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  • 1.
    Bardel, Annika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Wallander, Mari-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Svärdsudd, Kurt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Factors associated with adherence to drug therapy: a population-based study2007In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 63, no 3, p. 307-314Article in journal (Refereed)
    Abstract [en]

    Objective  To investigate adherence to prescription in a female population aged 35–65 years.

    Design  Postal questionnaire study of 2991 randomly sampled 35- to 64-year-old women in seven provinces of central Sweden. Methods  The study was performed in 1995 as a cross-sectional postal questionnaire study in seven counties in central Sweden. The questionnaire was sent to a random sample of 4200 women between the ages of 35 and 64, of whom 2991 (71.2%) responded. The questionnaire asked about drugs prescribed during the past year and about factors potentially affecting adherence. Results  The same women had different degrees of adherence to different medications. A large number of factors were associated with adherence. Multivariate analysis revealed that age, scheduled check-up, perceived importance of medication, concerns about medication safety and taking medication for a respiratory or a cardiovascular disease were significantly related to adherence. Adherence ranged from 15–98% depending on these factors, and was the lowest among young women who regarded their medication as unimportant and who had no scheduled check-up; the highest reported adherence was found among elderly women who regarded their medication as important and who had a scheduled check-up. Conclusion  Factors that were associated with the perceived importance of medication had a positive effect on adherence, while concerns about medication safety had a negative effect.

  • 2.
    Björkman, Sven
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Folkesson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jönsson, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pharmacokinetics and dose requirements of factor VIII over the age range 3-74 years: a population analysis based on 50 patients with long-term prophylactic treatment for haemophilia A2009In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 65, no 10, p. 989-998Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The three aims of this investigation were (1) to develop a population pharmacokinetic (PK) model for factor VIII (FVIII) in haemophilia A patients, with estimates of inter-occasion and inter-individual variance, (2) to investigate whether appropriate dosing of FVIII for regular prophylaxis can be calculated according to patient characteristics, and (3) to present dosing recommendations for initiating prophylactic treatment. METHODS: A population PK model was developed using data from four PK studies on patients aged 7-74 years. The model was tested on sparse FVIII data from 42 outpatient visits by haemophilia prophylaxis patients aged 3-66 years. Dose requirements for prophylaxis were calculated both according to the population model and from empirical Bayesian estimates of FVIII PK in the individual patients. RESULTS: The study data were well characterised by a two-compartment PK model. Body weight, age and type of FVIII preparation (plasma-derived or recombinant) were identified as significant covariates. Inter-occasion variance was lower than inter-individual variance for both clearance and volume of the central compartment. The model could reasonably predict FVIII PK in the sparse clinical data. Model-predicted doses (based on age and body weight) to maintain a recommended 0.01 U/mL trough level of FVIII with administration on alternate days started at around 60 U/kg in the small children, decreasing to 10 U/kg or less in middle age. However, "true" dose requirements, as estimated from individual PK parameter data, showed a much greater variation. CONCLUSION: Appropriate dosing of FVIII for prophylactic treatment cannot be calculated only from body weight and/or age. However, plausible starting doses for most patients would be 1,000 U every other day. FVIII levels should then be checked for dose adjustment.

  • 3.
    Björkman, Sven
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Åhlén, Victor
    Population pharmacokinetics of plasma-derived factor IX in adult patients with haemophilia B: implications for dosing in prophylaxis2012In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 68, no 6, p. 969-977Article in journal (Refereed)
    Abstract [en]

    Knowledge of the pharmacokinetics (PK) of plasma-derived factor IX (FIX) is still inadequate, with conflicting findings on its elimination half-life and as yet no analysis of the variance in PK between and within individuals. The aim of the study was thus to characterize the PK of plasma-derived FIX, including estimates of variance between and within patients, in adult patients and to predict the variation between individuals in dose requirement to produce a target trough level during regular prophylaxis. Plasma FIX versus time data were compiled from four published and one unpublished PK study involving a total of 26 adult patients with severe haemophilia B. The number of PK assessments per patient varied between one and eight, yielding in total 893 measured FIX levels from 80 study occasions. A population PK model was developed to describe the whole dataset. Parameter values from the model were used to calculate the dose requirement to maintain a trough level of 1% of normal FIX activity in each patient. The disposition of FIX was well described by a three-compartment PK model. The median elimination half-life was 31 h, and the variation between individuals was modest both in PK and in dose requirement during twice-weekly prophylaxis. With twice weekly dosing, the need for PK-based dose tailoring of FIX in adult patients appears to be limited. However, monitoring FIX levels should be considered in children, in patients who do not respond satisfactorily to standard dosing, and if treatment is switched from plasma-derived to recombinant FIX.

  • 4.
    Bodén, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Wettermark, Bjorn
    Brandt, Lena
    Kieler, Helle
    Factors associated with pregabalin dispensing at higher than the approved maximum dose2014In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 70, no 2, p. 197-204Article in journal (Refereed)
    Abstract [en]

    Concerns have been raised about the abuse potential of pregabalin. Therefore, the aim of our study was to characterize patients dispensed pregabalin at higher than the maximum allowed dose in a cohort study based on data extracted from Swedish national registers. All patients dispensed at least three prescriptions of pregabalin between July 2006 and December 2009 were included (n = 48,550). The daily dose was defined as the amount of pregabalin dispensed divided by the number of days between the second and third dispensings. Associations between sociodemographic and clinical variables and dispensing pregabalin at a dose exceeding the maximum daily allowed dose (600 mg) were investigated in multivariate regression models. Of the patients dispensed pregabalin during the study period, 8.5 % were dispensed a dose that exceeded the maximum daily allowed dose. A previous addictive disorder drug treatment or diagnosis was present in 20 and 31 % of patients dispensed pregabalin within and exceeding the recommended dose range, respectively. Our analysis revealed that those patients at increased risk of being dispensed pregabalin at higher than the maximum allowed dose were male [adjusted odds ratio (aOR) 1.40, 95 % confidence interval (CI) 1.31-1.49], were between 18 and 29 years of age compared with those aged a parts per thousand yen65 years (aOR 1.62, 95 % CI 1.45-1.82), had a low income (aOR 1.24, 95 % CI 1.10-1.40), had epilepsy compared with no diagnosis (aOR 1.41, 95 % CI 1.10-1.81), had a previous substance use disorder treatment or diagnosis (aOR 1.41, 95 % CI 1.31-1.52) or had previously been dispensed high doses of drugs with abuse potential (aOR 1.77, 95 % CI 1.62-1.94). Based on our results we conclude that patients at a high risk of addiction and patients with epilepsy are more likely to be dispensed pregabalin at higher than the maximum approved daily dose.

  • 5.
    Carlsson, Axel C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Wandell, Per
    Sundquist, Kristina
    Johansson, Sven-Erik
    Sundquist, Jan
    Differences and time trends in drug treatment of atrial fibrillation in men and women and doctors' adherence to warfarin therapy recommendations2013In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 69, no 2, p. 245-253Article in journal (Refereed)
    Abstract [en]

    Little is known about prescription trends in atrial fibrillation (AF) in primary health care in Sweden. The aim was to study time trends in pharmacotherapy, in men and women with AF. We also aimed at studying doctors' adherence to CHADS2 for prescribing warfarin. CHADS2 assesses stroke risk by presence of known risk factors, i.e., congestive heart failure, hypertension, age > 75 years, diabetes, previous stroke and transient ischemic attack. Data were obtained from primary health care records that contained individual clinical data. In total, 371,036 patients were included in the sample from 2002, and 424,329 patients were included in the sample from 2007. The study population consisted of individuals aged 45+ years who were diagnosed with AF in 2002 (1,330 men and 1,096 women) and 2007 (2,748 men and 2,234 women). The pharmacotherapies prescribed in 2002 and 2007 were analyzed separately in men and women. Logistic regression was used to calculate the association between the CHADS2 score and prescribed warfarin treatment. Selective beta-blockers, anti-coagulant therapy and lipid-lowering drugs were prescribed more frequently in 2007 than in 2002. In 2007, antithrombotic and RAS-blocking agents were prescribed more frequently to men, whereas beta-1 selective beta-blockers were prescribed more frequently to women. There was no consistent association between the CHADS2 score and prescribed warfarin treatment. Pharmacotherapy of AF has improved over time, though CHADS2 guidelines need to be implemented systematically in primary health care in Sweden to decrease the risk of stroke and improve quality of life in patients with AF.

  • 6.
    Cashin, Peter H
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Ehrsson, H
    Wallin, I
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Pharmacokinetics of cisplatin during hyperthermic intraperitoneal treatment of peritoneal carcinomatosis2013In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 69, no 3, p. 533-540Article in journal (Refereed)
    Abstract [en]

    Purpose

    Cisplatin during hyperthermic intraperitoneal chemotherapy (HIPEC) has not previously been measured with a selective technique. The primary aims were to examine the pharmacokinetics of active cisplatin and its monohydrated complex (MHC) during HIPEC using a specific measuring technique, to compare cisplatin’s systemic absorption with oxaliplatin, and to compare active cisplatin levels to that of total platinum.

    Methods

    Ten patients treated with cytoreductive surgery and HIPEC (cisplatin 50 mg/m2,doxorubicin 15 mg/m2) were recruited. Blood and perfusate samples were drawn during and after HIPEC. Cisplatin analysis was conducted using liquid chromatography (LC) with post-column derivatization with diethyldithiocarbamate and compared with inductively coupled plasma-mass spectrometry (ICP-MS).

    Results

    The mean half-life (t1/2) of perfusate cisplatin was 18.4 min, with area under the time-concentration curve (AUC) 0–90 min of 2.87 mM·min and estimated 0–60 min of 2.45 mM·min. The absorption t1/2 was 9.0 min for cisplatin and 18.2 min for oxaliplatin. The ratio of total platinum to active cisplatin increased in a linear manner by time of perfusion.

    Conclusions

    Cisplatin is absorbed quicker than oxaliplatin. Lowering the perfusion time to 60 min does not significantly change the pharmacokinetics of cisplatin, and is therefore to be considered. As the HIPEC perfusion progresses, the ICP-MS technique does not adequately reflect active cisplatin levels in the perfusate

  • 7. Chang, Ming
    et al.
    Soderberg, Mao Mao
    Scordo, Maria Gabriella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Tybring, Gunnel
    Dahl, Marja-Liisa
    CYP2C19*17 affects R-warfarin plasma clearance and warfarin INR/dose ratio in patients on stable warfarin maintenance therapy2015In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 71, no 4, p. 433-439Article in journal (Refereed)
    Abstract [en]

    We aimed to assess the influence of CYP2C19*17 on R-warfarin clearance as well as the effect of CYP2C19, CYP2C8, CYP2C9, and VKORC1 polymorphisms together with non-genetic factors on warfarin international normalized ratio (INR)/daily dose. One hundred fifty Caucasian Italian outpatients with data on steady-state plasma concentrations of S- and R-warfarin were genotyped for CYP2C19 (*2, *3, *4, *17), CYP2C9 (*2, *3), CYP2C8*3, and VKORC1*2. The statistical analysis was performed on the effect of genotypes/haplotypes, age, sex, and body weight on the clearance of warfarin enantiomers and dose-normalized INR. R-warfarin clearance was 32 % higher in carriers of CYP2C19*17 than in carriers of CYP2C19*2 (mean 2.5 mL/min, 95 % confidence interval (CI) 2.3-2.8 vs. 1.9 mL/min, 95 % CI 1.7-2.2; P (post hoc) = 0.01). Patients with CYP2C19*1/*1 genotype had an intermediate clearance (mean 2.1 mL/min, 95 % CI 1.8-2.4). The genotypes of VKORC1, CYP2C9, and CYP2C19, together with non-genetic factors (age, sex, and body weight) explained 52 % of the variability in warfarin INR/daily dose, of which CYP2C19 genotypes accounted for 7 %. This is the first study to include the gain-of-function CYP2C19*17 allele when assessing the impact of CYP2C19 polymorphisms on the clearance of warfarin enantiomers. CYP2C19 genotypes influenced the clearance of R-warfarin and contributed significantly to the variability in INR/daily dose, indirectly indicating a clinical relevance of R-warfarin.

  • 8.
    Clewe, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Goutelle, Sylvain
    Conte, John E., Jr.
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A pharmacometric pulmonary model predicting the extent and rate of distribution from plasma to epithelial lining fluid and alveolar cells-using rifampicin as an example2015In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 71, no 3, p. 313-319Article in journal (Refereed)
    Abstract [en]

    The purpose of the study was to develop a drug-unspecific approach to pharmacometric modeling for predicting the rate and extent of distribution from plasma to epithelial lining fluid (ELF) and alveolar cells (AC) for data emanating from studies involving bronchoalveolar lavage (BAL) sampling, using rifampicin (RIF) as an example. Data consisting of RIF plasma concentrations sampled at approximately 2 and 4 h postdose and ELF and AC concentrations quantified from one BAL sample, taken at approximately 4 h postdose, in 40 adult subjects without tuberculosis was used as an example for model development. This study emphasized the usage of drug-specific plasma pharmacokinetics (PK) for a correct characterization of plasma to pulmonary distribution. As such, RIF PK was described using absorption transit compartments and a one compartment distribution model coupled with an enzyme turn-over model. The ELF and AC distribution model consisted of characterization of the rate of distribution of drug from plasma to ELF and AC by two distribution rate constant, k (ELF) and k (AC), respectively. The extent of distribution to ELF and AC was described by unbound ELF/plasma concentration ratio (R (ELF/unbound-plasma)) and unbound AC/plasma concentration ratio (R (AC/unbound-plasma)) which typical values were predicted to be 1.28 and 5.5, respectively. The model together with a drug-specific plasma PK description provides a tool for handling data from both single and multiple BAL sampling designs and directly predicts the rate and extent of distribution from plasma to ELF and AC. The model can be further used to investigate design aspects of optimized BAL studies.

  • 9.
    Elsherbiny, Doaa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cohen, Karen
    Jansson, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Smith, Peter
    McIlleron, Helen
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Population pharmacokinetics of nevirapine in combination with rifampicin-based short course chemotherapy in HIV- and tuberculosis-infected South African patients2009In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 65, no 1, p. 71-80Article in journal (Refereed)
    Abstract [en]

    The aim was to develop a model to describe the population pharmacokinetics of nevirapine in South African human immunodeficiency virus (HIV)-infected patients who were taking nevirapine-based antiretroviral therapy concomitantly or in the absence of rifampicin-based tuberculosis therapy. Patients were divided into two groups: (1) patients receiving   nevirapine-containing antiretroviral regimen (200 mg twice daily) and continuation phase rifampicin-containing tuberculosis therapy (n = 27) in whom blood samples were obtained before and not less than 14 days after they completed tuberculosis therapy; (2) patients without tuberculosis who were receiving a nevirapine-containing antiretroviral regimen for at least 3 weeks (n = 26). The population pharmacokinetics of nevirapine was described using nonlinear mixed effects modelling   with NONMEM software. Based on the developed model, plasma concentration profiles after 300, 400 and 500 mg of nevirapine twice daily were simulated. Concomitant administration of rifampicin increased nevirapine oral clearance (CL/F) by 37.4% and reduced the absorption rate constant (k(a)) by almost sixfold. Rifampicin reduced the nevirapine average minimum concentration by 39%. Simulated doses of 300 mg twice daily elevated nevirapine concentrations above subtherapeutic levels in most patients, with minimum exposure above the recommended maximum concentration. The area under the concentration-time curve of 12-hydroxynevirapine was not different in the presence of rifampicin. 2-, 3- and 8-Hydroxynevirapine were not detectable (LLOQ = 0.025 mg/L). The developed model adequately describes nevirapine population   pharmacokinetics in a South African population when taken with/and in the absence of rifampicin treatment. The simulations suggest that an increased dose of 300 mg twice daily would achieve adequate nevirapine concentrations in most patients during rifampicin-containing treatment for tuberculosis.

  • 10.
    Elsherbiny, Doaa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ren, Yuan
    McIlleron, Helen
    Maartens, Gary
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Population pharmacokinetics of lopinavir in combination with rifampicin-based antitubercular treatment in HIV-infected South African children2010In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 66, no 10, p. 1017-1023Article in journal (Refereed)
    Abstract [en]

    The population pharmacokinetics (PK) of lopinavir in tuberculosis (TB)/human immunodeficiency virus (HIV) co-infected South African children taking super-boosted lopinavir (lopinavir/ritonavir ratio 1:1) as part of antiretroviral treatment in the presence of rifampicin were compared with the population PK of lopinavir in HIV-infected South African children taking standard doses of lopinavir/ritonavir (ratio 4:1).

    Lopinavir concentrations were measured in 15 TB/HIV-co-infected paediatric patients who were sampled during and after rifampicin-based TB treatment and in 15 HIV-infected children without TB. During TB therapy, the dose of ritonavir was increased to lopinavir/ritonavir 1:1 in order to compensate for the induction of rifampicin. The children received median (interquartile range=IQR) doses of lopinavir 292 mg/m(2) (274, 309) and ritonavir 301 mg/m(2) (286, 309) twice daily. After TB treatment completion the children received standard doses of lopinavir/ritonavir 4:1 (median [IQR] lopinavir dose 289 mg/m(2) [286, 303] twice daily) as did those without TB (median [IQR] lopinavir dose 265 mg/m(2) [249, 289] twice daily).

    Lopinavir oral clearance (CL/F) was about 30% lower in children without TB than in co-infected children treated with super-boosted lopinavir. However, the predicted lopinavir C-min was above the recommended minimum therapeutic concentration during TB/HIV co-treatment in the 15 children. Lopinavir CL/F increased linearly during the dosing interval.

    Increasing the ritonavir dose to achieve a lopinavir/ritonavir ratio of 1:1 when given in combination with rifampicin-based TB treatment did not completely compensate for the enhancement of lopinavir CL/F caused by rifampicin. The time-dependent lopinavir CL/F might be due to a time-dependent recovery from ritonavir inhibition of lopinavir metabolism during the dosing interval.

  • 11.
    Eriksson, Irene
    et al.
    Karolinska Inst, Dept Med Solna, Stockholm, Sweden.;Stockholm Cty Council, Dept Healthcare Dev, Stockholm, Sweden..
    Cars, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Piehl, Fredrik
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Malmström, Rickard E.
    Karolinska Inst, Dept Med Solna, Stockholm, Sweden.;Karolinska Univ Hosp, Clin Pharmacol, Stockholm, Sweden..
    Wettermark, Björn
    Karolinska Inst, Dept Med Solna, Stockholm, Sweden.;Stockholm Cty Council, Dept Healthcare Dev, Stockholm, Sweden..
    von Euler, Mia
    Karolinska Inst, Dept Med Solna, Stockholm, Sweden.;Karolinska Univ Hosp, Clin Pharmacol, Stockholm, Sweden.;Karolinska Inst, Dept Clin Sci & Educ, Sodersjukhuset, Stockholm, Sweden..
    Persistence with dimethyl fumarate in relapsing-remitting multiple sclerosis: a population-based cohort study2018In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 74, no 2, p. 219-226Article in journal (Refereed)
    Abstract [en]

    Purpose: To describe patients initiating dimethyl fumarate (DMF) and measure persistence with DMF, discontinuation, and switching in treatment-na < ve DMF patients and patients switching to DMF from other multiple sclerosis disease-modifying treatments (DMTs).

    Methods: A population-based cohort study of all Stockholm County residents initiating DMF from 9 May 2014 until 31 May 2017. All data were derived from a regional database that collects individual-level data on healthcare and drug utilization of all residents. The study outcomes were persistence with DMF and DMF discontinuation and switching to other DMTs. Persistence was measured as the number of days until either DMF discontinuation (treatment gap ae<yen> 60 days) or switching to another DMT.

    Results: The study included 400 patients (median follow-up = 2.5 years). The majority had previously been treated with other DMTs (61%). Throughout the follow-up period, 124 patients (31%) discontinued DMF and 114 patients (29%) switched treatment. Overall, 34% of patients initiating DMF stopped treatment within 1 year and only 43% of patients remained on DMF at 2 years from treatment initiation.

    Conclusions: DMF had a rapid market uptake likely due to high expectations held by both patients and clinicians. However, persistence with DMF in routine clinical practice was found to be low.

  • 12.
    Eriksson, Jan W
    et al.
    Department of Medicine, University of Göteborg, Sahlgren's Hospital, Göteborg, Sweden .
    Fowelin, J
    Urbanavicius, V
    Insulin concentrations and insulin sensitivity after short-term amiloride in healthy subjects1994In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 46, no 5, p. 469-472Article in journal (Refereed)
    Abstract [en]

    We have evaluated the short-term effects of amiloride on insulin action in vivo, since amiloride is known to impair insulin action in vitro.

    Seven healthy subjects were treated according to a randomized, double-blind, cross-over protocol. The treatment periods were 3 days each with amiloride 15 mg daily and placebo. Insulin action on glucose turnover was assessed directly after each treatment period with the hyper-insulinaemic euglycaemic glucose clamp technique.

    At the two insulin concentrations studied (∼ 30 mU·l−1 and ∼ 200 mU·l−1), the glucose infusion rate required to maintain constant euglycaemia did not differ after either amiloride or placebo. The rates of glucose production and utilization were also similar, whereas the so-called insulin sensitivity index at the lower insulin concentration was significantly reduced (by about 15 %) after amiloride. Moreover, amiloride produced significantly higher fasting insulin and C-peptide concentrations, whereas fasting glucose and NEFA concentrations were unaltered.

    In conclusion, these data suggest that short-term amiloride slightly impairs insulin sensitivity with respect to glucose uptake. However, overall glucose homoeostasis does not appear to be affected, probably due to a compensatory rise in plasma insulin.

  • 13.
    Fanta, Samuel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kinnunen, Mari
    Backman, Janne T.
    Kalso, Eija
    Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing2015In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 71, no 4, p. 441-447Article in journal (Refereed)
    Abstract [en]

    Low-dose ketamine is a lucrative therapeutic approach in cancer pain, perioperative treatment of pain, and management of treatment-resistant depression. The analgesic potency of its main metabolite norketamine is thought to be one third that of ketamine. However, few studies exist on the pharmacokinetics of orally administered S-ketamine. In our study, 11 healthy volunteers received S-ketamine 0.25 mg/kg orally and 0.125 mg/kg intravenously. S-ketamine and norketamine concentrations were measured up to 23.5 h post-dose. A population pharmacokinetic model was built to describe S-ketamine and norketamine pharmacokinetics. A three-compartment model for both S-ketamine and norketamine best described the data. To accommodate for the extensive formation of norketamine after oral S-ketamine, a separate presystemic absorption-phase component was included in addition to its systemic formation. The oral bioavailability of S-ketamine was low, 8 % (11 % interindividual variability), and its clearance was high, 95 L/h/70 kg (13 % interindividual variability). Simulations suggested that after oral dosing, norketamine AUC at steady state is 16.5 times higher than that of S-ketamine. Given that the analgesic effect of S-ketamine is due to both S-ketamine and norketamine, relatively small oral doses of S-ketamine can be assumed to be a feasible alternative to repeated intravenous dosing, for example in the setting of chronic pain.

  • 14.
    Frisk, Pia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Stockholm Cty Council, Publ Healthcare Serv Comm, POB 6909, S-10239 Stockholm, Sweden.
    Aggefors, K.
    Stockholm Cty Council, Publ Healthcare Serv Comm, POB 6909, S-10239 Stockholm, Sweden.
    Cars, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Feltelius, N.
    Med Prod Agcy, Uppsala, Sweden.
    Loov, S. A.
    Stockholm Cty Council, Publ Healthcare Serv Comm, POB 6909, S-10239 Stockholm, Sweden.
    Wettermark, B.
    Stockholm Cty Council, Publ Healthcare Serv Comm, POB 6909, S-10239 Stockholm, Sweden;Karolinska Inst, Dept Med Solna, Clin Epidemiol Unit Clin Pharmacol, Stockholm, Sweden.
    Weiland, O.
    Karolinska Univ Hosp Huddinge, Karolinska Inst, Div Infect Dis, Dept Med, Stockholm, Sweden.
    Introduction of the second-generation direct-acting antivirals (DAAs) in chronic hepatitis C: a register-based study in Sweden2018In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 74, no 7, p. 971-978Article in journal (Refereed)
    Abstract [en]

    Introduction of the direct-acting antivirals (DAAs) for treatment of chronic hepatitis C (CHC) infection has been challenging in all health systems. In Sweden, a national protocol for managed introduction was developed. It was optional, but all county councils agreed to implement and follow it. The purpose of this study was to study (a) cure rates among all patients initiated on treatment in 2014-2015, (b) prescribers' adherence to the drug recommendations and treatment eligibility criteria in the protocol, and (c) introduction rate in the six Swedish healthcare regions. A cross-sectional study where national data from the Prescribed Drug Register and the quality register InfCare Hepatitis defined the study population, and clinical data from the Patient Register and InfCare Hepatitis were used to monitor outcomes. Descriptive statistics were used. A total of 3447 patients were initiated on treatment during 2014-2015. The overall cure rate, based on data from 85% of the cohort, was 96%, with variation between genotypes. Adherence to drug recommendations increased over time and varied between 43.2 and 94.2%. Adherence to the treatment eligibility criteria was initially 80% and increased to 87% when treatment restrictions were widened. The introduction rate differed initially between the regions and reached stable levels 15-18 months after the launch of the first DAA. The estimated overall cure rate was 96%, with some variations between genotypes. A high level of adherence to the introduction protocol as well as similar introduction rates in the health care regions indicate that the introduction protocol, alongside with other measures taken, contributed considerably to a rapid uptake and equal distribution of DAAs in Sweden.

  • 15.
    Frisk, Pia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Stockholm Cty Council, Publ Healthcare Serv Comm, Dept Healthcare Dev, Box 6909, SE-10239 Stockholm, Sweden..
    Sporrong, Sofia K.
    Univ Copenhagen, Dept Pharm, Sect Social & Clin Pharm, Univ Parken 2, DK-2100 Copenhagen, Denmark..
    Ljunggren, Gunnar
    Stockholm Cty Council, Publ Healthcare Serv Comm, Dept Healthcare Dev, Box 6909, SE-10239 Stockholm, Sweden.;Karolinska Inst, Dept Learning Informat Management & Eth, Med Management Ctr, Berzelius Vag 3, SE-17177 Stockholm, Sweden..
    Wettermark, Björn
    Stockholm Cty Council, Publ Healthcare Serv Comm, Dept Healthcare Dev, Box 6909, SE-10239 Stockholm, Sweden.;Karolinska Univ Hosp, Clin Pharmacol, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Pharmacoepidemiol, Dept Med Solna, Karolinska Inst,Clin Epidemiol Unit T2, SE-17176 Stockholm, Sweden..
    von Euler, Mia
    Karolinska Inst, Dept Clin Sci & Educ, Sjukhusbacken 10, SE-11883 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Pharmacol L7 03, SE-17176 Solna, Sweden..
    Utilisation of prescription and over-the-counter triptans: a cross-sectional study in Stockholm, Sweden2016In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 72, no 6, p. 747-754Article in journal (Refereed)
    Abstract [en]

    Triptans are widely used in acute migraine, and in some countries, they are also available over-the-counter (OTC). In Sweden, sales have increased for both prescription and OTC triptans. This study aimed to describe current prescribing and utilisation patterns of prescription and OTC triptans in Stockholm, Sweden. Register data from 4759 patients dispensed triptans in 2014 were used to study documented diagnosis of migraine, concomitant acute and preventive treatment for migraine, and contraindications. Survey data from 49 patients purchasing OTC triptans in three pharmacies were used to capture physician-diagnosed migraine, concomitant acute and preventive treatment for migraine, a behaviour of combining or alternating between prescription and OTC triptans, and pharmacy counselling rates. Among the prescription triptan users, 52 % had a recorded diagnosis of migraine, 48 % had no other acute treatment, preventive treatment was rare (12 %) and contraindications were found in 2 % of the patients. Among the OTC triptan users, the majority (63 %) had been diagnosed by a physician and had a history of prescription triptan use, but combining or alternating between OTC and prescription triptans was rare. Concomitant acute treatment was reported in 53 % and preventive treatment was rare (4 %), despite high self-reported migraine frequencies. Some off-label use was detected, despite moderate to high counselling rates. Triptans are prescribed with attention to safety but with poor recording of migraine diagnosis. OTC triptan users generally have a history of prescription triptan use. Preventive treatment rates are low in both groups. Strategies to discern patients who need other treatment options should be considered.

  • 16. Gokalp, Osman
    et al.
    Gunes, Arzu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cam, Hakan
    Cure, Erkan
    Aydin, Osman
    Tamer, Mehmet Numan
    Scordo, Maria Gabriella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Dahl, Marja-Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mild hypoglycaemic attacks induced by sulphonylureas related to CYP2C9, CYP2C19 and CYP2C8 polymorphisms in routine clinical setting2011In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 67, no 12, p. 1223-1229Article in journal (Refereed)
    Abstract [en]

    To evaluate the impact of polymorphisms in the cytochrome P450 (CYP) 2C9, 2C19 and 2C8 genes on the risk of mild hypoglycaemic attacks in patients treated with sulphonylureas. One hundred and eight type 2 diabetic patients (50 men, 58 women), treated with oral antidiabetics, including at least one from the sulphonylurea group (glimepiride n = 50, gliclazide n = 46, or glipizide n = 12) for 3 months or longer, were included in the study. Symptoms of hypoglycaemia (sweating, tremor, anxiety and palpitations) during a 3 month period were recorded and confirmed by home glucose measurements. Gender, age, body mass index, creatinine clearance, HbA1c, oral antidiabetic dose and concomitant medication were assessed together with functional CYP2C9, CYP2C19 and CYP2C8 polymorphisms, analysed by real-time PCR methods. Fifteen patients (eight men, seven women) reported hypoglycaemia symptoms which were validated by their home glucose measurements (< 70 mg/dl). Heterozygosity and homozygosity for CYP2C9 variant alleles (*2 or *3) tended to be more frequent among patients who reported hypoglycaemic attacks (60 and 7%) than those who did not (39 and 3%). Similarly, the CYP2C8*1/*3 genotype tended to be more frequent in patients with (47%) than without (27%) hypoglycaemia, while no such trend was observed for CYP2C19 variants. However, only in the gliclazide group a significant association between CYP2C9 genotype and hypoglycaemic attacks was observed (P = 0.035). None of the other covariates showed any significant association with the risk of hypoglycaemic attacks. CYP2C9 polymorphisms leading to decreased enzyme activity show a modest impact on the risk of mild hypoglycaemia attacks during oral antidiabetic treatment, with a significant association in patients treated with gliclazide.

  • 17.
    Grundmark, Birgitta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Garmo, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Stattin, P
    Lambe, M
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Anti-androgen prescribing patterns, patient treatment adherence and influencing factors: results from the nationwide PCBaSe Sweden2012In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 68, no 12, p. 1619-1630Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    Adherence has not been studied in male oncology populations. The aim of this study on both the prescriber and user perspectives in prostate cancer treatment was to analyse real-life prescribing patterns of anti-androgens (AA), primarily bicalutamide, and factors influencing the patients' adherence to treatment.

    METHODS:

    A nationwide clinical cohort of incident prostate cancer, PCBaSe, was linked to the Swedish Prescribed Drug Register. Men with a planned first line monotherapy AA treatment were identified; dosages and extent of off-label treatment were investigated. Cumulative incidence proportions for reasons for drug discontinuation were calculated. Factors potentially influencing adherence were explored using the medical possession ratio based on the individual prescribed daily dose.

    RESULTS:

    First line monotherapy AA was planned in 4.4 % of all incident cases and in 2.1 % of low risk disease cases. Among 1,406 men prescribed bicalutamide, 1,109 (79 %) received the approved daily dose of 150 mg. Discontinuation reasons differed with disease severity. Off-label, low-dose prescription associated with age above 75 years and disease categorised as low risk was noted in 297 men (21 %). Sixty percent of the men adhered well, i.e. to ≥80 %. Age above 75 years and less severe disease were both negatively associated with adherence.

    CONCLUSIONS:

    Patient age and tumour risk group influenced the prescriber's choice of dose, pointing to important issues for critical reflection. Possible over-treatment was noted in low risk disease. Interventions to increase adherence in older men and in men with less severe disease are worth considering after critically reviewing the appropriateness of the treatment indication, especially in the latter case.

  • 18.
    Grundmark, Birgitta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Garmo, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Reducing the noise in signal detection of adverse drug reactions by standardizing the background: a pilot study on analyses of proportional reporting ratios-by-therapeutic area2014In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 70, no 5, p. 627-635Article in journal (Refereed)
    Abstract [en]

    Disproportionality screening analysis is acknowledged as a tool for performing signal detection in databases of adverse drug reactions (ADRs), e.g., in the European Union (EU) Drug Authority setting. The purpose of this study was to explore the possibility of decreasing false-positive signals of disproportionate reporting (SDR) by calculating the proportional reporting ratio (PRR)-by-therapeutic area (TA), while still maintaining the ability to detect relevant SDRs. In the EudraVigilance (EV) Database, output from PRR calculated with a restricted TA comparator background was compared in detail to output from conventional authority-setting PRR calculations for four drugs: bicalutamide, abiraterone, metformin, and vildagliptin, within the TAs of prostate gland disease and type 2 diabetes mellitus. ADR reports per investigated drug ranged from 2,400 to 50,000. The PRR-TA's ability to detect true-positive SDRs (as acknowledged in approved labeling) was increased compared to the conventional PRR, and performed 8-31 % better than a recently proposed stricter EU-SDR definition. The PRR-TA removed false SDRs confounded by disease or disease spill-over by up to 63 %, while retaining/increasing the number of unclassified SDRs relevant for manual validation, and thereby improving the ratio between confounded SDRs (i.e., noise) and unclassified SDRs for all investigated drugs (possible signals). The performance of the PRR was improved by background restriction with the PRR-TA method; the number of false-positive SDRs decreased, and the ability to detect true-positive SDRs increased, improving the signal-to-noise ratio. Further development and validation of the method is needed within other TAs and databases, and for disproportionality analysis methods.

  • 19.
    Gunes, Arzu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Dahl, Marja-Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Spina, Edoardo
    Scordo, Maria Gabriella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Further evidence for association between 5-HT2C receptor gene polymorphisms and extrapyramidal side effects in male schizophrenic patients2008In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 64, no 5, p. 477-482Article in journal (Refereed)
    Abstract [en]

     

    RATIONALE: Antipsychotic-induced extrapyramidal side effects (EPS) are still a major problem in the treatment of schizophrenia. Serotonin 2C receptors (5-HT(2C)) have regulatory effects on dopaminergic pathways in brain regions involved with EPS. Polymorphisms in the 5-HT(2C) gene (HTR2C) have been suggested to be associated with the risk of developing EPS. OBJECTIVE: Our purpose was to evaluate the impact of polymorphisms in the HTR2C gene on the occurrence of EPS in male schizophrenic patients. METHODS: Ninety-nine male Caucasian chronic schizophrenic patients on long-term treatment with classical antipsychotics were genotyped for the -997 G/A, -759 C/T, -697 G/C and Cys23Ser polymorphisms of HTR2C. EPS (dystonia, parkinsonism, tardive dyskinesia) were assessed by the Simpson-Angus Scale and the Abnormal Involuntary Movement Scale. Fifty-one patients had current or previous history of EPS, whereas 48 patients had no symptoms or history of EPS. To rule out a possible association between HTR2C polymorphisms and schizophrenia, 112 healthy male volunteers were also genotyped. RESULTS: Allele frequencies of -997A, -759T and -697C did not differ between the groups, whereas patients with EPS had a significantly (p = 0.025) higher frequency of the 23Ser allele (0.29) than did patients without EPS (0.15) or healthy volunteers (0.13). A similar trend was observed for a haplotype including the -997G, -759C, -697C and 23Ser alleles (p = 0.04). CONCLUSIONS: Results confirm previously reported associations between the HTR2C 23Ser allele and EPS occurrence and suggest the novel finding of an HTR2C haplotype association with EPS in male chronic schizophrenic patients.

  • 20. Güzey, C.
    et al.
    Scordo, Maria Gabriella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Spina, E.
    Landsem, Veslemøy Malm
    Spigset, O.
    Antipsychotic-induced extrapyramidal symptoms in patients with schizophrenia: associations with dopamine and serotonin receptor and transporter polymorphisms2007In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 63, no 3, p. 233-241Article in journal (Refereed)
    Abstract [en]

    Background: Little is known about the influence of polymorphisms of the dopamine and serotonin system on the risk for extrapyramidal symptoms (EPS) during treatment with antipsychotic drugs. Methods: Of 119 subjects with schizophrenia treated with antipsychotics, 63 had current or previous EPS (acute dystonia, parkinsonism, tardive dyskinesia), and 56 had no such symptoms. All subjects were genotyped for a total of eight dopamine and serotonin receptor and transporter polymorphisms: the Taq1A polymorphism of the dopamine D2 receptor (DRD2) gene, the Msc1 polymorphism of the dopamine D3 receptor (DRD3) gene, the variable number of tandem repeat (VNTR) polymorphism of the dopamine transporter (DAT1) gene, four polymorphisms (102T/C, His452Tyr, 516 C/T, and Thr25Asn) of the serotonin 5-HT2A receptor (5HTR2A) gene, and the 5HTTLPR polymorphism of the serotonin transporter (5HTT) gene. Results: The frequency of the A1 allele of the DRD2 Taq1A polymorphism was significantly higher in the EPS group than in the control group [16% vs. 7%, P=0.040; odds ratio (OR) 2.4; 95% confidence interval (CI) 1.1-5.7]. Also, the 9 repeat allele of the DAT1 VNTR polymorphism was significantly more common in the EPS group (42% vs. 28%, P=0.030; OR 1.9; 95% CI 1.1-3.3). Being a carrier of both DRD2 Taq1A A1 and DAT1 VNTR 9 repeat alleles was also significantly associated with the occurrence of EPS (19% vs. 6%, P=0.040; OR 4.0; 95% CI 1.05-15.2) No significant differences in allele frequencies were found for the other polymorphisms. Conclusion: Presence of the Taq1A A1 allele of the DRD2 and the 9 repeat allele of the DAT1 VNTR polymorphisms might be risk factors for EPS caused by antipsychotic drugs.

  • 21.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Brenning, Gunilla
    Medical Products Agency.
    Angioedema induced by tramadol – a potentially life-threatening condition2005In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 60, no 12, p. 901-903Article in journal (Refereed)
  • 22.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindbäck, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Stenestrand, Ulf
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Digoxin and mortality in atrial fibrillation: a prospective cohort study2007In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 63, no 10, p. 959-971Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study showed that rhythm-control treatment of patients with atrial fibrillation (AF) offered no survival advantage over a rate-control strategy. In a subgroup analysis of that study, it was found that digoxin increased the death rate [relative risk (RR) = 1.42), but it was suggested that this may have been attributable to prescription of digoxin for patients at greater risk of death, such as those with congestive heart failure (CHF). No study has investigated a priori the effect of digoxin on mortality in patients with AF. This study aimed to address this question. METHODS: Using data from the Registry of Information and Knowledge about Swedish Heart Intensive care Admissions (RIKS-HIA), we studied the 1-year mortality among patients admitted to coronary care units with AF, CHF, or AF+CHF with or without digoxin (n = 60,764) during 1995-2003. Adjustment for differences in background characteristics and other medications and treatments was made by propensity scoring. RESULTS: Twenty percent of patients with AF without CHF in this cohort were discharged with digoxin. This group had a higher mortality rate than the corresponding group not given digoxin [adjusted RR 1.42 (95% CI 1.29-1.56)], whereas no such difference was seen among patients with CHF with or without AF, although these patients had a nearly three-times higher mortality. CONCLUSION: The results suggest that long-term therapy with digoxin is an independent risk factor for death in patients with AF without CHF.

  • 23.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Martén, Leif
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Possible fluconazole-fentanyl interaction: a case report2006In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 62, no 6, p. 491-2Article in journal (Refereed)
  • 24.
    Hamberg, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Friberg, Lena E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hanséus, Katarina
    Barmhjärtcentrum, Skånes Universietessjukhus, Lund.
    Ekman-Joelsson, Britt-Marie
    Drottnings Silvias Barnsjukhus, Sahlgrenska Universitetssjukhuset, Göteborg.
    Sunnegårdh, Jan
    Drottnings Silvias Barnsjukhus, Sahlgrenska Universitetssjukhuset, Göteborg.
    Jonzon, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Lundell, Bo
    Jonsson, E. Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Warfarin dose prediction in children using pharmacometric bridging: comparison with published pharmacogenetic dosing algorithms2013In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 69, no 6, p. 1275-1283Article in journal (Refereed)
    Abstract [en]

    Purpose

    Numerous studies have investigated causes of warfarin dose variability in adults whereas studies in children are limited both in numbers and size. Mechanism-based population modelling provides an opportunity to condense and propagate prior knowledge from one population to another. The main objectives with this study were to evaluate the predictive performance of a theoretically bridged adult warfarin model in children, and to compare accuracy in dose prediction relative to published warfarin algorithms for children.

    Method

    An adult population PK/PD-model for warfarin, with CYP2C9 and VKORC1 genotype, age and target INR as dose predictors, was bridged to children using allometric scaling methods. Its predictive properties were evaluated in an external dataset of children 0-18 years old, including comparison of dose prediction accuracy with three pharmacogenetics-based algorithms for children.

    Results

    Overall, the bridged model predicted INR response well in 64 warfarin treated Swedish children (median age 4.3 years), but with a tendency to over predict INR in children ≤ 2 years old. The bridged model predicted 20 of 49 children (41%) within ± 20% of actual maintenance dose (median age 7.2 years). In comparison the published dosing algorithms predicted 33-41% of the children within ± 20% of actual dose. Dose optimization with the bridged model based on up to three individual INR observations increased the proportion within ± 20% of actual dose to 70%.

    Conclusion

    A mechanism-based population model developed on adult data provides a promising first step towards more individualized warfarin therapy in children.

  • 25.
    Hedenmalm, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Johansson, Annika
    Bäckman, Kristoffer
    Ohagen, Patrik
    Prematurely ended phase III trials in Sweden during the years 2002-20082011In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 67, no 9, p. 869-875Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to identify prematurely ended phase III clinical trials (CTs) and the proportion of such trials among all phase III CTs, review the reasons for the premature discontinuation of the CT, determine whether a data monitoring committee (DMC) was involved in this decision-making process, identify the data source on which the decision was based and review the consequences of the premature ending for product development. An additional aim was to identify risk factors for a premature ending. Prematurely ended phase III CTs in Sweden between 2002 and 2008 were identified by database searches. Identified trials were reviewed for treatment tested, study design, reasons for the premature ending, data source on which the decision was based and existence of and recommendation from a DMC. Three randomly selected but not prematurely ended control trials were identified, starting 1 May 2004, that were matched on the basis of application year. A total of 84 phase III CT applications (8%) were prematurely ended during the study period. Most trials were ended due to safety and/or efficacy concerns. A DMC was more common among trials in which mortality was the primary endpoint and oncology trials. A recommendation from the DMC to terminate the trial was most likely in the case of combined safety- and efficacy-related issues arising from within the trial. Possible risk factors for a premature ending included mortality as an endpoint, obesity as an indication and a longer than planned study duration. Approximately 30% of prematurely ended trials with active substances that did not have a marketing authorization at the time of the clinical trial application resulted in the discontinuation of further development of the substance. The DMCs in the phase III CTs reviewed here were used in accordance with guidelines. The use of DMCs was associated with possible risk factors for a premature ending and numerically, but not significantly associated with a premature ending.

  • 26.
    Hedenmalm, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lindh, Jonatan D.
    Karolinska Institutet.
    Säwe, Juliette
    SBU.
    Rane, Anders
    Karolinska Institutet.
    Increased liability of tramadol-warfarin interaction in individuals with mutations in the cytochrome p450 2D6 gene2004In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 60, no 5, p. 369-372Article in journal (Refereed)
    Abstract [en]

    Objective  This study aimed to investigate the importance of cytochrome P450 enzymes for the reported interaction between tramadol and warfarin.Materials and methods  Cases of suspected interaction between tramadol and warfarin resulting in International Normalised Ratios increases that were reported to the Swedish Adverse Drug Reactions Advisory Committee until March 2003 were included. Ten cases had been genotyped for known polymorphisms of CYP2D6, CYP2C9 and CYP2C19.Results  Seven of ten patients carried defective CYP2D6 alleles (population prevalence 42.2%) (one-sided binomial test, P=0.07). A further patient received concomitant drug treatments that may have resulted in CYP2D6 enzyme inhibition.Conclusion  The liability to an interaction between tramadol and warfarin may be related to the CYP2D6 activity.

  • 27.
    Hedenmalm, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Melander, Hans
    Medical Producs Agency.
    Alvan, Gunnar
    Medical Producs Agency.
    The conscientious judgement of a DSMB: statistical stopping rules re-examined2008In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 64, no 1, p. 69-72Article in journal (Refereed)
    Abstract [en]

    Objective:  In the light of the recent failure of a large cardiovascular mortality and morbidity study with torcetrapib, we have undertaken a post hoc review of the decisions taken by the Data and Safety Monitoring Board (DSMB) in that study. A number of other studies in which complex decisions were made by DSMBs are also reviewed. Results  The examples illustrate the complexities involved in the decision-making process by DSMBs and indicate that too much reliance on formal statistical stopping rules should be avoided due to a risk of delaying the identification of an unacceptable emergent safety signal. Methods  The review was based on information submitted by the sponsors of the studies to the Medical Products Agency. Conclusions  Multiple approaches to assessing the efficacy and safety in clinical trials need to be considered in order to facilitate early stopping of clinical trials with a negative risk benefit balance. Such systems may, for example, include the use of p-value flags and/or a complementary statistical analysis of the likelihood of achieving the study objective based on the data obtained to date.

  • 28.
    Hedenmalm, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Spigset, Olav
    Agranulocytosis and other blood dyscrasias associated with dipyrone (metamizole)2002In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 58, no 4, p. 265-274Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Agranulocytosis is a potentially lethal adverse drug reaction of dipyrone (metamizole). According to case-control studies, the frequency is low, approximately one per million users. The aim of the study was to describe the pattern of blood dyscrasias associated with dipyrone, identify possible risk factors and calculate the incidence of agranulocytosis associated with dipyrone. METHODS: All spontaneous reports of serious blood dyscrasias associated with dipyrone in Sweden were reviewed. The reports were scrutinised for additional information, including bone marrow findings. The reported incidence of agranulocytosis was estimated from total prescription sales of dipyrone. RESULTS: The reported incidence of agranulocytosis with dipyrone in Sweden was estimated to be at least 1:1439 (95% confidence interval 1:850, 1:4684) prescriptions. Ninety-two percent of the cases of blood dyscrasias occurred during the first 2 months of treatment. Additional risk factors were identified in 36% of the patients. In a total of five cases of which four were fatal, all three haematopoieses were affected according to bone marrow sample findings. Among the fatal cases, a higher proportion had bi- or tricytopenia than among the non-fatal cases ( P<0.005). CONCLUSION: Based on sales data and spontaneous reporting of adverse drug reactions in Sweden, the risk of agranulocytosis with dipyrone seems to be considerably higher than the previously estimated risks. Dipyrone is also associated with other blood dyscrasias, and the prognosis for combined dyscrasias seems to be poorer than for isolated agranulocytosis.

  • 29. Hornestam, Björn
    et al.
    Jerling, Markus
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Held, Peter
    Intravenously administered digoxin in patients with acute atrial fibrillation: a population pharmacokinetic/pharmacodynamic analysis based on the Digitalis in Acute Atrial Fibrillation trial2003In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 58, no 11, p. 747-755Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Atrial fibrillation is commonly treated with intravenously administered digoxin. The main objective of this study was to investigate the relationship between plasma concentration of digoxin and heart rate. SUBJECTS AND METHODS: Plasma concentrations of digoxin were analysed in 105 patients allocated to digoxin therapy in the Digitalis in Acute Atrial Fibrillation (DAAF) trial. A pharmacokinetic/pharmacodynamic (PK/PD) model for the relationship among digoxin dose, plasma concentration and heart rate in patients remaining in atrial fibrillation was constructed using non-linear, mixed-effect modelling. One hundred and twenty-two placebo-treated patients were included as a control group. In 56 patients, one late sample at 16 h after the first dose of digoxin was obtained while in 49 patients an early sample at 0.25-0.5 h and a late sample 16 h after the first dose were obtained. Heart rate was measured at 0, 2, 6, 12 and 16 h after inclusion, with data from 98, 89, 67, 56 and 53 patients available at each time point, respectively. RESULTS: A two-compartment model best described the time course of digoxin concentrations in plasma. Digoxin and creatinine clearance correlated strongly and mean plasma concentration of digoxin at 16 h was within recommended levels (1.6+/-1.0 nM). The decrease in heart rate in placebo-treated patients was, on average, 0.5 beats/min (bpm) per hour. In patients on digoxin, a linear relationship between the estimated digoxin concentration at the effect site and the drop-in heart rate was found. The half-life for the digoxin distribution to the effect compartment was approximately 3.8 h. The degree of reduction was related to the initial heart rate and patients with higher heart rate had a more pronounced decrease. The model predicted that a digoxin concentration of 1 nM at the effect site reduces heart rate by 9.4%. CONCLUSION: A PK/PD model for the relationship between the plasma concentration of digoxin, the estimated concentration at the effect site and the reduction in heart rate during atrial fibrillation could be defined using a population pharmacokinetic approach. Our data indicate that a more aggressive dosing regimen of digoxin may be more effective in terms of heart rate reduction.

  • 30. Jobski, Kathrin
    et al.
    Enders, Dirk
    Amann, Ute
    Suzart, Kiliana
    Wallander, Mari-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Schink, Tania
    Garbe, Edeltraut
    Use of rivaroxaban in Germany: a database drug utilization study of a drug started in hospital2014In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 70, no 8, p. 975-981Article in journal (Refereed)
    Abstract [en]

    The purpose of this drug utilization study was to describe the use of rivaroxaban in Germany during a time period in which approval was limited to the prevention of venous thromboembolism following hip or knee replacement. Additionally, we explored the feasibility of reconstructing inpatient drug use of rivaroxaban in a database where with a few exceptions inpatient prescribing information is not available. Source of data was one statutory health insurance providing data on about seven million insurants throughout Germany. Analyses were based on a cohort of rivaroxaban users from launch (October 2008) to December 2009 and encompassed potential indications for rivaroxaban use, treatment duration, and co-prescribing of potentially interacting drugs. Start of rivaroxaban treatment was defined by the date of surgery. During the study period, 425 rivaroxaban users were identified contributing 440 treatment periods. For more than 82 % of these episodes labelled indications could be determined. Treatment durations exceeded recommendations in 95 % of the episodes following knee replacement whereas rivaroxaban use after elective hip surgery was found to be longer than recommended in 56 %. Prescribing of potentially interacting medication was rare except for non-steroidal anti-inflammatory drugs. Overall, no important off-label use of rivaroxaban was identified. Based on several assumptions that have to be considered in the interpretation of the results our study describes a database approach to reconstruct inpatient drug use for a drug started after a coded hospital procedure, when treatment continues after hospital discharge and no change in drug use is expected in the outpatient setting.

  • 31. Johansson, Saga
    et al.
    Wallander, Mari-Ann
    Section of Preventive Cardiology, Göteborg University, Sweden.
    Ruigomez, A
    Garcia, R
    Treatment patterns among newly diagnosed heart failure patients in general practice2002In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 57, no 11, p. 813-817Article in journal (Refereed)
    Abstract [en]

    AIM

    To examine treatment patterns of heart failure (HF) in general practice and to evaluate factors influencing the choice of that treatment, such as age, sex, severity of disease and co-morbidity.

    METHODS

    We used previously identified and confirmed incident cases of HF (patients aged 40-84 years) from the General Practice Research Database in the UK (n = 938). We collected recorded information on demographics. co-morbidity and drug treatment prescribed 1 year before and after the incident diagnosis in 1996.

    RESULTS

    Most of the study cohort was over 60 years old and presented with several concomitant diseases. Use of most cardiovascular drugs significantly increased after the diagnosis of HF. There was a greater than threefold increase in the use of angiotensin-converting enzyme inhibitors, while use of nitrates decreased after diagnosis of HF among men. Use of beta-blockers and calcium channel blockers slightly decreased after diagnosis.

    CONCLUSION

    We found that well-established treatment practices were followed by general practitioners. Severity of the disease favoured use of diuretics and a previous ischaemic heart disease and hypertension favoured use of beta-blockers and aspirin. Women and elderly patients were less likely to receive treatment with angiotensin-converting enzyme inhibitors.

  • 32. Kim, In-Wha
    et al.
    Yun, Hwi-yeol
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Choi, Boyoon
    Han, Nayoung
    Kim, Myeong Gyu
    Park, Seonyang
    Oh, Jung Mi
    Population pharmacokinetics analysis of cyclophosphamide with genetic effects in patients undergoing hematopoietic stem cell transplantation2013In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 69, no 8, p. 1543-1551Article in journal (Refereed)
    Abstract [en]

    To build a population pharmacokinetic (PK) model of cyclophosphamide (CY) and its metabolite, 4-hydroxycyclophosphamide (HCY), in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) and to identify covariates, including genetic polymorphisms, which affect CY and HCY PK parameters. The study cohort comprised 21 patients undergoing HSCT who received CY intravenously between 2009 and 2011. Clinical characteristics and CY and HCY concentration data were collected for all patients, and ABCB1, ABCC2, GSTA1, GSTM1, GSTP1, GSTT1, CYP2B6, CYP2C19, and CYP3A5 genotyping was performed. A hypothetical enzyme compartment was conducted using the NONMEM program. A population PK analysis showed that the ABCC2 1249 genotype and aspartate aminotransferase levels significantly affected non-induced clearance (CL (UI)) and induced clearance (CL (I)) of CY, respectively. The final estimate of the mean CL (UI) and CL (I) of CY was 15.5 and 0.683 L/h, respectively, and the mean volume of distribution (V (1)) of CY was 88.0 L. The inter-individual variability for CL (UI), CL (I), and V (1) of CY was 52.8, 200, and 18.0 %, respectively. Additionally, the CL (UI) of CY was significantly decreased to approximately 51 % in patients with the 1249 GA heterozygous genotype compared to those with the 1249 GG wild-type genotype (p < 0.05). There were only three heterozygous GA variants of ABCC2 1249 in the study patients. The population PK model developed in this study implies an influence of genetic factors on the clearance of CY. Clearance was moderately reduced in patients with the ABCC2 1249GA heterozygous genotype.

  • 33.
    Kohnke, Hugo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Scordo, Gabriella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Pengo, Vittorio
    Padrini, Roberto
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Apolipoprotein E (APOE) and warfarin dosing in an Italian population2005In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 61, no 10, p. 781-3Article in journal (Refereed)
  • 34.
    Kohnke, Hugo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Sörlin, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Granath, Göran
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Warfarin dose related to apolipoprotein E (APOE) genotype2005In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 61, no 5-6, p. 381-8Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Warfarin is an anticoagulant which acts through interference with the recycling of vitamin K in the liver, leading to reduced activation of several clotting factors. Apolipoprotein E plays a central role in the uptake of the lipid-soluble vitamin K. The apolipoprotein E (APOE) alleles E2, E3 and E4 encode the three major isoforms of apolipoprotein E. The aim of this project was to evaluate whether variation in the APOE gene influences warfarin dose.METHODS: We genotyped APOE in 183 warfarin-treated patients. Information about warfarin dose, prothrombin time, age, gender, body weight, treatment indication and duration, other diseases and concurrent medication was taken from the patients' medical records. Cytochrome P(450) 2C9 genotyping had been performed previously, and patients were stratified according to CYP2C9 genotype.RESULTS: Patients homozygous for APOE*E4 tended to receive higher warfarin doses than others. Among CYP2C9 extensive metabolisers, APOE*E4 homozygous patients received significantly higher warfarin doses than patients with one or no E4 alleles; 56.9 compared with 34.3 and 34.6 mg/week, (Bonferroni corrected P=0.008 and 0.007, respectively). APOE genotype explains 6% of warfarin dose variance among CYP2C9 extensive metabolisers (analysis of variance, P=0.009).CONCLUSION: Previous studies have shown that individuals carrying the APOE*E4 allele have a faster uptake of lipoproteins into the liver and lower levels of circulating vitamin K than others. It is therefore plausible that patients carrying E4 alleles have an enhanced uptake of vitamin K into the liver and require higher doses of warfarin to compensate for this.

  • 35.
    Langdon, Grant
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Gueorguieva, Ivelina
    Aarons, Leon
    Karlsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Linking preclinical and clinical whole-body physiologically based pharmacokinetic models with prior distributions in NONMEM2007In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 63, no 5, p. 485-498Article in journal (Refereed)
    Abstract [en]

    Purpose: The aim of this study was to evaluate the performance of the NONMEM prior functionality compared to a full Bayesian method when applied to population physiological models using diazepam as a case study. Methods: Whole-body physiologically based pharmacokinetic (WBPBPK) models for diazepam were initially developed, tested and calibrated for rats and man using a full Bayesian analysis as implemented in WinBUGS. The final models were implemented in NONMEM and the results from the two analyses compared in terms of parameter estimates, measures of parameter precision and run times. Results: NONMEM population parameter estimates were in close agreement with those produced by the Bayesian analysis although there was a substantial shortening of run time for both the animal WBPBPK model (4.5 vs. 21 h) and human WBPBPK models (2 vs. 167 h). The adequacy of the model and the final parameter estimates were judged to be sufficient by the model's ability to describe individual tissue concentration-time profiles. The model provided a good overall description of the plasma concentration-time data in both rat and man with comparable parameter precision. A limited nonparametric bootstrap (n = 50) was performed to assess parameter sensitivity, bias and imprecision. No systematic bias was seen when comparing bootstrap means to final parameter estimates. Conclusions: The ease of implementation and reductions in run time hopefully provide a further step forward in allowing the wider use of these complex and information-rich models together with clinical data in the future.

  • 36.
    Lundqvist, Hans
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Antoni, Gunnar
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Genotoxic hazard of radiopharmaceuticals in humans: chemical and radiation aspects coupled to microdosing2007In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 63, no 7, p. 641-645Article in journal (Refereed)
    Abstract [en]

    Introduction  To obtain the pharmacokinetic properties of drug candidates at an early stage of the development process, a microdosing (phase 0) concept to radiolabel drug candidates and administer them at subtoxic mass to a few volunteers has been suggested. Radiopharmaceuticals are special in the sense that the chemical carrier might be genotoxic, whereas it is well established that ionizing radiation coupled to the molecule is genotoxic, and that the mechanism that causes cancer is similar to certain genotoxic chemicals. Regulatory perspectives of the levels of toxicity  An analysis shows that, e.g., positron emission tomography (PET) pharmaceuticals carry a mass less than what is regarded as an acceptable level of a genotoxic impurity. It has also been shown that the estimated genotoxicity hazard of the radioactivity is 10–100 times higher than that of the administered chemicals. Conclusion  As radiation doses at this level are accepted in clinical trials, the conclusion is that the regulatory demands on radiopharmaceuticals produced at high specific radioactivity should be reconsidered in order to facilitate the use of the microdosing concept for drug development.

  • 37.
    Magliulo, Laura
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Dahl, Marja-Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lombardi, Grazia
    Fallarini, Silvia
    Villa, Laura Maria
    Biolcati, Aldo
    Scordo, Maria Gabriella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Do CYP3A and ABCB1 genotypes influence the plasma concentration and clinical outcome of donepezil treatment?2011In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 67, no 1, p. 47-54Article in journal (Refereed)
    Abstract [en]

    Purpose The aim of our study was to evaluate the impact of CYP3A4, CYP3A5, and ABCB1 polymorphisms on donepezil disposition and clinical outcome. Methods Fifty-four Italian patients diagnosed with probable mild to moderate Alzheimer's disease, treated with donepezil (37 patients 5 mg/day, 17 patients 10 mg/day) were genotyped for CYP3A4 (*1B, *3, and *4), CYP3A5 (*2, *3, and *6) and ABCB1 (3435C>T, 2677G>T/A, and 1236C>T) polymorphisms. All patients were evaluated for the degree of cognitive impairment with Mini Mental State Examination (MMSE) screening test at baseline (before treatment) and after at least 3 months of donepezil treatment at stable dose, when the drug plasma levels were measured. Results Three patients carried one detrimental CYP3A4 allelic variant, and 12 carried one functional CYP3A5*1 allele. No statistically significant association was found between CYP3A4 or CYP3A5 genotypes and plasma donepezil concentrations, or between genotypes and clinical response (as measured by change in MMSE score). Nine ABCB1 haplotypes were observed, the most common being 1236C/2677G/3435C (46%) and 1236T/2677T/3435T (41%). Patients homozygous for the T/T/T haplotype had slightly though not significantly lower plasma donepezil concentration-to-dose ratios than those carrying other genotypes [median (95% CI) 0.18 (0.13-0.45) vs. 0.31 (0.30-0.44) mg/l/mg/kg, respectively]. These patients also showed a slightly better clinical response (as measured by change in MMSE score) than the other genotype groups [median (95% CI) 0 (-1.3 to 3.3) vs. -1.0 (-2.1 to 0.0), respectively]. Conclusions Our data suggest that the CYP3A4 and CYP3A5 polymorphisms are unlikely to influence donepezil metabolism and/or clinical outcome. On the other hand, the ABCB1 polymorphisms may play a role in donepezil disposition and clinical outcome.

  • 38.
    Mahteme, Haile
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Wallin, I
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Påhlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Ehrsson, Hans
    Systemic exposure of the parent drug oxaliplatin during hyperthermic intraperitoneal perfusion2008In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, European Journal of Clinical Pharmacology, Vol. 64, no 9, p. 907-911Article in journal (Refereed)
    Abstract [en]

    Objective To evaluate the perfusate and systemic kinetics of oxaliplatin during hyperthermic intraperitoneal chemotherapy (HIPEC) using a selective analytical technique. Methods HIPEC was carried out in eight patients by the open abdomen coliseum technique for 30 min at 41.5-43 degrees C with an average of 427 mg/m(2) of oxaliplatin in 5% dextrose solution. Blood and perfusate samples were collected during the perfusion. Additional blood samples were taken up to 2 h after the end of perfusion. The analysis was performed by liquid chromatography and post-column derivatization with N,N-diethyldithiocarbamate using microwave heating. Results The mean elimination half-life of oxaliplatin in the perfusate was 29.5 min (range 21.1-41.2 min) and in the peripheral circulation 24.7 min (range 21.7-27.7 min). The ratio of the areas under the time concentration curve in perfusate and blood was 12.8 +/- 2.9. Conclusion The systemic exposure of oxaliplatin measured after HIPEC using a selective analytical technique is considerably lower than previously reported results obtained by atomic absorption spectroscopy.

  • 39. Nordmark, Anna
    et al.
    Andersson, Anita
    Baranczewski, Pawel
    Läkemedelsverket, Uppsala.
    Wanag, Ewa
    Ståhle, Lars
    Assessment of interaction potential of AZD2066 using in vitro metabolism tools, physiologically based pharmacokinetic modelling and in vivo cocktail data2014In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 70, no 2, p. 167-178Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Static and dynamic (PBPK) prediction models were applied to estimate the drug-drug interaction (DDI) risk of AZD2066. The predictions were compared to the results of an in vivo cocktail study. Various in vivo measures for tolbutamide as a probe agent for cytochrome P450 2C9 (CYP2C9) were also compared.

    METHODS: In vitro inhibition data for AZD2066 were obtained using human liver microsomes and CYP-specific probe substrates. DDI prediction was performed using PBPK modelling with the SimCYP simulator™ or static model. The cocktail study was an open label, baseline, controlled interaction study with 15 healthy volunteers receiving multiple doses of AD2066 for 12 days. A cocktail of single doses of 100 mg caffeine (CYP1A2 probe), 500 mg tolbutamide (CYP2C9 probe), 20 mg omeprazole (CYP2C19 probe) and 7.5 mg midazolam (CYP3A probe) was simultaneously applied at baseline and during the administration of AZD2066. Bupropion as a CYP2B6 probe (150 mg) and 100 mg metoprolol (CYP2D6 probe) were administered on separate days. The pharmacokinetic parameters for the probe drugs and their metabolites in plasma and urinary recovery were determined.

    RESULTS: In vitro AZD2066 inhibited CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP2D6. The static model predicted in vivo interaction with predicted AUC ratio values of >1.1 for all CYP (except CYP3A4). The PBPK simulations predicted no risk for clinical relevant interactions. The cocktail study showed no interaction for the CYP2B6 and CYP2C19 enzymes, a possible weak inhibition of CYP1A2, CYP2C9 and CYP3A4 activities and a slight inhibition (29 %) of CYP2D6 activity. The tolbutamide phenotyping metrics indicated that there were significant correlations between CLform and AUCTOL, CL, Aemet and LnTOL24h. The MRAe in urine showed no correlation to CLform.

    CONCLUSIONS: DDI prediction using the static approach based on total concentration indicated that AZD20066 has a potential risk for inhibition. However, no DDI risk could be predicted when a more in vivo-like dynamic prediction method with the PBPK with SimCYP™ software based on early human PK data was used and more parameters (i.e. free fraction in plasma, no DDI risk) were taken into account. The clinical cocktail study showed no or low risks for clinical relevant DDI interactions. Our findings are in line with the hypothesis that the dynamic prediction method predicts DDI in vivo in humans better than the static model based on total plasma concentrations.

  • 40.
    Oosten, Astrid W.
    et al.
    Erasmus MC Canc Inst, Dept Med Oncol, Groene Hilledijk 301, NL-3075 EA Rotterdam, Netherlands..
    Abrantes, João A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Univ Coimbra, Fac Pharm, Dept Pharmacol, Coimbra, Portugal.;Univ Coimbra, CNC Ctr Neurosci & Cell Biol, Coimbra, Portugal..
    Jönsson, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    de Bruijn, Peter
    Erasmus MC Canc Inst, Dept Med Oncol, Groene Hilledijk 301, NL-3075 EA Rotterdam, Netherlands..
    Kuip, Evelien J. M.
    Erasmus MC Canc Inst, Dept Med Oncol, Groene Hilledijk 301, NL-3075 EA Rotterdam, Netherlands..
    Falcao, Amilcar
    Univ Coimbra, Fac Pharm, Dept Pharmacol, Coimbra, Portugal.;Univ Coimbra, CNC Ctr Neurosci & Cell Biol, Coimbra, Portugal..
    van der Rijt, Carin C. D.
    Erasmus MC Canc Inst, Dept Med Oncol, Groene Hilledijk 301, NL-3075 EA Rotterdam, Netherlands.;Netherlands Comprehens Canc Org, Utrecht, Netherlands..
    Mathijssen, Ron H. J.
    Erasmus MC Canc Inst, Dept Med Oncol, Groene Hilledijk 301, NL-3075 EA Rotterdam, Netherlands..
    Treatment with subcutaneous and transdermal fentanyl: results from a population pharmacokinetic study in cancer patients2016In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 72, no 4, p. 459-467Article in journal (Refereed)
    Abstract [en]

    Transdermal fentanyl is effective for the treatment of moderate to severe cancer-related pain but is unsuitable for fast titration. In this setting, continuous subcutaneous fentanyl may be used. As data on the pharmacokinetics of continuous subcutaneous fentanyl are lacking, we studied the pharmacokinetics of subcutaneous and transdermal fentanyl. Furthermore, we evaluated rotations from the subcutaneous to the transdermal route. Fifty-two patients treated with subcutaneous and/or transdermal fentanyl for moderate to severe cancer-related pain participated. A population pharmacokinetic model was developed and evaluated using non-linear mixed-effects modelling. For rotations from subcutaneous to transdermal fentanyl, a 1:1 dose conversion ratio was used while the subcutaneous infusion was continued for 12 h (with a 50 % tapering after 6 h). A 6-h scheme with 50 % tapering after 3 h was simulated using the final model. A one-compartment model with first-order elimination and separate first-order absorption processes for each route adequately described the data. The estimated apparent clearance of fentanyl was 49.6 L/h; the absorption rate constant for subcutaneous and transdermal fentanyl was 0.0358 and 0.0135 h(-1), respectively. Moderate to large inter-individual and inter-occasion variability was found. Around rotation from subcutaneous to transdermal fentanyl, measured and simulated plasma fentanyl concentrations rose and increasing side effects were observed. We describe the pharmacokinetics of subcutaneous and transdermal fentanyl in one patient cohort and report several findings that are relevant for clinical practice. Further research is warranted to study the optimal scheme for rotations from the subcutaneous to the transdermal route.

  • 41. Sandqvist, A. M.
    et al.
    Henrohn, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schneede, J.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Egerod, H. C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bondesson, Ulf G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Wikström, Björn G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    High inter-individual variability of vardenafil pharmacokinetics in patients with pulmonary hypertension2013In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 69, no 2, p. 197-207Article in journal (Refereed)
    Abstract [en]

    To evaluate the pharmacokinetic parameters of a single oral dose of vardenafil in patients with pulmonary hypertension (PH). Sixteen patients with PH received vardenafil in single oral doses (20, 10 or 5 mg), and repeated blood sampling for up to 9 h was performed. Vardenafil plasma concentration was determined using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were calculated using model-independent analysis. The plasma vardenafil concentration increased rapidly and exhibited a median time to maximum plasma concentration (t(max)) of 1 h and a mean elimination half-life (t(1/2)) of 3.4 h. The geometric mean and standard deviation of (1) the peak plasma concentration (C-max) was 21.4 +/- 1.7 mu g/L, (2) the normalized C-max (C-max,C- norm) 79.1 +/- 1.6 g/L, (3) the area under the time-concentration curve (AUC) 71.5 +/- 1.6 mu g center dot h/L and (4) the normalized AUC (AUC(norm)) 261.6 A +/- 1.7 g center dot h/L. Patients co-medicated with bosentan reached t(max) later and had a 90% reduction of C-max, C-max,C- norm, AUC and AUC(norm). The pharmacokinetic profile of vardenafil overall revealed considerable inter-individual variability in patients with PH. Co-medication with bosentan resulted in a pharmacokinetic drug interaction, leading to significantly decreased plasma concentrations of vardenafil. Therapeutic drug monitoring for individual dose optimization may be warranted.

  • 42.
    Sandqvist, Anna
    et al.
    Umea Univ, Div Clin Pharmacol, Dept Pharmacol & Clin Neurosci, Umea, Sweden..
    Henrohn, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Egeröd, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Natl Vet Inst SVA, Dept Chem, Uppsala, Sweden..
    Wernroth, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Natl Vet Inst SVA, Dept Chem, Uppsala, Sweden..
    Schneede, Jorn
    Umea Univ, Div Clin Pharmacol, Dept Pharmacol & Clin Neurosci, Umea, Sweden..
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Acute vasodilator response to vardenafil and clinical outcome in patients with pulmonary hypertension2015In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 71, no 10, p. 1165-1173Article in journal (Refereed)
    Abstract [en]

    Purpose Acute vasodilator testing is recommended in patients with pulmonary arterial hypertension to identify individuals who may benefit from long-term treatment with oral calcium channel blockers. The aim of this study was to investigate the use of vardenafil in acute vasoreactivity testing compared to adenosine. Methods A total of 20 patients eligible for right heart catheterisation were enrolled. Acute vasoreactivity testing was carried out with intravenous (iv) adenosine (n = 18) followed by oral vardenafil (n = 20). Haemodynamic responses were recorded at baseline and after 60 min (vardenafil). Responders were defined according to consensus guideline criteria. Results Both vardenafil and adenosine significantly decreased mean pulmonary arterial pressure (mPAP, p < 0.001 and p = 0.026, respectively) and pulmonary vascular resistance (p < 0.001 and p > 0.001, respectively), and significantly increased cardiac output (p = 0.001 and p = 0.005, respectively). Vardenafil reduced mPAP more than adenosine (p = 0.044), while adenosine resulted in higher responses of cardiac index (p = 0.009) and pulmonary arterial oxygen saturation (p = 0.042). Acute adverse reactions were common with adenosine, while no side effects were observed after a single oral dose vardenafil. Vardenafil identified five responders (out of 20), while adenosine identified three responders (out of 18). During a 7-year follow-up, vardenafil responders had significantly lower NT-proBNP levels compared to non-responders. Conclusions Vardenafil may be safely used for acute vasoreactivity testing in patients with PH. A single oral dose of vardenafil is better tolerated than iv adenosine and may identify additional responders who could benefit from long-term vasodilator treatment.

  • 43. Sauermann, Robert
    et al.
    Feurstein, Thomas
    Karch, Rudolf
    Kjellsson, Maria C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jäger, Walter
    Böhmdorfer, Michaela
    Püspök, Andreas
    Langenberger, Herbert
    Wild, Thomas
    Winkler, Stefan
    Zeitlinger, Markus
    Abscess penetration of cefpirome: concentrations and simulated pharmacokinetic profiles in pus2012In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 68, no 10, p. 1419-1423Article in journal (Refereed)
    Abstract [en]

    PURPOSE

    Abscess patients frequently receive antibiotic therapy when incision cannot be performed or in addition to incision. However, antibiotic concentrations in human abscesses are widely unknown.

    METHODS

    Pharmacokinetics of cefpirome in 12 human abscesses located in different body regions was studied. Cefpirome (2 g) was administered as an intravenous short infusion, and concentrations were measured in plasma over an 8-h period and in abscesses at incision. A pharmacokinetic two-stage model was applied.

    RESULTS

    At abscess incision performed 158 ± 112 min after the start of the infusion, the cefpirome concentrations in the abscess fluid varied markedly, ranging from ≤0.1 (limit of quantification) to 47 (mean 8.4 ± 14.1 ) mg/L. Cefpirome was detectable in nine of 12 abscesses. Maximum concentrations were calculated to be 183 ± 106 mg/L in plasma and 12 ± 16 mg/L in the abscess. A cefpirome concentration of 2 mg/L, which is the minimum concentration inhibiting growth of 90% of the most relevant bacterial pathogens, was exceeded spontaneously in six of 12 abscesses after a single dose. Cefpirome concentrations in the abscess did not correlate with either the pH or the ratio of surface area to volume of the abscesses, nor with plasma pharmacokinetics.

    CONCLUSIONS

    Cefpirome may be useful to treat abscess patients because it was detectable in most abscesses after a single dose. However, the penetration of cefpirome into abscesses is extremely variable and cannot be predicted by measuring other available covariates.

  • 44. Schwan, Sofie
    et al.
    Sundström, Anders
    Stjernberg, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Hallberg, Ebba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    A signal for an abuse liability for pregabalin-results from the Swedish spontaneous adverse drug reaction reporting system2010In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 66, no 9, p. 947-953Article in journal (Refereed)
    Abstract [en]

    Pregabalin is a gamma-aminobutyric acid (GABA) analogue approved for the treatment of epilepsy, neuropathic pain and generalised anxiety disorder. As a GABA analogue, there has been some concern about an abuse liability. We aimed to investigate the possible abuse liability of pregabalin. By applying a Bayesian data-mining algorithm to reports of possible drug abuse or addiction in the Swedish national register of adverse drug reactions (SWEDIS), we calculated the information component (IC) for pregabalin and reports of abuse and addiction. Out of 198 reports indicative of abuse or addiction to any drug, 16 concerned pregabalin. The IC became significantly elevated in the fourth quarter of 2008, rising to 3.99 (95% confidence interval 3.21-4.59) at the end of 2009. Based on the signal from the present study, we conclude that pregabalin is likely to be associated with an abuse potential.

  • 45.
    Senek, Marina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Aquilonius, Sten-Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Bergquist, Filip
    Constantinescu, Radu
    Ericsson, Anders
    Lycke, Sara
    Medvedev, Alexander
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Systems and Control. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Automatic control.
    Memedi, Mevludin
    Ohlsson, Fredrik
    Spira, Jack
    Westin, Jerker
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Levodopa/carbidopa microtablets in Parkinson’s disease: A study of pharmacokinetics and blinded motor assessment2017In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 73, no 5, p. 563-571Article in journal (Refereed)
  • 46.
    Senek, Marina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Population pharmacokinetics of levodopa/carbidopa microtablets in healthy subjects and Parkinson’s disease patients2018In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 74, no 10, p. 1299-1307Article in journal (Refereed)
    Abstract [en]

    Objectives: Low dose, dispersible, levodopa/carbidopa microtablets with an automatic dose dispenser have been developed to facilitate individualized levodopa treatment. The aim of this study was to characterize the pharmacokinetics (PK) of levodopa and carbidopa after microtablet administration, and evaluate the impact of potential covariates.

    Methods: The population PK analysis involved data from 18 healthy subjects and 18 Parkinson's disease patients included in two single-dose, open-label levodopa/carbidopa microtablet studies. The analysis was carried out using non-linear mixed effects modeling. Bodyweight was included on all disposition parameters according to allometric scaling. Potential influence of additional covariates was investigated using graphical evaluation and adjusted adaptive least absolute shrinkage and selection operator.

    Results: Dispositions of levodopa and carbidopa were best described by a two- and one-compartment model respectively. Double-peak profiles were described using two parallel absorption compartments. Levodopa apparent clearance was found to decrease with increasing carbidopa dose (15% lower with 75 compared to 50mg of carbidopa) and disease stage (by 18% for Hoehn and Yahr 1 to 4). Carbidopa apparent clearance was found to decrease with age (28% between the age of 60 and 80years). An external evaluation showed the model to be able to reasonably well predict levodopa concentrations following multiple-dose microtablet administration in healthy subjects.

    Conclusions: The presented models adequately described the PK of levodopa and carbidopa, following microtablet administration. The developed model may in the future be combined with a pharmacokinetic-pharmacodynamic target and used for individualized dose selection, utilizing the flexibility offered by the microtablets.

  • 47. Sherwin, Catherine M. T.
    et al.
    Svahn, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Van Der Linden, Antje
    Broadbent, S
    Medlicott, J
    Reith, David M.
    Individualised dosing of amikacin in neonates: a pharmacokinetic/pharmacodynamic analysis2009In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 65, no 7, p. 705-713Article in journal (Refereed)
    Abstract [en]

    To examine the pharmacokinetics of amikacin and its pharmacokinetic pharmacodynamic (PKPD) relationship in neonates. To develop an alternative dosing strategy for amikacin in neonates. A population PKPD analysis was performed using data collected from 80 neonates with gestational ages from 24 to 41 weeks. The final pharmacokinetic model analysed 358 amikacin concentrations. All neonates were > 72 hours postnatal age. Simulations were performed to develop a new dosing strategy. The final covariate model was clearance = 0.23 x (current weight/2)(0.691) x (postmenstrual age/40)(3.23) and volume of distribution = 0.957 x (current weight/2)(0.89). Following the logistic regression analysis of treatment failure, new amikacin target concentrations were estimated and used in development of an alternative dosing strategy. Simulation of a new dosing regimen yielded the following recommendations: 15 mg/kg at 36-h intervals, 14 mg/kg at 24-h intervals and 15 mg/kg at 24-h intervals for neonates a parts per thousand currency sign28 weeks, 29-36 weeks and a parts per thousand yen37 weeks postmenstrual age respectively.

  • 48. Siponen, Sanna M.
    et al.
    Ahonen, Riitta S.
    Kettis, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hameen-Anttila, Katri P.
    Complementary or alternative?: Patterns of complementary and alternative medicine (CAM) use among Finnish children2012In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 68, no 12, p. 1639-1645Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to measure patterns of complementary and alternative medicine (CAM) use among Finnish children and to explore whether CAM use among children is mainly complementary or alternative. We carried out a cross-sectional population-based survey in spring 2007. The study population consisted of a representative sample (n = 6,000) of Finnish children under 12 years of age. A questionnaire was sent to their parents, and 4,032 questionnaires were returned (response rate 67 %). Pearson's chi-square test and logistic regression analysis were conducted to measure factors associated with CAM use. The prevalence of CAM use among children was 11 %. Fish oils and fatty acids (6 %) followed by probiotics (4 %) were the most commonly reported CAMs used. Being the first born, using vitamins and having at least one symptom predicted the use of CAMs. Parental use of vitamins and CAMs were also associated with CAM use among children. In the preceding 2 days, 3 % of children in the study had used only CAMs, and 7 % had used a CAM concomitantly with prescribed and/or over-the-counter medicines. Our results indicate that the use of CAMs among Finnish children is mainly for improving health and alleviating symptoms, especially in families where at least one parent also uses these modalities. CAMs were mainly used as complementary rather than as an alternative to conventional care. Healthcare professionals should be aware of this complementary use of CAMs and medicines in patients to avoid risks of potential interactions.

  • 49. Strandell, Johanna
    et al.
    Wahlin, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pharmacodynamic and pharmacokinetic drug interactions reported to VigiBase, the WHO global individual case safety report database2011In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 67, no 6, p. 633-641Article in journal (Refereed)
    Abstract [en]

    Objective Drug interactions resulting in adverse drug reactions (ADRs) represent a major health problem both for individuals and the community. Despite this, limited information is reported in the literature on the drug interaction categories responsible for causing ADRs. In the study reported here, we investigated the drug combinations most frequently co-reported as interacting in the WHO Global Individual Case Safety Report (ICSR) database, VigiBase, and categorised these according to the drug interaction mechanism. Methods Reports in which drug combinations were co-reported as interacting in at least 20 reports in VigiBase during the past 20 years were included in the study. Each drug combination was reviewed in the literature to identify the mechanism of interaction and subsequently classified as pharmacodynamic and/or pharmacokinetic reaction. Report characteristics were also analysed. Results A total of 3766 case reports of drug interactions from 47 countries were identified. Of the 123 different drug combinations reported, 113 were described in the literature to interact. The mechanism of the drug interaction was categorised as pharmacodynamic (46 combinations; 41%), pharmacokinetic (28; 25%), a combination of both types (18; 16%) and unidentified (21; 19%). Pharmacodynamic drug interactions primarily concerned pharmacological additive effects, whereas enzyme inhibition was the most frequent pharmacokinetic interaction. The combinations reviewed primarily implicated drugs such as warfarin, heparin, carbamazepine and digoxin. Conclusions Drug interactions reported in globally collected ADR reports cover both pharmacodynamic, specifically additive pharmacological effects, and pharmacokinetic mechanisms primarily accredited to the inhibition of hepatic cytochrome P450 enzymes. These ADR reports often concern serious threats to patients' safety and are particularly related to the use of high risk drugs such as warfarin and heparin.

  • 50.
    Svensson, Ulrika S H
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Alin, Hassan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bergqvist, Yngve
    Ashton, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Population pharmacokinetic and pharmacodynamic modelling of artemisinin and mefloquine enantiomers in patients with falciparum malaria.2002In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 58, no 5, p. 339-351Article in journal (Refereed)
    Abstract [en]

     Objectives: The aims of this study were to investigate whether artemisinin influences the pharmacokinetics of mefloquine enantiomers or vice versa and to model the antiparasitic effect of these drugs alone and in combination in Plasmodium falciparum malaria patients. Methods: Forty-two male and female patients., were randomised to treatment with either oral artemisinin 500 mg daily for 3 days followed by oral mefloquine 750 mg on day 4, oral artemisinin 5,00 mg daily for 3 days plus oral mefloquine 750 mg on day 1 or a single 750-mg oral dose of mefloquine. The data was modelled using NONMEM. Results: All patients were successfully treated regardless of treatment. The fastest parasite clearance rates were observed in patients receiving artemisinin together with mefloquine on the first day of treatment. Apharmacodynamic model based on the life cycle of P. falciparum successfully described the efficacy ofartemisinin, me floquine and the combination. The time artemisinin concentration stays above a minimum inhibitory concentration was estimated to 2.97 h (relative standard error 4.7 h). The two mefloquineenantiomers exhibited different pharmacokinetics, with an oral clearance of 3.51 (7.9) l/h and 0.602 (6.9) l/h for RS-mefloquine and SRL mefloquine, respectively. In patients receiving only artemisinin the first 3 days,artemisinin oral clearance was 6.9-fold higher the last day of treatment compared with the first day. There was no difference in the pharmacokinetics of mefloquine enantiomers when mefloquine was given alone, incombination with artemisinin or after a 3-day regimen of artemisinin. There was a tendency towards, although non-significant, higher artemisinin concentrations when artemisinin was given together with mefloquinecompared with when given alone. Conclusions: No significant pharmacokinetic interactions were observed after co-administration of artemisininand mefloquine. The P. falciparum malaria pharmacodynamic model successfully described the antimalarial effect of artemisinin, mefloquine and a combination of the two drugs.

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