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 (AUC(0-τ)) and 32% to 45% for maximum observed plasma concentration (C(max)) across doses. After 5 days of dosing, AUC(0-τ) was dose-proportional and C(max) 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.
Matthys
Gemma
G
GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
Park
Jung Wook
JW
McGuire
Sandra
S
Wire
Mary Beth
MB
Bowen
Carolyn
C
Williams
Daphne
D
Jenkins
Julian
J
Peng
Bin
B
D000328:Adult; D019540:Area Under Curve; D001565:Benzoates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006401:Hematologic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects; D010976:Platelet Count; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D053628:Receptors, Thrombopoietin / Q000037:antagonists & inhibitors*; D015203:Reproducibility of Results; D013921:Thrombocytopenia / Q000188:drug therapy; D034061:Thrombopoiesis / Q000187:drug effects*; D013997:Time Factors; D055815:Young Adult
D001565:Benzoates; D006401:Hematologic Agents; D006834:Hydrazines; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; C520809:eltrombopag