Pharmacogenomics and Personalized Medicine (Mar 2023)
Current Understanding of Inherited Modifiers of FVIII Pharmacokinetic Variation
Abstract
Laura L Swystun, David Lillicrap Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON, CanadaCorrespondence: David Lillicrap, Richardson Laboratory, Queen’s University, 88 Stuart Street, Kingston, Ontario, K7L 3N6, Canada, Tel +1 613 548-1304, Fax +1 613 548-1356, Email [email protected]: The inherited bleeding disorder hemophilia A involves the quantitative deficiency of the coagulation cofactor factor VIII (FVIII). Prophylactic treatment of severe hemophilia A patients with FVIII concentrates aims to reduce the frequency of spontaneous joint bleeding and requires personalized tailoring of dosing regimens to account for the substantial inter-individual variability of FVIII pharmacokinetics. The strong reproducibility of FVIII pharmacokinetic (PK) metrics between repeat analyses in the same individual suggests this trait is genetically regulated. While the influence of plasma von Willebrand factor antigen (VWF:Ag) levels, ABO blood group, and patient age on FVIII PK is well established, estimates suggest these factors account for less than 35% of the overall variability in FVIII PK. More recent studies have identified genetic determinants that modify FVIII clearance or half-life including VWF gene variants that impair VWF-FVIII binding resulting in the accelerated clearance of VWF-free FVIII. Additionally, variants in receptors that regulate the clearance of FVIII or the VWF-FVIII complex have been associated with FVIII PK. The characterization of genetic modifiers of FVIII PK will provide mechanistic insight into a subject of clinical significance and support the development of personalized treatment plans for patients with hemophilia A.Keywords: factor VIII, hemophilia A, von Willebrand factor, pharmacokinetics, clearance receptor
