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Elucidation of Factor VIII Activity Pharmacokinetics: A Pooled Population Analysis in Patients With Hemophilia A Treated With Moroctocog Alfa
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden..
Pfizer Inc, Collegeville, PA USA..
Pfizer Ltd, Global Clin Pharmacol, Sandwich, Kent, England..
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2017 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 102, no 6, p. 977-988Article in journal (Refereed) Published
Abstract [en]

This study investigated the disposition of coagulation factor VIII activity in 754 patients with moderate to severe hemophilia A following the administration of moroctocog alfa, a B-domain deleted recombinant factor VIII. Data analyzed included patients aged 1 day to 73 years enrolled in 13 studies conducted over a period of 20 years in 25 countries. A two-compartment population pharmacokinetic model with a baseline model described the pooled data well. Body size, age, inhibitors, race, and analytical assay were identified as significant predictors of factor VIII disposition. In addition, simulations of prophylactic dosing schedules in several pediatric cohorts showed large variability and suggest that younger patients would require higher weight-adjusted doses than adolescents to achieve target factor VIII trough activity when receiving every other day or twice weekly dosing.

Place, publisher, year, edition, pages
2017. Vol. 102, no 6, p. 977-988
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-342208DOI: 10.1002/cpt.716ISI: 000414921800026PubMedID: 28437834OAI: oai:DiVA.org:uu-342208DiVA, id: diva2:1183987
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2019-04-05Bibliographically approved
In thesis
1. Pharmacometric Approaches to Improve Dose Individualization Methods in Hemophilia A
Open this publication in new window or tab >>Pharmacometric Approaches to Improve Dose Individualization Methods in Hemophilia A
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hemophilia A is a bleeding disorder caused by the lack of functional coagulation factor VIII (FVIII). The overall aim of this thesis was to improve dose individualization of FVIII replacement therapy in hemophilia A using pharmacometric approaches.

A population pharmacokinetic (PK) model of FVIII activity following the administration of moroctocog alfa was developed based on data from a large heterogeneous cohort of moderate to severe hemophilia A patients. Body weight, age, neutralizing anti-FVIII inhibitors, race, and analytical assay were found to be significant predictors of FVIII activity PK. In addition, large inter-individual variability (IIV) and inter-occasion variability (IOV) was identified highlighting the need for dose individualization.

High magnitudes of IOV are known to impair model-based therapeutic drug monitoring. Using a population PK model of FVIII activity, several approaches to handle IOV in Bayesian forecasting of individual PK parameters were assessed across a wide range of features. Considering IOV in Bayesian forecasting, but ignoring IOV in dose calculation, led to the most precise individualized doses, in particular, when sparse data was used.

The dose-exposure-response relationship of FVIII replacement therapy remains unclear. A parametric repeated time-to-categorical event (RTTCE) model was developed to characterize the relationship between the dose of octocog alfa, plasma FVIII activity, bleeding frequency and severity, and covariates, using data from clinical trials. The bleeding hazard was found to decrease throughout time and to be affected by plasma FVIII activity and number of previous bleeds. Unexplained IIV in the bleeding hazard was found to be large.

Bayesian forecasting based on the RTTCE model was used to predict the future occurrence of bleeds, and to contrast the predicted outcome using individual i) PK, ii) bleeding, and iii) PK, bleeding and covariate information, from data collected in clinical trials. The results support that individual bleed information can inform the optimization of prophylactic dosing regimens in severe hemophilia A patients.

In summary, the pharmacometric approaches presented provide a valuable quantitative framework to improve dose individualization in hemophilia A. Furthermore, enhanced dosing has the potential to reduce bleeding frequency and to lower the high costs associated to treatment.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 70
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 270
Keywords
Bayesian forecasting, coagulation factor VIII, dose adaptation, hemophilia/haemophilia A, inter-occasion variability, NONMEM, pharmacodynamics, pharmacokinetics, pharmacometrics, therapeutic drug monitoring
National Category
Health Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-381218 (URN)978-91-513-0631-5 (ISBN)
Public defence
2019-05-29, B41, Biomedicinskt centrum, Husargatan 3, 09:15 (English)
Opponent
Supervisors
Available from: 2019-05-06 Created: 2019-04-05 Last updated: 2019-06-17

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Abrantes, João A.Nielsen, Elisabet I.Jönsson, Siv

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