Pharmacokinetics and pharmacodynamics of eltrombopag in healthy Japanese males

Abstract

The pharmacokinetics and pharmacodynamics of eltrombopag, a thrombopoietin receptor agonist developed for idiopathic thrombocytopenic purpura, were investigated in healthy Japanese adult males after single and repeat doses of eltrombopag in two clinical studies. In the first study, subjects received a single oral dose of eltrombopag tablets at 30, 50, 75 and 100 mg and placebo in the fasted state. In the second study, each subject received single and once daily for 10 days repeat doses of eltrombopag (25, 50 or 75 mg) or placebo tablets. Plasma eltrombopag concentrations and platelet counts were measured in both studies. AUC and Cmax were proportional to dose within the range of 30-100 mg. The AUC0-24 values after repeat doses of eltrombopag 25, 50 and 75 mg were 56, 130 and 161 μg·hr/mL, respectively, increasing nearly proportionally to the dose increase. The plasma concentration reached steady state in approximately 7 days after starting the repeat dose, and the change in pharmacokinetics caused by repeat dose was small. The AUC values obtained after single and repeat dose in Japanese subjects were nearly two-fold higher than those previously reported in non-Japanese subjects (predominantly white). No significant changes in platelet count were observed after single oral doses up to 100 mg of eltrombopag. When 25, 50 and 75 mg were administered once daily for 10 days, the maximum increase in platelet count from the baseline was 54%, 72% and 90%, respectively, showing a dose-dependent increase. These increases were higher as compared with the previously reported increases in platelet count observed after 30, 50 and 75 mg were administered once daily for 10 days to non-Japanese healthy adults. The increase in platelet count from baseline became higher with increasing AUC in Japanese healthy adults. These results suggest that the difference in platelet count increase between Japanese and non-Japanese is probably associated with the observed inter-ethnic difference in AUC. Eltrombopag might be used at a lower dosage in Japanese than in non-Japanese to attain similar degrees of platelet count increase.