Coupled Pharmacokinetic Model Unveils Drug-drug Interactions in Plasma Concentration
Hong Huang, Chaoyang Li, Qianqian Chen, Chumeng Zhuang, Li Yu, Weifeng Jin, Xiaohong Li
Abstract
In oral drug pharmacokinetics (PK), drug-drug interactions are inevitable, yet traditional compartmental models struggle to effectively quantify such processes. This study proposes a linearly coupled two-compartment PK model, where the coupling term is defined as a linear function of another drug’s amount to strike a balance between model simplicity and physiological interpretability. The model introduces parameter heterogeneity and linear interaction terms based on the classical compartmental structure, more accurately capturing concentration-dependent dynamic changes during combined drug administration.
Introduction
Pharmacokinetics (PK) plays an important part in both preclinical and clinical drug studies by quantifying the dynamic behavior of drugs within the organism, which can elucidate their efficacy and safety. Data analysis is an essential aspect of PK studies. Typically, PK modeling is under the framework of the compartmental model that utilizes differential equations and the law of amount conservation to effectively characterize temporal changes in the amount or concentration of a single drug.
Materials and Methods:
In this study, the absorption, distribution, and elimination rates of one drug are considered to be influenced by monotonic changes in the amount of the other drug. In addition, this study is based on an important assumption that it is only applicable to specific dose ranges. Similar to treating extremely small segments of a curve as straight lines when calculating curve integrals,the heterogeneity of pharmacokinetic model parameters is defined as a linear relationship, with the sign of the slope indicating their interaction. For clarity, X will be used to represent one drug and Y to represent the other.
Discussion
The model developed in this study is based on a fundamental assumption: drugs exhibit linear pharmacokinetic (PK) parameter relationships within a specific dosage range, meaning that drug-drug interactions (DDI) are assumed to follow a linear relationship. By introducing linear coupling terms, the model captures the effects between drugs. This approach simplifies the model structure and computational complexity to some extent, making it particularly suitable for scenarios with low drug concentrations where interactions primarily display approximately linear responses. However, certain drug interactions in real-world clinical settings may exhibit pronounced nonlinear or saturable pharmacokinetic characteristics.
Citation: Huang H, Li C, Chen Q, Zhuang C, Yu L, Jin W, et al. (2026) Coupled pharmacokinetic model unveils drug-drug interactions in plasma concentration. PLoS One 21(2): e0339052. https://doi.org/10.1371/journal.pone.0339052
Editor: Eshetie Melese Birru, The kids Research Institute Australia, AUSTRALIA
Received: May 20, 2025; Accepted: December 1, 2025; Published: February 10, 2026.
Copyright: © 2026 Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: This research was supported by the Zhejiang Natural Science Foundation (grant numbers LZYQ25H270001 to Y.L.; LY24H270007 to J.W.F.; LY22H270002 to Y.L.), the Zhejiang Postdoctoral Research Foundation (grant number ZJ2023021 to Y.L.), and the National Natural Science Foundation of China (grant number 81904083 to Y.L.).
Competing interests: NO authors have competing interests.
