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Björkman, S
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Publications (10 of 18) Show all publications
Lindqvist, A., Rip, J., Gaillard, P. J., Björkman, S. & Hammarlund-Udenaes, M. (2013). Enhanced Brain Delivery of the Opioid Peptide DAMGO in Glutathione PEGylated Liposomes: A Microdialysis Study. Molecular Pharmaceutics, 10(5), 1533-1541
Open this publication in new window or tab >>Enhanced Brain Delivery of the Opioid Peptide DAMGO in Glutathione PEGylated Liposomes: A Microdialysis Study
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2013 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 10, no 5, p. 1533-1541Article in journal (Refereed) Published
Abstract [en]

Glutathione PEGylated (GSH-PEG) liposomes were evaluated for their ability to enhance and prolong blood-to-brain drug delivery of the opioid peptide DAMGO (H-Tyr-d-Ala-Gly-MePhe-Gly-ol). An intravenous loading dose of DAMGO followed by a 2 h constant rate infusion was administered to rats, and after a washout period of 1 h, GSH-PEG liposomal DAMGO was administered using a similar dosing regimen. DAMGO and GSH-PEG liposomal DAMGO were also administered as a 10 min infusion to compare the disposition of the two formulations. Microdialysis made it possible to determine free DAMGO in brain and plasma, while the GSH-PEG liposomal encapsulated DAMGO was measured with regular plasma sampling. The antinociceptive effect of DAMGO was determined with the tail-flick method. All samples were analyzed using liquid chromatography–tandem mass spectrometry. The short infusion of DAMGO resulted in a fast decline of the peptide concentration in plasma with a half-life of 9.2 ± 2.1 min. Encapsulation in GSH-PEG liposomes prolonged the half-life to 6.9 ± 2.3 h. Free DAMGO entered the brain to a limited extent with a steady state ratio between unbound drug concentrations in brain interstitial fluid and in blood (Kp,uu) of 0.09 ± 0.04. GSH-PEG liposomes significantly increased the brain exposure of DAMGO to a Kp,uu of 0.21 ± 0.17 (p < 0.05). By monitoring the released, active substance in both blood and brain interstitial fluid over time, we were able to demonstrate that GSH-PEG liposomes offer a promising platform for enhancing and prolonging the delivery of drugs to the brain.

Keywords
drug delivery, nanocarrier, liposomes, blood-brain barrier, microdialysis, pharmacokinetics, antinociception, opioid peptide
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-191593 (URN)10.1021/mp300272a (DOI)000318669600007 ()22934681 (PubMedID)
Available from: 2013-01-10 Created: 2013-01-10 Last updated: 2018-01-11Bibliographically approved
Björkman, S. (2013). Pharmacokinetics of PDFIX and RFIX concentrates - implications for prophylaxis and on-demand therapy. Paper presented at 6th Annual Congress of the European Association for Haemophilia and Allied Disorders; 6-8 Feb 2013; Warwaw, Poland. Haemophilia, 19(S2), 7-7
Open this publication in new window or tab >>Pharmacokinetics of PDFIX and RFIX concentrates - implications for prophylaxis and on-demand therapy
2013 (English)In: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 19, no S2, p. 7-7Article in journal, Meeting abstract (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-196889 (URN)000314828400008 ()
Conference
6th Annual Congress of the European Association for Haemophilia and Allied Disorders; 6-8 Feb 2013; Warwaw, Poland
Available from: 2013-03-14 Created: 2013-03-14 Last updated: 2017-12-06Bibliographically approved
Lindvall, K., Astermark, J., Björkman, S., Ljung, R., Carlsson, K. S., Persson, S. & Berntorp, E. (2012). Daily dosing prophylaxis for haemophilia: A randomized crossover pilot study evaluating feasibility and efficacy. Haemophilia, 18(6), 855-859
Open this publication in new window or tab >>Daily dosing prophylaxis for haemophilia: A randomized crossover pilot study evaluating feasibility and efficacy
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2012 (English)In: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 18, no 6, p. 855-859Article in journal (Refereed) Published
Abstract [en]

Regular replacement therapy (prophylaxis) for haemophilia has been shown to prevent development of disabling arthropathy and to provide a better quality of life compared to treatment on demand; however, at a substantially higher cost. Calculations based on pharmacokinetic principles have shown that shortening dose intervals may reduce cost. The aim of this prospective, randomized, crossover pilot study was to address whether daily dosing is feasible, if it reduces concentrate consumption and is as effective in preventing bleeding as the standard prophylactic dosing regimen. In a 12 + 12 month crossover study, 13 patients were randomized to start either their own previously prescribed standard dose, or daily dosing adjusted to maintain at least the same trough levels as obtained with the standard dose. Ten patients completed the study. A 30% reduction in cost of factor concentrates was achieved with daily prophylaxis. However, the number of bleeding events increased in some patients in the daily dosing arm and patients reported decreased quality of life during daily prophylaxis. Daily treatment had a greater impact on daily life, and the patients found it more stressful.Prophylaxis with daily dosing may be feasible and efficacious in some patients. A substantial reduction of factor consumption and costs can be realized, but larger studies are needed before the introduction of daily prophylaxis into clinical routine can be recommended.

Keywords
Factor VIII/IX, Haemophilia, Prophylaxis, QoL
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-184943 (URN)10.1111/j.1365-2516.2012.02879.x (DOI)000310553600018 ()
Available from: 2012-11-19 Created: 2012-11-15 Last updated: 2017-12-07Bibliographically approved
Björkman, S. & Åhlén, V. (2012). Population pharmacokinetics of plasma-derived factor IX in adult patients with haemophilia B: implications for dosing in prophylaxis. European Journal of Clinical Pharmacology, 68(6), 969-977
Open this publication in new window or tab >>Population pharmacokinetics of plasma-derived factor IX in adult patients with haemophilia B: implications for dosing in prophylaxis
2012 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 68, no 6, p. 969-977Article in journal (Refereed) Published
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.

Keywords
Factor IX, Haemophilia B, Pharmacokinetics, Dosing, Prophylaxis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-175595 (URN)10.1007/s00228-012-1211-z (DOI)000304141800008 ()
Available from: 2012-06-13 Created: 2012-06-11 Last updated: 2017-12-07Bibliographically approved
Björkman, S., Oh, M., Spotts, G., Schroth, P., Fritsch, S., Ewenstein, B. M., . . . Collins, P. W. (2012). Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight. Blood, 119(2), 612-618
Open this publication in new window or tab >>Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight
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2012 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 119, no 2, p. 612-618Article in journal (Refereed) Published
Abstract [en]

Comparison of the pharmacokinetics (PK) of a coagulation factor between groups of patients can be biased by differences in study protocols, in particular between blood sampling schedules. This could affect clinical dose tailoring, especially in children. The aim of this study was to describe the relationships of the PK of factor VIII (FVIII) with age and body weight by a population PK model. The potential to reduce blood sampling was also explored. A model was built for FVIII PK from 236 infusions of recombinant FVIII in 152 patients (1-65 years of age) with severe hemophilia A. The PK of FVIII over the entire age range was well described by a 2-compartment model and a previously reported problem, resulting from differences in blood sampling, to compare findings from children and adults was practically abolished. The decline in FVIII clearance and increase in half-life with age could be described as continuous functions. Retrospective reduction of blood sampling from 11 to 5 samples made no important difference to the estimates of PK parameters. The obtained findings can be used as a basis for PK-based dose tailoring of FVIII in clinical practice, in all age groups, with minimal blood sampling.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-168588 (URN)10.1182/blood-2011-07-360594 (DOI)000299268900041 ()
Available from: 2012-02-14 Created: 2012-02-13 Last updated: 2017-12-07Bibliographically approved
Sadiq, M. W., Borgs, A., Okura, T., Shimomura, K., Kato, S., Deguchi, Y., . . . Hammarlund-Udenaes, M. (2011). Diphenhydramine Active Uptake at the Blood-Brain Barrier and Its Interaction with Oxycodone in Vitro and in Vivo. Journal of Pharmaceutical Sciences, 100(9), 3912-3923
Open this publication in new window or tab >>Diphenhydramine Active Uptake at the Blood-Brain Barrier and Its Interaction with Oxycodone in Vitro and in Vivo
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2011 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 100, no 9, p. 3912-3923Article in journal (Refereed) Published
Abstract [en]

Diphenhydramine (DPHM) and oxycodone are weak bases that are able to form cations. Both drugs show active uptake at the blood-brain barrier (BBB). There is thus a possibility for a pharmacokinetic interaction between them by competition for the same uptake transport system. The experiments of the present study were designed to study the transport of DPHM across the BBB and its interaction with oxycodone in vitro and in vivo. In vitro, the interaction between the drugs was studied using conditionally immortalized rat brain capillary endothelial cells (TR-BBB13 cells). The in vivo relevance of the in vitro findings was studied in rats using brain and blood microdialysis. DPHM was actively transported across the BBB in vitro (TR-BBB13 cells). Oxycodone competitively inhibited DPHM uptake with a K(i) value of 106 mu M. DPHM also competitively inhibited oxycodone uptake with a K(i) value of 34.7 mu M. In rats, DPHM showed fivefold higher unbound concentration in brain interstitial fluid (ISF) than in blood, confirming a net active uptake. There was no significant interaction between DPHM and oxycodone in vivo. This accords with the results of the in vitro experiments because the unbound plasma concentrations that could be attained in vivo, without causing adverse effects, were far below the Ki values.

Keywords
blood-brain barrier, drug interactions, organic cation transporters (OCTs), pharmacokinetics, active transport, HPLC (high-performance/pressure liquid chromatography), mass spectrometry
National Category
Medical and Health Sciences Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-159250 (URN)10.1002/jps.22567 (DOI)000294666600030 ()
Available from: 2011-09-26 Created: 2011-09-26 Last updated: 2018-01-12Bibliographically approved
Björkman, S., Blanchette, V. S., Fischer, K., Oh, M., Spotts, G., Schroth, P., . . . Collins, P. W. (2010). Comparative pharmacokinetics of plasma- and albumin-free recombinant factor VIII in children and adults: the influence of blood sampling schedule on observed age-related differences and implications for dose tailoring. Journal of Thrombosis and Haemostasis, 8(4), 730-736
Open this publication in new window or tab >>Comparative pharmacokinetics of plasma- and albumin-free recombinant factor VIII in children and adults: the influence of blood sampling schedule on observed age-related differences and implications for dose tailoring
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2010 (English)In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 8, no 4, p. 730-736Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Dose tailoring of coagulation factors requires reliably estimated and reproducible pharmacokinetics (PK) in the individual patient. OBJECTIVES: To investigate the contribution of both biological and methodological factors to the observed variability of factor VIII (FVIII) PK, with the focus on differences between children and adults, and to examine the implications for dosing. PATIENTS: Data from 52 1-6-year-old and 100 10-65-year-old patients with hemophilia A (FVIII < or = 2 IU dL(-1)) in three clinical studies were included. RESULTS: In vivo recovery was lower, weight-adjusted clearance was higher and FVIII half-life was on average shorter in children than in adults. However, a reduced blood sampling schedule for children was estimated to account for up to one half of the total observed differences. Intrapatient variance in PK was smaller than interpatient variance in 10-65-year-olds. Age and ratio of actual to ideal weight only showed weak relationships with PK parameters. Variance in PK caused large variance in the calculated dose required to maintain a target FVIII trough level during prophylactic treatment. CONCLUSION: Differences in blood sampling schedules should be taken into account when results from different PK studies are compared. However, even with this consideration, PK cannot be predicted from observable patient characteristics but must be determined for the individual. Because the influence of reducing the blood sampling was minor in comparison to the true variance between patients, a reduced blood sampling protocol can be used. Low intrapatient variability supports the use of PK measurements for dose tailoring of FVIII.

Keywords
factor VIII, hemophilia A, pharmacokinetics
National Category
Pharmaceutical Sciences Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-123012 (URN)10.1111/j.1538-7836.2010.03757.x (DOI)000275922500017 ()20398185 (PubMedID)
Available from: 2010-04-22 Created: 2010-04-22 Last updated: 2018-01-12Bibliographically approved
Collins, P. W., Björkman, S., Fischer, K., Blanchette, V., Oh, M., Schroth, P., . . . Ewenstein, B. M. (2010). Factor VIII requirement to maintain a target plasma level in the prophylactic treatment of severe hemophilia A: influences of variance in pharmacokinetics and treatment regimens. Journal of Thrombosis and Haemostasis, 8(2), 269-275
Open this publication in new window or tab >>Factor VIII requirement to maintain a target plasma level in the prophylactic treatment of severe hemophilia A: influences of variance in pharmacokinetics and treatment regimens
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2010 (English)In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 8, no 2, p. 269-275Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Prophylactic factor (F)VIII has been shown to reduce bleeds and arthropathy in patients with severe hemophilia A. OBJECTIVES: Assuming that the trough FVIII level is an important determinant of the efficacy of prophylaxis, this paper addresses the effect of the inter-patient variability in pharmacokinetics and different dosing regimens on trough levels. METHODS: Simulations used FVIII half-lives and in vivo recoveries (IVR), observed during clinical trials with Advate [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method], and commonly used prophylactic regimens to calculate their effect on FVIII levels during prophylaxis. RESULTS AND CONCLUSIONS: Half-life and dose frequency had a larger effect on trough FVIII and time per week with FVIII<1 IU dL(-1) than IVR and infused dose per kg. The combined effect of these parameters resulted in substantial inter-patient variability in the amount of FVIII required to sustain a desired trough level. Prophylactic regimens based on Monday, Wednesday, Friday dosing were less cost effective in maintaining a desired trough level throughout the week. Dose escalation on Friday to cover the weekend would require potentially harmful doses of FVIII in many patients, especially in young children where more than 50% would require a Friday dose of over 100 IU kg(-1) and some would require more than 400 IU kg(-1). Knowledge of individual patients' half-lives and alteration of frequency of infusions may allow the more cost-effective use of FVIII and potentially expand access to prophylaxis to a greater number of patients, especially in regions where healthcare resources are scarce.

Place, publisher, year, edition, pages
International Society on Thrombosis and Haemostasis, 2010
National Category
Pharmaceutical Sciences Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-123015 (URN)10.1111/j.1538-7836.2009.03703.x (DOI)000273687600009 ()19943875 (PubMedID)
Available from: 2010-04-22 Created: 2010-04-22 Last updated: 2018-01-12Bibliographically approved
Collins, P. W., Blanchette, V. S., Fischer, K., Björkman, S., Oh, M., Fritsch, S., . . . Ewenstein, B. (2009). Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A. Journal of Thrombosis and Haemostasis, 7(3), 413-420
Open this publication in new window or tab >>Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A
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2009 (English)In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 7, no 3, p. 413-420Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The role of prophylactic factor VIII (FVIII) to decrease hemophilic bleeding and arthropathy is well established. The rationale for this strategy is to convert patients with severe hemophilia A to a moderate clinical phenotype by reducing time spent with a FVIII level <1 IU dL(-1). Studies to date, however, have not demonstrated a strong link between FVIII level and the bleeding rate. OBJECTIVES: To assess the effect of FVIII level on break-through bleeding in patients with severe hemophilia A on prophylaxis. PATIENTS/METHODS: This study analysed data from 44 patients aged 1-6 and 99 patients aged 10-65 years with severe hemophilia A (FVIII <1 IU dL(-1)) who were treated with prophylactic FVIII as part of clinical studies assessing pharmacokinetics, safety and efficacy of a recombinant FVIII (Advate). Each patient had pharmacokinetic measurements and FVIII infusions recorded, and these were used to calculate time spent with a FVIII below 1, 2 and 5 IU dL(-1). RESULTS: The data demonstrate that increasing time with a FVIII below 1 IU dL(-1) is associated with increased total bleeds and hemarthroses. Lack of adherence to the intended frequency of FVIII infusion was the most important determinant of low FVIII and increased bleeding. In children aged 1-6 years, the rate of bleeding was also influenced by FVIII half-life and clearance. Conclusions: These data have important implications for the management of patients with severe hemophilia.

Keywords
bleeding, factor VIII, hemophilia A, pharmacokinetics, prophylaxis
National Category
Pharmaceutical Sciences Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-123016 (URN)10.1111/j.1538-7836.2008.03270.x (DOI)000263256100006 ()19143924 (PubMedID)
Available from: 2010-04-22 Created: 2010-04-22 Last updated: 2018-01-12Bibliographically approved
Björkman, S. E., Folkesson, A. & Berntorp, E. (2007). In vivo recovery of factor VIII and factor IX: intra- and interindividual variance in a clinical setting. Haemophilia, 13(1), 2-8
Open this publication in new window or tab >>In vivo recovery of factor VIII and factor IX: intra- and interindividual variance in a clinical setting
2007 (English)In: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 13, no 1, p. 2-8Article in journal (Refereed) Published
Abstract [en]

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

Keywords
dosing, factor VIII, factor IX, in vivo recovery, pharmacokinetics, variance
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-23493 (URN)10.1111/j.1365-2516.2006.01401.x (DOI)000243982900002 ()17212717 (PubMedID)
Available from: 2007-01-29 Created: 2007-01-29 Last updated: 2018-01-12Bibliographically approved
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