# Investigation of the ABCB1 Gene Polymorphism and Food Effects on the Avatrombopag Pharmacokinetics in Chinese Individuals: A Population Pharmacokinetic/Pharmacodynamic Analysis

## TL;DR

This study examines how food and genetic factors affect the drug avatrombopag in Chinese individuals, finding that dosing adjustments may not be necessary for consistent results.

## Contribution

The study identifies the combined effects of food and CYP2C9/ABCB1 polymorphisms on avatrombopag pharmacokinetics in Chinese individuals.

## Key findings

- Food intake reduced pharmacokinetic variability by about 50% in avatrombopag.
- CYP2C9 intermediate metabolizers had 1.70-fold higher drug exposure under fed conditions.
- ABCB1 (C1236T) heterozygotes showed 1.37-fold increased drug exposure.

## Abstract

Background/Objectives: Avatrombopag (AVA), a thrombopoietin receptor agonist used to treat thrombocytopenia in patients with chronic liver disease, exhibits significant pharmacokinetic (PK) variability, particularly under fasting conditions. This study investigates the combined influence of food intake and genetic polymorphisms in CYP2C9 and ABCB1 on the PK and pharmacodynamics (PD) of AVA, with the goal of informing individualized dosing strategies. Methods: A pharmacogenetic analysis was conducted in 92 healthy participants, who received 20 mg of AVA under both fasting and fed conditions. A population PK/PD model was developed to evaluate the covariates effects on the PK variability. Monte Carlo simulations were used to predict AVA exposure and platelet count profiles under diverse dosing scenarios. Results: Food intake significantly reduced PK variability, with approximately 50% reductions in clearance (CL/F) and volume of distribution (Vd/F) compared to fasting conditions. Under fed conditions, CYP2C9 intermediate metabolizers showed a 1.70-fold increase in exposure compared to normal metabolizers, but this difference was not observed under fasting conditions. ABCB1 polymorphisms showed minimal impact, with the exception of ABCB1 (C1236T) heterozygotes, which exhibited 1.37-fold increased exposure. Despite the observed PK variability, simulations demonstrated a consistent platelet count response across dosing regimens. Conclusions: While food intake and genetic polymorphisms in CYP2C9 and ABCB1 influenced AVA PK, these factors may not require dose adjustments, as platelet count responses remained consistent across genotypes and dosing conditions in the Chinese participants. These findings support simplified dosing strategies without the need for pharmacogenetic testing in Chinese individuals and may contribute to more individualized thrombocytopenia management.