Population Pharmacokinetic and Pharmacodynamic Modeling of Enteric-Coated Aspirin Capsule and Tablet Formulations in Healthy Subjects.

Abstract

Purpose: This study aimed to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model to predict the PKs of acetylsalicylic acid (ASA) and salicylic acid (SA), and their effects on thromboxane B2 (TXB2) inhibition following oral administration of two enteric-coated aspirin formulations.

Patients and methods: Data from two Phase I studies in healthy Korean subjects were used to develop the PK-PD model. A nonlinear mixed effect modeling approach was implemented using Monolix^®, based on 669 plasma concentrations of ASA and SA and 83 serum TXB2 concentrations from 44 subjects. Simulx^® was used for model-based simulation and external validation using published literature data. Differences in absorption profiles between two formulations were assessed as a covariate effect.

Results: The PK of aspirin was well described by a one-compartment model for ASA and a two-compartment model for SA, incorporating pre-systemic metabolism and dual absorption. A turnover model with an Emax function captured the TXB2 inhibition. The capsule formulation showed faster absorption (0.22 h^-1) than the tablet (0.053 h^-1), but this did not affect TXB2 inhibition. Body weight significantly influenced ASA-to-SA metabolism and SA clearance. External validation confirmed that the model adequately predicted PK and PD profiles at both 80 mg and 160 mg doses, with simulated TXB2 inhibition showing similar responses between formulations at steady state, exceeding 80%.

Conclusion: This model adequately described the PK and PD of enteric-coated aspirin and demonstrated comparable TXB2 inhibition between the capsule and tablet formulations, supporting their potential interchangeability in clinical practice.