Population pharmacokinetics of continuous infusion of factor VIII in hemophilia-A patients undergoing orthopedic surgery

M Larger1,2, F Bressolle1,3, Y Chevalier4, V Chamouard4, C Negrier4, R Boulieu1,2. 1University Lyon1, Clinical Pharmacy and Pharmacokinetics, France, 2CHU de Lyon, Clinical Pharmacokinetics, France, 3University of Montpellier, Clinical Pharmacokinetics, France, 4CHU de Lyon, Centre traitement hémophilie, France

Objectives : Hemophilia is a recessively inherited bleeding disorder characterized by a deficiency of factor VIII. Treatment of hemorrhage and prophylaxis against bleeding following surgery is based on the infusion of coagulation factor VIII.

The aim of the study was to develop a population pharmacokinetic model taking into account blood losses during and after orthopedic surgery in adult hemophilia A patients, to accurately estimate both inter- and residual variability in pharmacokinetic parameters, and to evaluate the influence of potential covariates.

Methods: Factor VIII pharmacokinetic parameters were calculated from 24 patients. Among them, 7 were HIV+. The observations were analyzed with the mixed-effects (population) compartment pharmacokinetic package NONMEM and the first-order conditional estimation method. Factor VIII pharmacokinetics were modeled using a two-compartment model. The model’s performance was assessed by examining the prediction error (PE), both MDPE (median of all PEs) and MDAPE (median of all absolute PEs) were calculated. Moreover, the visual predictive checks were carried out by simulating 1000 virtual data sets to assess the performance of the model.

Results: During the model-building process, central volume of distribution (V1) was related to bodyweight (P = 0.0263) and viral status (P = 0.0078). Moreover, the peripheral volume of distribution was related to body weight (P=0.0362). In the final model, only the viral status was significant for V1 when compared with the base model. The final model displayed good descriptive and predictive performance. Posterior predictive checks and robustness analysis showed that the models adequately described the pharmacokinetic parameters. The HIV covariate accounted for 29.8% of the unexplained variation across patients for V1. V1 increased by 33.3% (from 3550 mL to 4732 mL) in HIV+ patients compared to HIV- patients.

Conclusions : In this paper, a population pharmacokinetic model taking into account blood losses during and after orthopedic surgery was developed. The increase in V1 observed in HIV+ patients need for higher doses. In these patients, the total administered dose was increased by 26% to maintain adequate factor VIII concentrations.