Pharmacokinetics, Pharmacodynamics, Pharmacogenomics, Safety, and Tolerability of Avatrombopag in Healthy Japanese and White Subjects

Abstract

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.

Pharmacokinetic/pharmacodynamic drug–drug interactions of avatrombopag when coadministered with dual or selective CYP2C9 and CYP3A interacting drugs

“…Therefore, avatrombopag is recommended to be taken with a meal. Increases in platelet count are evident as early as 3–5 days after avatrombopag administration, and the highest changes in platelet count were observed by approximately 6–10 days . The safety and tolerability of avatrombopag were confirmed up to single doses of 80 mg in healthy subjects.…”

“…Avatrombopag showed linear pharmacokinetics (PK) and increases platelet count in a dose‐dependent manner across a range of 20 mg to 60 mg dose in healthy subjects . Following single dosing under fasted and fed conditions, mean peak concentrations occurred at 6–8 h and subsequently declined with a half‐life of 16–19 h in healthy subjects.…”

Avatrombopag, an oral thrombopoietin receptor agonist: results of two double‐blind, dose‐rising, placebo‐controlled Phase 1 studies

“…Avatrombopag was generally well tolerated in all of these clinical studies (Bussel et al , ; Jurczak et al , ; Terrault et al , ). There has been no evidence for increased thromboembolic events, hepatotoxicity (Terrault et al , ) or significant food interactions with avatrombopag (Nomoto et al , ) reported in these studies.…”

“…The reduced incidence of hepatic events and the lack of dietary interactions in healthy subjects from one study (Nomoto et al , ), may serve to distinguish avatrombopag from eltrombopag clinically. Such comparisons, however, clearly suffer from a lack of direct comparison of the two drugs in a single clinical trial in healthy subjects, or in patients with CLD or ITP.…”

Immune Thrombocytopenia in Adults: Modern Approaches to Diagnosis and Treatment

“…Rituximab can be considered, but it often takes several weeks to work. A TPO-RA can be tried; we favor romiplostim owing to its higher potency [43][44][45] and recommend administration of high-dose treatment upfront (5-10 µg/kg for 1-2 doses). This requires continued patience as TPO-RAs do not work immediately and require a minimum of 5 to 7 days before an effect is seen.…”