The use of pharmacokinetics in dose individualization of factor VIII in the treatment of hemophilia A

ABSTRACT

Introduction: Hemophilia A is a bleeding disorder resulting from a lack of clotting factor VIII (FVIII), and treatment typically consists of prophylactic replacement of the deficient factor. However, high between subject variability precludes the development of a ‘one size fits all’ dosing strategy and necessitates an individualized approach. We sought to summarize the data on the pharmacokinetics of FVIII available as a basis for the development of population pharmacokinetic models to be used in dose tailoring.

Areas covered: We reviewed the pharmacokinetics of FVIII as used for the treatment of hemophilia A, with a focus on the variability observed between patients and the application of pharmacokinetic methods to dose individualization. We also explored the covariates affecting pharmacokinetic parameters, the differences between plasma-derived and recombinant FVIII and the development of extended half-life products.

Expert opinion: The pharmacokinetics of factor VIII in patients with hemophilia shows a high interpatient variability, and is affected by age, weight, level of von Willebrand factor, and blood group. A population approach to estimating individual pharmacokinetics is likely to provide the most successful strategy to tailor factor concentrate dosing to the individual needs and to ensure optimal patient outcomes, while also improving the cost-effectiveness of prophylactic replacement therapy.

KEYWORDS:

• Dose individualization
• factor VIII
• haemophilia A
• population pharmacokinetics

Article highlights

• High between subject variability in haemophilia A patients precludes the development of a ‘one size fits all’ dosing strategy and necessitates an individualized approach.

• PopPK can be used to identify sources of variability in PK response, and to produce estimates for individual PK parameters from only a few patient samples, providing safer and more cost-effective treatment.

• Age, ideal body weight, blood type, and levels of vWF are important patient characteristics in the parameterization of PopPK models for FVIII; the source of the factor concentrate (recombinant or plasma-derived) does not impact PK.

• For a truly individualized approach, other factors such as inhibitor development and disease phenotype must also be considered.

This box summarizes key points contained in the article.

Declaration of interest

A Iorio is PI of the WAPPS project and has received research and consultancy funds from Bayer, Baxalta, Biogen, NovoNordisk and Pfizer. All funds were granted to McMaster University and no funds were received for this manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

The Web-Accessible Population Pharmacokinetic Service (WAPPS) was funded by the B-CHERP (Baxter - Canadian Hemophilia Epidemiology Research Project) peer review grant opportunity for the years 2013-2015. B-CHERP is a grant opportunity offered by the Canadian Hemophilia Society, which handles the peer-review process in full independence from the funder.