Bayesian Population Pharmacokinetic Modeling of Eltrombopag in Chronic Hepatitis C Patients

Mohammad I. Saleh, Suhad Bani Melhim, Hanguin M. Al-Ramadhani, Sameh Alzubiedi

Eltrombopag is a thrombopoietic growth factor that is approved for the treatment of thrombocytopenia in chronic hepatitis C virus (HCV) patients. We aimed to describe eltrombopag population pharmacokinetics in hepatitis C patients. Bayesian statistical approach will be applied to screen for patients' characteristics associated with eltrombopag pharmacokinetic parameters. A population pharmacokinetic analysis was conducted using WinBUGS version 1.4.3. Data from 483 individuals with chronic HCV infection were analyzed. This analysis is a secondary analysis of two clinical studies (ENABLE1 and ENABLE2) sponsored by GlaxoSmithKline. Several patients' characteristics were examined as possible covariates of the population pharmacokinetic model. Prior information from previous studies was incorporated in the bayesian model as prior distribution to estimate pharmacokinetic parameters. A two-compartment pharmacokinetic model with first-order absorption with exponential error model best fit the data. We identified East Asian race and total bilirubin level as predictors of eltrombopag clearance. Typical value for distributional clearance was 0.762 L/h (95% Bayesian credible set, 0.703-0.826), for volume of distribution of the central and peripheral compartments were 12 L (10.9-13.4) and 10.9 L (10.4-11.5), and for absorption lag time was 0.947 h (0.918-0.977). Assuming an average total bilirubin of 21.7 µmol/L, the typical elimination clearance value for an East Asian patient was 0.14 L/h and for other races was 0.20 L/h. Eltrombopag pharmacokinetic behavior was described using population bayesian approach. This model can be applied to optimize eltrombopag dosing in order to reduce the incidence of thrombocytopenia in HCV-infected patient receiving interferon-based therapy.