A Limited Sampling Strategy for Estimating Individual Pharmacokinetic Parameters of Coagulation Factor VIII in Patients With Hemophilia A

Abstract

Therapeutic drug monitoring of factor VIII is well established in the treatment of patients with hemophilia attributable to important interindividual variability. The individual initial factor VIII dosage is usually calculated according to individual pharmacokinetic parameters obtained after a dose test administered before the surgery, using at least five-concentration data. The authors proposed a limited sampling strategy to estimate individual pharmacokinetic parameters from one- or two-concentration data in patients with hemophilia A before surgery. The mean population pharmacokinetic parameters and the interindividual variability (CV) were obtained from a group of 33 patients according to a two-compartment model using NONMEM. Eighteen additional patients were used to estimate the predictive performances of the population parameters and to evaluate the limited sampling strategies. Population parameters were clearance 2.6 mL/h per kilogram (CV 45.4%), initial volume of distribution 2.8 L (CV 21.1%). From two sampling times (0.5 and 6 hours or 0.5 and 8 hours after the end of infusion), the estimation of pharmacokinetic parameters was precise and not biased. Until now, in the hemophilic center of Lyon, the factor VIII dosage before surgery was based on the determination of the clearance, estimated from five- to nine-concentration data and on the target concentration (infusion rate = clearance x target). Ruffo et al proposed a limited sampling strategy (two-stage method) to estimate pharmacokinetic parameters from two concentration measurements drawn 3 and 9 hours after the dose. No information was given on the bias and precision of the estimation. This paper reports a one-stage method for a population pharmacokinetic study of factor VIII. The Bayesian estimation of individual pharmacokinetic parameters based on only two sampling times (0.5 and 6 hours or 0.5 and 8 hours after the end of infusion) is useful to define the best factor VIII dosage in hemophilic patients before surgery.