Multi-variate analysis of factors governing the pharmacokinetics of exogenous factor VIII in haemophiliacs

Abstract

The pharmacokinetics of Factor VIII was evaluated by mathematical modeling in a large-scale study in 62 haemophilia-A subjects, in whom 137 plasma Factor VIII-time curves were measured during single dose (n = 87) and repeated-dose (n = 47) treatments for prophylaxis or minor bleeding episodes. The pharmacokinetic parameters [mean (SD)] estimated from single-dose curves were: clearance 3.85 ml.h-1.kg-1, volume of distribution 58.2 ml.kg-1, mean residence time 15.9 h. Parameters calculated from repeated-dose curves were: clearance 3.93 ml.h-1.kg-1, volume of distribution 61.8 ml.kg-1, and half-life 12.2 h. In patients with mild haemophilia, pharmaco-statistical analysis revealed that the endogenous synthesis of Factor VIII was constant and was not influenced by the administration of exogenous Factor VIII. The coefficient of variation for intra-individual variability of Factor VIII kinetics (estimated according to the Standard Two-Stage method) was 20.7% in single-dose curves and 23.2% in repeated-dose curves.