Population PK/PD Modeling of Eltrombopag in Healthy Volunteers and Patients With Immune Thrombocytopenic Purpura and Optimization of Response-Guided Dosing

Abstract

The relationship between plasma eltrombopag concentrations and increases in platelet counts (PLTC) was characterized in healthy volunteers (HVs) and patients with immune thrombocytopenic purpura (ITP) using population pharmacokinetic/pharmacodynamic (PK/PD) models. The semiphysiological model included 3 PK, 1 precursor production, 2 maturation, and 1 blood platelet compartments and assumed a linear increase in platelet production rate with eltrombopag concentrations. Thrombopoiesis was assumed to be the same in HVs and patients, whereas platelets degraded more rapidly in patients. A mixture model was used, with nonresponders accounting for 19% of the patients. The following covariates were predictive of higher PLTC in ITP patients based on PK or PD differences in descending order of magnitude: East Asian race, age 65 years or older, baseline PLTC greater than 15 Gi/L, female, and concurrent corticosteroid. Simulations support starting eltrombopag at a dose of 50 mg once daily, except in East Asian patients, for whom 25 mg once daily is warranted. Doses can be titrated at 2-week intervals (or longer) to achieve target PLTC.