Pharmacokinetics and Pharmacodynamics Clinical Pharmacokinetics, Platelet Response, and Safety of Eltrombopag at Supratherapeutic Doses of up to 200 mg Once Daily in Healthy Volunteers

This was a double‐blind, placebo‐controlled, randomized, parallel, dose‐escalation study to assess the pharmacokinetics, platelet response, safety, and tolerability of supratherapeutic doses of eltrombopag (100 mg, 150 mg, and 200 mg once daily) administered for 5 days to 33 healthy adult volunteers. Plasma eltrombopag concentrations accumulated between days 1 and 5, with average increases of 66% to 81% for area under the plasma concentration‐time curve from time zero to the end of the 24‐hour dosing interval (AUC0‐τ) and 32% to 45% for maximum observed plasma concentration (Cmax) across doses. After 5 days of dosing, AUC0‐τ was dose‐proportional and Cmax was less than dose‐proportional over eltrombopag 100 to 200 mg with slope estimates (90% confidence intervals) of 0.92 (0.45‐1.39) and 0.76 (0.29‐1.22), respectively. Platelet counts peaked at day 14, and maximum change from baseline platelet count increased dose‐dependently, with mean platelet count increases of 14, 67, 107, and 150 Gi/L for placebo and eltrombopag 100 mg, 150 mg, and 200 mg, respectively. There was no notable difference in day 14 mean platelet aggregation between eltrombopag (59 to 74%) and placebo (67%), although this was not tested statistically. There was no notable difference in adverse event frequency across eltrombopag doses. Eltrombopag pharmacokinetics and platelet response were dose‐dependent, and doses up to 200 mg/d were well tolerated, with safety profiles similar to placebo.