaches to handling pharmacodynamic baseline responses2008Ingår i: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 35, nr 3, s. 269-283Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A few approaches for handling baseline responses are available for use in pharmacokinetic (PK)-pharmacodynamic (PD) analysis. They include: (method 1-B1) estimation of the typical value and interindividual variability (IIV) of baseline in the population, (B2) inclusion of the observed baseline response as a covariate acknowledging the residual variability, (B3) a more general version of B2 as it also takes the IIV of the baseline in the population into account, and (B4) normalization of all observations by the baseline value. The aim of this study was to investigate the relative performance of B1-B4. PD responses over a single dosing interval were simulated from an indirect response model in which a drug acts through stimulation or inhibition of the response according to an Emax model. The performance of B1-B4 was investigated under 22 designs, each containing 100 datasets. NONMEM VI beta was used to estimate model parameters with the FO and the FOCE method. The mean error (ME, %) and root mean squared error (RMSE, %) of the population parameter estimates were computed and used as an indicator of bias and imprecision. Absolute ME (|ME|) and RMSE from all methods were ranked within the same design, the lower the rank value the better method performance. Average rank of each method from all designs was reported. The results showed that with B1 and FOCE, the average of |ME| and RMSE across all typical individual parameters and all conditions was 5.9 and 31.8%. The average rank of |ME| for B1, B2, B3, and B4 was 3.7, 3.8, 3.3, and 5.2 for the FOCE method, and 4.6, 4.3, 4.7, and 6.4 for the FO method. The smallest imprecision was noted with the use of B1 (rank of 3.1 for FO, and 2.9 for FOCE) and increased, in order, with B3 (3.9-FO and 3.6-FOCE), B2 (4.8-FO; 4.7-FOCE), and B4 (6.4-FO; 6.5-FOCE). We conclude that when considering both bias and imprecision B1 was slightly better than B3 which in turn was better than B2. Differences between these methods were small. B4 was clearly inferior. The FOCE method led to a smaller bias, but no marked reduction in imprecision of parameter estimates compared to the FO method.

  • 33. Dyhre, Henrik
    et al.
    Söderberg, Lars
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Carlsson, Christer
    Local anesthetics in lipid-depot formulations--neurotoxicity in relation to duration of effect in a rat model2006Ingår i: Regional anesthesia and pain medicine, ISSN 1098-7339, E-ISSN 1532-8651, Vol. 31, nr 5, s. 401-408Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND AND OBJECTIVES: The aim of this study was to investigate the possible local neurotoxicity of a number of lipid-depot formulations of local anesthetics in relation to their duration of action in sciatic-nerve block. METHODS: Formulations that contain 2%, 4%, 8%, 16%, 32%, or 64% of a mixture of bupivacaine and lidocaine base 4:1 in medium-chain triglyceride were prepared and evaluated, together with 0.5%, 1.0%, and 2.0% bupivacaine HCl solutions, bupivacaine 4.2% or 7.0% in medium-chain triglyceride, and 20% lidocaine base in a polar lipid vehicle. The duration of sensory and motor sciatic-nerve block was determined in rats. A week later, the sciatic nerves were dissected and removed for histopathologic examination by light microscopy. RESULTS: The duration of sensory and motor-nerve block was prolonged almost 4 times with the 32% and 13 times with the 64% bupivacaine:lidocaine formulation, in comparison to the 0.5% aqueous solution. The 64% formulation was applied by injection and also placed directly on the nerve with similar results. Slight to moderate signs of neurotoxicity were only found after administration of the 64% formulation. CONCLUSIONS: The findings suggest that depot formulations of local anesthetics with advantageous pharmaceutical and pharmacologic properties can be prepared by use of bupivacaine as the active component and natural lipids as carriers. A favorable balance between effects and toxicity may conceivably be obtained. After supplemental testing in more sensitive models for toxicity, such formulations could be candidates for clinical trials.

  • 34.
    Ebrahimi, Nadia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Användning av inhalationssteroider och risk för pneumoni hos KOL-patienter: en retrospektiv studie vid Lungkliniken, Karolinska Universitetssjukhuset2015Självständigt arbete på grundnivå (yrkesexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Användning av inhalationssteroider och risk för pneumoni hos KOL-patienter: en retrospektiv studie vid Lungkliniken, Karolinska Universitetssjukhuset

     Nadia Ebrahimi

    Handledare: Michael Runold, Institutionen för farmaceutisk biovetenskap/avdelningen för farmakokinetik och läkemedelsterapi, 30 hp, Examinator: Margareta Hammarlund-Udenaes

    Introduktion: Kroniskt obstruktiv lungsjukdom, KOL, är en ledande orsak till morbiditet och mortalitet i världen. Inhalationssteroider (ICS) används med långverkande β2-agonister (LABA) för att minska försämringsperioder, förbättra livskvalitén och eventuellt minska dödligheten hos KOL-patienter. Dock har en ökad risk för pneumoni rapporterats hos KOL patienter som behandlats med ICS. Upprepade pneumonier är även en vanlig orsak till inläggning på sjukhus samt har betydelse för progress av KOL. 

    Syfte: Studiens syfte var att undersöka den kliniska handläggningen av KOL-patienter samt belysa eventuell komorbiditet liksom om samtidig behandling med ICS förelåg. För att bedöma om skillnader förelåg mellan flutikason och budesonid avseende pneumoni så jämfördes detta med förskrivningsmönstret för ICS hos KOL-patienter på Lungkliniken.

    Material och metoder: En retrospektiv epidemiologisk observationsstudie vid lungkliniken,  Karolinska, baserad på journalgranskning av alla sjukhusvårdade KOL-patienter med pneumoni på lungkliniken mellan år 2005-2014.

    Resultat: 1011 patienter fick förskrivet budesonid vid lungkliniken mellan 2011 och 2013. Under samma tid fick 336 patienter förskrivet flutikason. Av de patienter som vårdades inneliggande för pneumoni på lungkliniken under samma tid stod 51 på budesonid och 26 på flutikason. Skillnaden var inte signifikant (p=0,105).

    Konklusion: Denna observationsstudie visade att inhalationssteroiderna, flutikason och budesonid inte skiljer sig åt avseende pneumoni hos sjukhusvårdade KOL-patienter vid lungkliniken, Karolinska. 

  • 35.
    Elsherbiny, Doaa A.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Asimus, Sara A.
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Ashton, Michael
    Simonsson, Ulrika S. H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    A model based assessment of the CYP2B6 and CYP2C19 inductive properties by artemisinin antimalarials: implications for combination regimens2008Ingår i: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 35, nr 2, s. 203-217Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The study aim was to assess the inductive properties of artemisinin antimalarials using mephenytoin as a probe for CYP2B6 and CYP2C19 enzymatic activity. The population pharmacokinetics of S-mephenytoin and its metabolites S-nirvanol and S-4'-hydroxymephenytoin, including enzyme turn-over models for induction, were described by nonlinear mixed effects modeling. Rich data (8-16 samples/occasion/subject) were collected from 14 healthy volunteers who received mephenytoin before and during ten days of artemisinin administration. Sparse data (3 samples/occasion/subject) were collected from 74 healthy volunteers who received mephenytoin before, during and after five days administration of artemisinin, dihydroartemisinin, arteether, artemether or artesunate. The production rate of CYP2B6 was increased 79.7% by artemisinin, 61.5% by arteether, 76.1% by artemether, 19.9% by dihydroartemisinin and 16.9% by artesunate. The production rate of CYP2C19 increased 51.2% by artemisinin, 14.8% by arteether and 24.9% by artemether. In conclusion, all studied artemisinin derivatives induced CYP2B6. CYP2C19 induction by arteether and artemether as well as CYP2B6 and CYP2C19 induction by artemisinin was confirmed. The inductive capacity is different among the artemisinin drugs, which is of importance when selecting drugs to be used in antimalarial combination therapy such that the potential for drug-drug interactions is minimized.

  • 36. Eriksson, Ulf G
    et al.
    Mandema, Jaap W
    Karlsson, Mats O
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Frison, Lars
    Gisleskog, Per Olsson
    Wählby, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Hamren, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Gustafsson, David
    Eriksson, Bengt I
    Pharmacokinetics of melagatran and the effect on ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous melagatran and oral ximelagatran: a population model analysis2003Ingår i: Clinical Pharmacokinetics, ISSN 0312-5963, E-ISSN 1179-1926, Vol. 42, nr 7, s. 687-701Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    OBJECTIVE: Ximelagatran, an oral direct thrombin inhibitor, is rapidly bioconverted to melagatran, its active form. The objective of this population analysis was to characterise the pharmacokinetics of melagatran and its effect on activated partial thromboplastin time (APTT), an ex vivo measure of coagulation time, in orthopaedic surgery patients sequentially receiving subcutaneous melagatran and oral ximelagatran as prophylaxis for venous thromboembolism. To support the design of a pivotal dose-finding study, the impact of individualised dosage based on bodyweight and calculated creatinine clearance was examined. DESIGN AND METHODS: Pooled data obtained in three small dose-guiding studies were analysed. The patients received twice-daily administration, with either subcutaneous melagatran alone or a sequential regimen of subcutaneous melagatran followed by oral ximelagatran, for 8-11 days starting just before initiation of surgery. Nonlinear mixed-effects modelling was used to evaluate rich data of melagatran pharmacokinetics (3326 observations) and the pharmacodynamic effect on APTT (2319 observations) in samples from 216 patients collected in the three dose-guiding trials. The pharmacokinetic and pharmacodynamic models were validated using sparse data collected in a subgroup of 319 patients enrolled in the pivotal dose-finding trial. The impact of individualised dosage on pharmacokinetic and pharmacodynamic variability was evaluated by simulations of the pharmacokinetic-pharmacodynamic model.

    RESULTS: The pharmacokinetics of melagatran were well described by a one-compartment model with first-order absorption after both subcutaneous melagatran and oral ximelagatran. Melagatran clearance was correlated with renal function, assessed as calculated creatinine clearance. The median population clearance (creatinine clearance 70 mL/min) was 5.3 and 22.9 L/h for the subcutaneous and oral formulations, respectively. The bioavailability of melagatran after oral ximelagatran relative to subcutaneous melagatran was 23%. The volume of distribution was influenced by bodyweight. For a patient with a bodyweight of 75kg, the median population estimates were 15.5 and 159L for the subcutaneous and oral formulations, respectively. The relationship between APTT and melagatran plasma concentration was well described by a power function, with a steeper slope during and early after surgery but no influence by any covariates. Simulations demonstrated that individualised dosage based on creatinine clearance or bodyweight had no clinically relevant impact on the variability in melagatran pharmacokinetics or on the effect on APTT. CONCLUSIONS: The relatively low impact of individualised dosage on the pharmacokinetic and pharmacodynamic variability of melagatran supported the use of a fixed-dose regimen in the studied population of orthopaedic surgery patients, including those with mild to moderate renal impairment.

  • 37. Fanta, Samuel
    et al.
    Jönsson, Siv
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Backman, Janne T
    Karlsson, Mats O
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Hoppu, Kalle
    Developmental pharmacokinetics of ciclosporin: a population pharmacokinetic study in paediatric renal transplant candidates2007Ingår i: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 64, nr 6, s. 772-784Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims

    To use population pharmacokinetic modelling to characterize the influence of developmental and demographic factors on the pharmacokinetic variability of ciclosporin.

    Methods

    Pharmacokinetic modelling was performed in NONMEM using a dataset comprising 162 pretransplant children, aged 0.36–17.5 years. Ciclosporin was given intravenously (3 mg kg−1) and orally (10 mg kg−1) on separate occasions followed by blood sampling for 24 h.

    Results

    A three-compartment model with first-order absorption without lag-time best described the pharmacokinetics of ciclosporin. The most important covariate affecting systemic clearance (CL) and distribution volume (V) was body weight (BW; scaled allometrically), responsible for a fourfold difference in uncorrected ciclosporin CL and a sixfold difference in ciclosporin V. The other significant covariates, haematocrit, plasma cholesterol and creatinine, were estimated to explain 20–30% of interindividual differences in CL and V of ciclosporin. No age-related changes in oral bioavailability or in BW-normalized V were seen. The BW-normalized CL (CL/BW) declined with age and prepubertal children (<8 years) had an approximately 25% higher CL/BW than did older children. Normalization of CL for allometric BW (BW3/4) removed its relationship to age.

    Conclusion

    The relationship between CL and allometric BW is consistent with a gradual reduction in relative liver size, until adult values, and a relatively constant CYP3A4 content in the liver from about 6–12 months of age to adulthood. Ciclosporin oral bioavailability, known previously to display large interindividual variability, is not influenced by age. These findings can enable better individualization of ciclosporin dosing in infants, children and adolescents.

  • 38.
    Friberg, Lena E
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Pharmacokinetic-Pharmacodynamic Modelling of Anticancer Drugs: Haematological Toxicity and Tumour Response in Hollow Fibres2003Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Established quantitative relationships between dose, plasma concentrations and response [pharmacokinetic-pharmacodynamic (PKPD) models] have a high potential in improving therapeutic indices of anticancer drug therapy and in increasing drug development efficiency. PKPD modelling is a helpful tool for characterising and understanding schedule dependence. The aim of this thesis was to develop PKPD models of anticancer drugs for tumour effects and haematological toxicity, which is the most frequent dose-limiting toxicity.

    PK and haematological toxicity after several schedules were studied in rats and semi-physiological PKPD models for the whole time course of myelosuppression were developed from animal and patient data. The possibility to implant hollow fibres filled with tumour cells in immunocompetent rats was investigated for simultaneous assessment of PK, tumour response and haematological toxicity. Population data analyses were performed using the software NONMEM.

    When all injections were administered within eight hours, fractionated schedules of 5-fluorouracil and epirubicin produced similar haematological toxicity in rats as a single dose, when the non-linear PK of 5-fluorouracil was accounted for. When the time interval was extended to two days for 5-fluorouracil, the fractionated regimens were more toxic.

    The developed semi-physiological PKPD models included transit compartments that mimic maturation stages in bone marrow and explain the time lag. Feedback mechanisms characterised the rebound. The models successfully described myelosuppression in patients (DMDC) and rats (5-fluorouracil), after different administration schedules. Further developments made it possible to characterise the time course of myelosuppression after administration of each one of six different drugs, with parameters related to the haematopoietic system consistent across drugs.

    The developed hollow fibre model in immunocompetent rats was successfully applied to monitor PK, toxicity and the time course of antitumour effects. PKPD modelling illustrated that the schedule dependence of the anticancer agent CHS 828 is partly due to dose-dependent bioavailability and partly due to a schedule-dependent PD effect.

    Delarbeten
    1. Haematological toxicity following different dosing schedules of 5-fluorouracil and epirubicin in rats
    Öppna denna publikation i ny flik eller fönster >>Haematological toxicity following different dosing schedules of 5-fluorouracil and epirubicin in rats
    Visa övriga...
    2000 (Engelska)Ingår i: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 20, nr 3A, s. 1519-1525Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    AIM

    To study the effects of single and fractionated doses of 5-fluorouracil and epirubicin on the leukocyte counts in rats.

    METHODS

    Six different dosing patterns of each drug were injected within one day. The leukocytes were followed for 11-15 days. Pharmacokinetic models were developed using NONMEM. Quantitative and qualitative pharmacokinetic-pharmacodynamic relationships were investigated.

    RESULTS

    A one-compartment model with non-linear elimination described 5-fluorouracil pharmacokinetics and a three-compartment model described epirubicin concentration data. Sigmoidal or basic Emax-models quantified the relationships between individual AUCs and decreases in leukocytes, for both drugs. Similar relationships between AUC and toxicity were found, regardless of whether the drugs were given as single or fractionated doses.

    CONCLUSION

    Quantitative relationships between AUC and the effect on leukocytes were established for 5-fluorouracil and epirubicin. However, no schedule dependence was indicated for the schedules used in the study.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-90233 (URN)10928065 (PubMedID)
    Tillgänglig från: 2003-04-15 Skapad: 2003-04-15 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    2.
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    3.
    Posten kunde inte hittas. Det kan bero på att posten inte längre är tillgänglig eller att du har råkat ange ett felaktigt id i adressfältet.
    4. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs
    Öppna denna publikation i ny flik eller fönster >>Model of chemotherapy-induced myelosuppression with parameter consistency across drugs
    Visa övriga...
    2002 (Engelska)Ingår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 20, nr 24, s. 4713-4721Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    PURPOSE:

    To develop a semimechanistic pharmacokinetic-pharmacodynamic model describing chemotherapy-induced myelosuppression through drug-specific parameters and system-related parameters, which are common to all drugs.

    PATIENTS AND METHODS:

    Patient leukocyte and neutrophil data after administration of docetaxel, paclitaxel, and etoposide were used to develop the model, which was also applied to myelosuppression data from 2'-deoxy-2'-methylidenecytidine (DMDC), irinotecan (CPT-11), and vinflunine administrations. The model consisted of a proliferating compartment that was sensitive to drugs, three transit compartments that represented maturation, and a compartment of circulating blood cells. Three system-related parameters were estimated: baseline, mean transit time, and a feedback parameter. Drug concentration-time profiles affected the proliferation of sensitive cells by either an inhibitory linear model or an inhibitory E(max) model. To evaluate the model, system-related parameters were fixed to the same values for all drugs, which were based on the results from the estimations, and only drug-specific parameters were estimated. All modeling was performed using NONMEM software.

    RESULTS:

    For all investigated drugs, the model successfully described myelosuppression. Consecutive courses and different schedules of administration were also well characterized. Similar system-related parameter estimates were obtained for the different drugs and also for leukocytes compared with neutrophils. In addition, when system-related parameters were fixed, the model well characterized chemotherapy-induced myelosuppression for the different drugs.

    CONCLUSION:

    This model predicted myelosuppression after administration of one of several different chemotherapeutic drugs. In addition, with fixed system-related parameters to proposed values, and only drug-related parameters estimated, myelosuppression can be predicted. We propose that this model can be a useful tool in the development of anticancer drugs and therapies.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-90236 (URN)10.1200/JCO.2002.02.140 (DOI)12488418 (PubMedID)
    Tillgänglig från: 2003-04-15 Skapad: 2003-04-15 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    5. Determination of drug effect on tumour cells, host animal toxicity and drug pharmacokinetics in a hollow-fibre model in rats
    Öppna denna publikation i ny flik eller fönster >>Determination of drug effect on tumour cells, host animal toxicity and drug pharmacokinetics in a hollow-fibre model in rats
    Visa övriga...
    2000 (Engelska)Ingår i: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 46, nr 6, s. 493-500Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    PURPOSE

    Based on the previously published hollow-fibre assay mainly used for early in vivo anticancer drug screening, we wanted to develop an extended hollow-fibre model in which antitumour activity, haematological toxicity and pharmacokinetics could be studied in the same animal.

    METHOD

    The breast cancer cell lines MDA-MB-231 and MCF-7 were cultured in semipermeable hollow fibres. The fibres were implanted subcutaneously into immunocompetent male Sprague Dawley rats, and the rats were treated with 5-fluorouracil (5-FU, 125 mg/kg), epirubicin (EPI, 10 mg/kg) or cyclophosphamide (CP, 120 mg/kg) intraperitoneally, the new cyanoguanidine CHS 828 (375 mg/kg or 75 mg/kg x 5) orally, or vehicle only. After 6 days the fibres were retrieved and the cell density was evaluated. Haematological parameters were monitored and two to four samples per animal were drawn to determine the pharmacokinetic parameters in NONMEM.

    RESULTS

    Drug treatment had generally low effects on the tumour cells. Of the standard drugs (5-FU, EPI and CP), only CP exerted a statistically significant antiproliferative effect. CHS 828 had only a minor effect as a single dose, but divided into five daily doses had a pronounced effect on both cell lines. 5-FU, EPI and CP all caused a marked decrease in leucocytes, platelets and haemoglobin, while CHS 828 did not seem to affect these parameters. The pharmacokinetics of 5-FU and EPI were in accordance with previously established pharmacokinetic models. The pharmacokinetics of CP and CHS 828 were both described by one-compartment models.

    CONCLUSIONS

    This study illustrates the possibility of measuring antitumour effect, haematological toxicity and pharmacokinetics in the same animal using the hollow-fibre model.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-90237 (URN)10.1007/s002800000181 (DOI)11138463 (PubMedID)
    Tillgänglig från: 2003-04-15 Skapad: 2003-04-15 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    6. Pharmacokinetic-pharmacodynamic modeling of the schedule-dependent effect of CHS 828 in a rat hollow fiber model
    Öppna denna publikation i ny flik eller fönster >>Pharmacokinetic-pharmacodynamic modeling of the schedule-dependent effect of CHS 828 in a rat hollow fiber model
    Visa övriga...
    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:uu:diva-90238 (URN)
    Tillgänglig från: 2003-04-15 Skapad: 2003-04-15 Senast uppdaterad: 2011-03-01
    Ladda ner fulltext (pdf)
    FULLTEXT01
  • 39.
    Friberg, Lena E.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Hassan, Saadia B.
    Jonsson, Elin
    Larsson, Rolf
    Karlsson, Mats O.
    Pharmacokinetic-pharmacodynamic modeling of the schedule-dependent effect of CHS 828 in a rat hollow fiber modelManuskript (Övrigt vetenskapligt)
  • 40.
    Friberg, Lena E.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Henningsson, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Maas, Hugo
    Nguyen, Laurent
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Model of Chemotherapy-Induced Myelosuppression With Parameter Consistency Across Drugs2002Ingår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 20, nr 24, s. 4713-4721Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE:

    To develop a semimechanistic pharmacokinetic-pharmacodynamic model describing chemotherapy-induced myelosuppression through drug-specific parameters and system-related parameters, which are common to all drugs.

    PATIENTS AND METHODS:

    Patient leukocyte and neutrophil data after administration of docetaxel, paclitaxel, and etoposide were used to develop the model, which was also applied to myelosuppression data from 2'-deoxy-2'-methylidenecytidine (DMDC), irinotecan (CPT-11), and vinflunine administrations. The model consisted of a proliferating compartment that was sensitive to drugs, three transit compartments that represented maturation, and a compartment of circulating blood cells. Three system-related parameters were estimated: baseline, mean transit time, and a feedback parameter. Drug concentration-time profiles affected the proliferation of sensitive cells by either an inhibitory linear model or an inhibitory E(max) model. To evaluate the model, system-related parameters were fixed to the same values for all drugs, which were based on the results from the estimations, and only drug-specific parameters were estimated. All modeling was performed using NONMEM software.

    RESULTS:

    For all investigated drugs, the model successfully described myelosuppression. Consecutive courses and different schedules of administration were also well characterized. Similar system-related parameter estimates were obtained for the different drugs and also for leukocytes compared with neutrophils. In addition, when system-related parameters were fixed, the model well characterized chemotherapy-induced myelosuppression for the different drugs.

    CONCLUSION:

    This model predicted myelosuppression after administration of one of several different chemotherapeutic drugs. In addition, with fixed system-related parameters to proposed values, and only drug-related parameters estimated, myelosuppression can be predicted. We propose that this model can be a useful tool in the development of anticancer drugs and therapies.

  • 41.
    Friberg, Lena E.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Henningsson, Anja
    Maas, Hugo
    Nguyen, Laurent
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Model of chemotherapy-induced myelosuppression with parameter consistency across drugs2002Ingår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 20, nr 24, s. 4713-4721Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE:

    To develop a semimechanistic pharmacokinetic-pharmacodynamic model describing chemotherapy-induced myelosuppression through drug-specific parameters and system-related parameters, which are common to all drugs.

    PATIENTS AND METHODS:

    Patient leukocyte and neutrophil data after administration of docetaxel, paclitaxel, and etoposide were used to develop the model, which was also applied to myelosuppression data from 2'-deoxy-2'-methylidenecytidine (DMDC), irinotecan (CPT-11), and vinflunine administrations. The model consisted of a proliferating compartment that was sensitive to drugs, three transit compartments that represented maturation, and a compartment of circulating blood cells. Three system-related parameters were estimated: baseline, mean transit time, and a feedback parameter. Drug concentration-time profiles affected the proliferation of sensitive cells by either an inhibitory linear model or an inhibitory E(max) model. To evaluate the model, system-related parameters were fixed to the same values for all drugs, which were based on the results from the estimations, and only drug-specific parameters were estimated. All modeling was performed using NONMEM software.

    RESULTS:

    For all investigated drugs, the model successfully described myelosuppression. Consecutive courses and different schedules of administration were also well characterized. Similar system-related parameter estimates were obtained for the different drugs and also for leukocytes compared with neutrophils. In addition, when system-related parameters were fixed, the model well characterized chemotherapy-induced myelosuppression for the different drugs.

    CONCLUSION:

    This model predicted myelosuppression after administration of one of several different chemotherapeutic drugs. In addition, with fixed system-related parameters to proposed values, and only drug-related parameters estimated, myelosuppression can be predicted. We propose that this model can be a useful tool in the development of anticancer drugs and therapies.

  • 42.
    Friberg, Lena E
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Karlsson, Mats O
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Mechanistic models for myelosuppression2003Ingår i: Investigational new drugs, ISSN 0167-6997, E-ISSN 1573-0646, Vol. 21, nr 2, s. 183-194Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    As myelosuppression is the dose-limiting toxicity for most chemotherapeutic drugs, modelers attempt to find relationships between drug and toxicity to optimize treatment. Mechanistic models, i.e. models based on physiology and pharmacology, are preferable over empirical models, as prior information can be utilized and as they generally are more reliable for extrapolations. To account for different dosing-regimens and possible schedule-dependent effects, the whole concentration-time profile should be used as input into the pharmacokinetic-pharmacodynamic model. It is also of importance to model the whole time course of myelosuppression to be able to predict both the degree and duration of toxicity as well as consecutive courses of therapy. A handful of (semi)-mechanistic pharmacokinetic-pharmacodynamic models with the above properties have been developed and are reviewed. Ideally, a model of myelosuppression should separate drug-specific parameters from system related parameters to be applicable across drugs and useful under different clinical settings. Introduction of mechanistic models of myelosuppression in the design and evaluation of clinical trials can guide in the decision of optimal sampling times, contribute to knowledge of optimal doses and treatment regimens at an earlier time point and identify sub-groups of patients at a high risk of myelosuppression.

  • 43.
    Friberg, Lena
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Hassan, Saadia Bashir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Lindhagen, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Pharmacokinetic-Pharmacodynamic modelling of the schedule-dependent effect of the anti-cancer agent CHS 828 in a rat hollow fibre model2005Ingår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 25, nr 1, s. 163-173Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    N-(6-Chlorophenoxyhexyl)-N'-cyano-N''-4-pyridylguanidine (CHS 828) is a novel anticancer agent that shows schedule-dependent effects in vitro and in vivo, as well as in Phase I clinical trials. A rat hollow fibre model was used to investigate whether this dependency is due to pharmacokinetic and/or pharmacodynamic factors. The effect on two cell lines, MDA-MB-231 (breast cancer) and CCRF-CEM (leukaemia) were studied after CHS 828 was administered orally as a single dose or in a 5-day schedule, at different total dose levels. The 5-day schedules were associated with greater effects on both cell lines compared with single doses. A one-compartment pharmacokinetic model, with a half-life of 2.3h and a consecutive zero- and first-order process to describe dissolution and absorption, fit the concentration data. Pharmacokinetics were dose-dependent, as the fraction absorbed decreased with increasing dose. Clearance increased with accumulative exposure. Twenty hours after administration, concentrations started to increase again, probably due to coprophagy. Pharmacokinetic-pharmacodynamic models characterized the cell growth and cell kill over time and showed that schedule-dependent antitumour effects were present also when the dose-dependent pharmacokinetics were accounted for. The prolonged schedules of CHS 828 were therefore associated with greater antitumour effects than single doses of the same total exposure.

  • 44.
    Gupta, Anubha
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Chatelain, Pierre
    Massingham, Roy
    Jonsson, Niclas E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Stereoselective pharmacokinetics of cetirizine in the guinea pig: Role of protein binding2006Ingår i: Biopharmaceutics & drug disposition, ISSN 0142-2782, E-ISSN 1099-081X, Vol. 27, nr 6, s. 291-297Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose. To characterize the pharmacokinetics of cetirizine enantiomers in the guinea pig including protein binding in both the guinea pig and human plasma.

    Methods. Plasma concentrations of cetirizine enantiomers in the guinea pig were determined using a LC-MS/MS method after a short i.v. infusion (1, 2 and 4 mg/kg) of racemic cetirizine. Protein binding was determined using an in vitro equilibrium dialysis technique. A pharmacokinetic model was developed using NONMEM and the differences in pharmacokinetic parameters of levocetirizine and dextrocetirizine were estimated.

    Results. The plasma concentration time data of both the enantiomers were best described by a three-compartment pharmacokinetics model. The clearance (CL) of levocetirizine and dextrocetirizine was 1.2 and 2.7 ml/min, respectively, and the volume of distribution at steady state (V-ss) was 457 ml and 996 ml, respectively. The fraction unbound (f(u)) in guinea pig plasma for levocetirizine and dextrocetirizine was 7-10% and 16-21% while in human plasma, it was 8% and 12%, respectively. The factor describing the difference in the pharmacokinetic parameters of the cetirizine enantiomers was estimated to be 2.26.

    Conclusions. Cetirizine pharmacokinetics is stereoselective in the guinea pig. For levocetirizine, CL and V-ss were half those of dextrocetirizine, indicating that protein binding is an important factor affecting the pharmacokinetics of cetirizine. The effect of protein binding on the pharmacokinetics of the cetirizine enantiomers could be extrapolated to humans.

  • 45.
    Gupta, Anubha
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Jansson, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Chatelain, Pierre
    Massingham, Roy
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Quantitative determination of cetirizine enantiomers in guinea pig plasma, brain tissue and microdialysis samples using liquid chromatography/tandem mass spectrometry2005Ingår i: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 19, nr 12, s. 1749-1757Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sensitive enantioselective liquid chromatographic assays using tandem mass spectrometric detection were developed and validated for the determination of S-cetirizine (S-CZE) and R-cetirizine (R-CZE) in guinea pig plasma, brain tissue, and microdialysis samples. Enantioselective separation was achieved on an alpha1-acid glycoprotein column within 14 min for all methods. A cetirizine analog, ucb 20028, was used as internal standard. Cetirizine and the internal standard were detected by multiple reaction monitoring using transitions m/z 389.1 --> 200.9 and 396.1 --> 276.1, respectively. The samples were prepared using protein precipitation with acetonitrile. For guinea pig plasma, the assay was linear over the range 0.25-5000 ng/mL for both S-CZE and R-CZE, with a lower limit of quantification (LLOQ) of 0.25 ng/mL. For the brain tissue and microdialysis samples, the assays were linear over the range 2.5-250 ng/g and 0.25-50 ng/mL, respectively, and the LLOQ values were 2.5 ng/g and 0.25 ng/mL, respectively. The intra- and inter-day precision values were < or =7.1% and < or =12.6%, respectively, and the intra- and inter-day accuracy varied by less than +/-8.0% and +/-6.0% of the nominal value, respectively, for both enantiomers in all the matrices investigated.

  • 46. Gupta, S
    et al.
    Svensson, Ulrika S H
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Ashton, M
    In vitro evidence for auto-induction of artemisinin metabolism in the rat2001Ingår i: European journal of drug metabolism and pharmacokinetics, ISSN 0378-7966, E-ISSN 2107-0180, Vol. 26, nr 3, s. 173-178Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Artemisinin disappearance rate was more rapid in incubations with liver microsomes from rats pre-treated with oral artemisinin (60 mg/kg/day for 5 days) compared with microsomes from control animals. A single pathway Michaelis-Menten saturable elimination model was fitted to the concentration-time data of artemisinin incubations by non-linear regression. Model parameters were obtained after fitting results for each animal separately and by pooling data for pre-treated and control animals. Parameter estimates (% coefficient of variation) from fitting the pooled data was maximum velocities (V-max) = 1.8 (12) mmole/min/mg protein and Michaelis constants (K-m) = 20 (22) muM for artemisinin pre-treated and V-max = 0.85 (35) mmole/min/mg protein and K-m = 67 (52) muM for control animals indicating a 2-fold increase in V-max and a 3-fold decrease in Km with microsomes from artemisinin pre-treated animals. Estimates of intrinsic clearance in microsomes from the pre-treated animals were 8-fold higher compared with controls. Thus, artemisinin appears to be a potent auto-inducer of drug metabolism in rats as has also been observed in humans. The present findings suggest caution in the interpretation of repeat-dose rat toxicity studies with artemisinin unless its pharmacokinetics are simultaneously monitored, since during multiple administration, the exposure of the drug will not be constant over time.

  • 47.
    Gustafsson, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Transport av stora molekyler över blod-hjärnbarriären2016Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Introduktion: Neuronen i hjärnan kräver en noggrant kontrollerad miljö för att bibehålla sin funktion. Som en del i den kontrollen finns blod-hjärnbarriären (BBB) i hjärnans kapillärer, som trots stor överföringspotential inte släpper igenom de flesta molekyler. Endotelcellerna i kapillärerna är sammanfogade i s.k. ”tight junctions”, vilka omöjliggör paracellulär transport av vattenlösliga och/eller stora molekyler till hjärnan. För att kunna transportera stora molekyler över BBB krävs därför ofta någon form av vesikel som utnyttjar en någon form av endogen, aktiv transport. Mekanismerna för dessa är till stor del outredda. Syfte: Att analysera transporten av stora molekyler över blod-hjärnbarriären i ett kvantitativt perspektiv med fokus på substanser >1 kDa och dessas farmakokinetiska parametrar för att kunna ge en indikation på var framtida forskningsinsatser behövs, samt vilka transportvägar som verkar lovande för behandling med läkemedel i kliniken. Material och metoder: Projektet genomfördes som en litteraturstudie där vetenskapliga artiklar samlades in digitalt från databaser som PubMed, Scopus och GoogleScholar med fokus på studier in vivo där kvantitativa mätningar gjorts. Resultat: Flera olika metoder för att öka transportens utsträckning och hastighet till hjärnan som modulering av tight junctions, ”adsorptive”-medierad transcytos och receptormedierad transcytos redogörs för. Konklusion: Metoderna i litteraturen har med varierande framgång lyckats transportera stora molekyler över BBB på ett effektivt sätt. Mer grundforskning behövs.

  • 48.
    Hammarlund-Udenaes, Margareta
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Paalzow, Lennart K
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    de Lange, Elisabeth C M
    Drug equilibration across the blood-brain barrier: pharmacokinetic considerations based on the microdialysis method1997Ingår i: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 14, nr 2, s. 128-134Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE: The purpose of the study was to investigate the influence of different rates of transport into and out of the brain, including passive and active transport, on unbound brain concentrations and profile in relation to the blood concentration profile. Special emphasis is put on hydrophilic drugs. METHODS: Simulations were performed with a model including one body compartment and one brain compartment, with linear or saturable transport into and out of the brain. Comparisons were made with experimental results from microdialysis (MD) studies. RESULTS: Three features were evident when combining the MD results: 1) equilibration across the blood-brain barrier (BBB) is rapid, 2) half-life is similar in brain and blood for most drugs, and 3) unbound brain concentrations seldom reach the level of unbound blood concentrations. A low concentration ratio brain:blood is not mainly caused by a low influx, but rather by different influx and efflux clearances. Active transport out of the brain can explain the results, but also active transport into the brain under certain conditions. A small volume of distribution in brain vs. that in the rest of the body contributes to a rapid equilibration and similar half-lives. CONCLUSIONS: Assumptions of slow equilibration of hydrophilic drugs and similar unbound concentrations across the BBB at steady state are contradicted. The results are more in line with recent findings on the presence of P-glycoprotein and other transport mechanisms at the BBB. Non-passive transport across the BBB seems to be the case for almost all drugs studies with MD so far.

  • 49.
    Hamrén, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Safety and Efficacy Modelling in Anti-Diabetic Drug Development2008Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    A central aim in drug development is to ensure that the new drug is efficacious and safe in the intended patient population.

    Mathematical models describing the pharmacokinetic-pharmacodynamic (PK-PD) properties of a drug are valuable to increase the knowledge about drug effects and disease and can be used to inform decisions. The aim of this thesis was to develop mechanism-based PK-PD-disease models for important safety and efficacy biomarkers used in anti-diabetic drug development.

    Population PK, PK-PD and disease models were developed, based on data from clinical studies in subjects with varying degrees of renal function, non-diabetic subjects with insulin resistance and patients with type 2 diabetes mellitus (T2DM), receiving a peroxisome proliferator-activated receptor (PPAR) α/γ agonist, tesaglitazar.

    The PK model showed that a decreased renal elimination of the metabolite in renally impaired subjects leads to increased levels of metabolite undergoing interconversion and subsequent accumulation of tesaglitazar. Tesaglitazar negatively affects the glomerular filtration rate (GFR), and since renal function affects tesaglitazar exposure, a PK-PD model was developed to simultaneously describe this interrelationship. The model and data showed that all patients had decreases in GFR, which were reversible when discontinuing treatment.

    The PK-PD model described the interplay between fasting plasma glucose (FPG), glycosylated haemoglobin (HbA1c) and haemoglobin in T2DM patients. It provided a mechanistically plausible description of the release and aging of red blood cells (RBC), and the glucose dependent glycosylation of RBC to HbA1c. The PK-PD model for FPG and fasting insulin, incorporating components for β-cell mass, insulin sensitivity and impact of disease and drug treatment, realistically described the complex glucose homeostasis in the heterogeneous patient population.

    The mechanism-based PK, PK-PD and disease models increase the understanding about T2DM and important biomarkers, and can be used to improve decision making in the development of future anti-diabetic drugs.

    Delarbeten
    1. Mechanistic modelling of tesaglitazar pharmacokinetic data in subjects with various degrees of renal function: evidence of interconversion
    Öppna denna publikation i ny flik eller fönster >>Mechanistic modelling of tesaglitazar pharmacokinetic data in subjects with various degrees of renal function: evidence of interconversion
    2008 (Engelska)Ingår i: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 65, nr 6, s. 855-863Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    AIMS

    To develop a mechanistic pharmacokinetic (PK) model for tesaglitazar and its metabolite (an acyl glucuronide) following oral administration of tesaglitazar to subjects with varying renal function, and derive an explanation for the increased plasma exposure of tesaglitazar in subjects with impaired renal function.

    METHODS

    Data were from a 6-week study in subjects with renal insufficiency and matched controls undergoing repeated oral dosing with tesaglitazar (n = 41). Compartmental population PK modelling was employed to describe the PK of tesaglitazar and its metabolite, in plasma and urine, simultaneously. Two hypotheses were tested to investigate the increased exposure of tesaglitazar in subjects with renal functional impairment: tesaglitazar metabolism is correlated with renal function, or metabolite elimination is reduced in renal insufficiency, leading to increased hydrolysis (interconversion) to the parent compound via biliary circulation.

    RESULTS

    The hypothesis for interconversion was best supported by the data. The population PK model included first-order absorption, two-compartment disposition and separate renal (0.027 l h(-1)) and metabolic (1.9 l h(-1)) clearances for tesaglitazar. The model for the metabolite; one-compartment disposition with renal (saturable, V-max = 0.19 mu mol l(-1) and Km = 0.04 mmol l(-1)) and nonrenal clearances (1.2 l h(-1)), biliary secretion (12 h(-1)) to the gut, where interconversion and reabsorption (0.8 h(-1)) of tesaglitazar occurred.

    CONCLUSION

    A mechanistic population PK model for tesaglitazar and its metabolite was developed in subjects with varying degrees of renal insufficiency. The model and data give insight into the likely mechanism (interconversion) of the increased tesaglitazar exposure in renally impaired subjects, and separate elimination and interconversion processes without dosing of the metabolite.

    Nyckelord
    acyl glucuronide, interconversion, mechanistic modelling, NONMEM, population pharmacokinetics, tesaglitazar
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-97051 (URN)10.1111/j.1365-2125.2008.03110.x (DOI)000255751300008 ()
    Tillgänglig från: 2008-04-17 Skapad: 2008-04-17 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    2. Pharmacokinetic-Pharmacodynamic Assessment of the Interrelationships Between Tesaglitazar Exposure and Renal Function in Patients With Type 2 Diabetes Mellitus
    Öppna denna publikation i ny flik eller fönster >>Pharmacokinetic-Pharmacodynamic Assessment of the Interrelationships Between Tesaglitazar Exposure and Renal Function in Patients With Type 2 Diabetes Mellitus
    2012 (Engelska)Ingår i: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 52, nr 9, s. 1317-1327Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The effects of tesaglitazar on renal function (assessed as urinary clearance of 125I-sodium iothalamate or estimated by the modification of diet in renal disease formula) were studied in a 24-week open-label trial in type 2 diabetes mellitus patients randomized to daily doses of either tesaglitazar 2 mg or pioglitazone 45 mg. The aim of the analysis was to develop a population pharmacokinetic-pharmacodynamic model that could simultaneously describe the interrelationship between tesaglitazar exposure and reduction in renal function over time in patients with type 2 diabetes mellitus. The pharmacokinetic-pharmacodynamic model could adequately describe the interplay between tesaglitazar and glomerular filtration rate. A one-compartment model in which the apparent clearance was influenced by glomerular filtration rate characterized the pharmacokinetics of tesaglitazar. An indirect-response model was used for the slow time course of change in glomerular filtration rate, which decreased from 100 to 78 mL/min/1.73m2 after 12 weeks of treatment. All tesaglitazar-treated patients had a reduction in glomerular filtration rate, and available demographic variables could not explain differences in response. Patients treated with an angiotensin converting enzyme inhibitor were more sensitive to tesaglitazar and had larger glomerular filtration rate decrease compared to nontreated patients. Approximately 8 weeks after discontinuing treatment, mean glomerular filtration rate had returned towards baseline. The model and data give valuable insights into the dynamic changes in glomerular filtration rate over time.

    Nyckelord
    Tesaglitazar, peroxisome proliferator–activated receptor (PPAR), renal function, pharmacokinetics-pharmacodynamics (PK-PD)
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-97052 (URN)10.1177/0091270011416937 (DOI)000308227400004 ()
    Tillgänglig från: 2008-04-17 Skapad: 2008-04-17 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    3. Models for plasma glucose, HbA1c, and hemoglobin interrelationships in patients with type 2 diabetes following tesaglitazar treatment
    Öppna denna publikation i ny flik eller fönster >>Models for plasma glucose, HbA1c, and hemoglobin interrelationships in patients with type 2 diabetes following tesaglitazar treatment
    2008 (Engelska)Ingår i: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 84, nr 2, s. 228-235Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Pharmacokinetic (PK) pharmacodynamic (PD) modeling was applied to understand and quantitate the interplay between tesaglitazar (a peroxisome proliferator-activated receptor alpha/gamma agonist) exposure, fasting plasma glucose (FPG), hemoglobin (Hb), and glycosylated hemoglobin (HbA1c) in type 2 diabetic patients. Data originated from a 12-week dose-ranging study with tesaglitazar. The primary objective was to develop a mechanism-based PD model for the FPG-HbA1c relationship. The secondary objective was to investigate possible mechanisms for the tesaglitazar effect on Hb. Following initiation of tesaglitazar therapy, time to new FPG steady state was similar to 9 weeks, and tesaglitazar potency in females was twice that in males. The model included aging of red blood cells (RBCs) using a transit compartment approach. The RBC life span was estimated to 135 days. The transformation from RBC to HbA1c was modeled as an FPG-dependent process. The model indicated that the tesaglitazar effect on Hb was caused by hemodilution of RBCs.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-97053 (URN)10.1038/clpt.2008.2 (DOI)000258445200019 ()
    Tillgänglig från: 2008-04-17 Skapad: 2008-04-17 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    4. A Model for Glucose, Insulin, and Beta-Cell Dynamics in Subjects With Insulin Resistance and Patients With Type 2 Diabetes
    Öppna denna publikation i ny flik eller fönster >>A Model for Glucose, Insulin, and Beta-Cell Dynamics in Subjects With Insulin Resistance and Patients With Type 2 Diabetes
    2010 (Engelska)Ingår i: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 50, nr 8, s. 861-872Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Type 2 diabetes mellitus (T2DM) is a progressive, metabolic disorder characterized by reduced insulin sensitivity and loss of beta-cell mass (BCM), resulting in hyperglycemia. Population pharmacokinetic-pharmacodynamic (PKPD) modeling is a valuable method to gain insight into disease and drug action. A semi-mechanistic PKPD model incorporating fasting plasma glucose (FPG), fasting insulin, insulin sensitivity, and BCM in patients at various disease stages was developed. Data from 3 clinical trials (phase II/III) with a peroxisome proliferator-activated receptor agonist, tesaglitazar, were used to develop the model. In this, a modeling framework proposed by Topp et al was expanded to incorporate the effects of treatment and impact of disease, as well as variability between subjects. The model accurately described FPG and fasting insulin data over time. The model included a strong relation between insulin clearance and insulin sensitivity, predicted 40% to 60% lower BCM in T2DM patients, and realistic improvements of BCM and insulin sensitivity with treatment. The treatment response on insulin sensitivity occurs within the first weeks, whereas the positive effects on BCM arise over several months. The semi-mechanistic PKPD model well described the heterogeneous populations, ranging from nondiabetic, insulin-resistant subjects to long-term treated T2DM patients. This model also allows incorporation of clinical-experimental studies and actual observations of BCM.

    Nyckelord
    type-2 diabetes, insulin resistance, beta-cell function, NONMEM, peroxisome proliferator-activated receptor agonist
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-95985 (URN)10.1177/0091270009349711 (DOI)000280041600002 ()20484615 (PubMedID)
    Tillgänglig från: 2007-05-15 Skapad: 2007-05-15 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    Ladda ner fulltext (pdf)
    FULLTEXT01
    Ladda ner (pdf)
    COVER01
  • 50. Hamrén, Bengt
    et al.
    Björk, Elisabeth
    Sunzel, Maria
    Karlsson, Mats O
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Models for plasma glucose, HbA1c, and hemoglobin interrelationships in patients with type 2 diabetes following tesaglitazar treatment2008Ingår i: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 84, nr 2, s. 228-235Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pharmacokinetic (PK) pharmacodynamic (PD) modeling was applied to understand and quantitate the interplay between tesaglitazar (a peroxisome proliferator-activated receptor alpha/gamma agonist) exposure, fasting plasma glucose (FPG), hemoglobin (Hb), and glycosylated hemoglobin (HbA1c) in type 2 diabetic patients. Data originated from a 12-week dose-ranging study with tesaglitazar. The primary objective was to develop a mechanism-based PD model for the FPG-HbA1c relationship. The secondary objective was to investigate possible mechanisms for the tesaglitazar effect on Hb. Following initiation of tesaglitazar therapy, time to new FPG steady state was similar to 9 weeks, and tesaglitazar potency in females was twice that in males. The model included aging of red blood cells (RBCs) using a transit compartment approach. The RBC life span was estimated to 135 days. The transformation from RBC to HbA1c was modeled as an FPG-dependent process. The model indicated that the tesaglitazar effect on Hb was caused by hemodilution of RBCs.

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