Pharmacokinetics, Pharmacodynamics, Pharmacogenomics, Safety, and Tolerability of Avatrombopag in Healthy Japanese and White Subjects.
Avatrombopag, an orally administered, small-molecule thrombopoietin receptor (c-Mpl) agonist, is currently in clinical development for the potential treatment of severe thrombocytopenia in patients with chronic liver disease undergoing an elective procedure. The objectives of this study were to characterize and compare the pharmacokinetics (including the food effect) and pharmacodynamics (platelet count) of avatrombopag following single doses in Japanese and white subjects. Following single dosing under fasted and fed conditions, mean peak concentrations occurred at 5 to 8 hours and subsequently declined with a half-life of 16 to 18 hours in Japanese and white subjects. Administration with food did not alter the rate or extent of avatrombopag absorption but substantially reduced pharmacokinetic variability relative to the fasted state. CYP2C9 polymorphism (*2, *3) was associated with higher pharmacokinetic variability but not with any clinically important effect on variability in platelet response. Plasma exposures of avatrombopag increased in a dose-proportional manner over the dose range tested. After a single dose, platelet count increased in a dose-related manner, reaching a maximum by day 11 and returning to baseline levels by day 27. No clinically important differences were found when avatrombopag pharmacokinetics and pharmacodynamics were compared between Japanese and white subjects. Administration of avatrombopag was generally well tolerated.
Eisai Co, Ltd, Tokyo, Japan.
Maiko
M
Nomoto
Eisai, Inc, Woodcliff Lake, NJ, USA.
Gina
G
Pastino
Eisai, Inc, Woodcliff Lake, NJ, USA.
Bhaskar
B
Rege
Eisai, Inc, Woodcliff Lake, NJ, USA.
Jagadeesh
J
Aluri
Eisai, Inc, Woodcliff Lake, NJ, USA.
Jim
J
Ferry
California Clinical Trials Medical Group, Inc, Glendale, CA, USA.
David
D
Han
D000328:Adult; D044466:Asian People; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D005215:Fasting / Q000378:metabolism; D005260:Female; D018565:Food-Drug Interactions; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D053628:Receptors, Thrombopoietin / Q000819:agonists*; D013844:Thiazoles / Q000097:blood / Q000494:pharmacology*; D013876:Thiophenes / Q000097:blood / Q000494:pharmacology*; D044465:White People; D055815:Young Adult
D053628:Receptors, Thrombopoietin; D013844:Thiazoles; D013876:Thiophenes; C082218:MPL protein, human; C533238:avatrombopag; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9
avatrombopag; ethnic differences; pharmacokinetics; platelet count; thrombocytopenia