Open AccessDevelopment of a Multicompartment Permeability‐Limited Lung PBPK Model and Its Application in Predicting Pulmonary Pharmacokinetics of Antituberculosis Drugs
Author(s) -
Gaohua L,
Wedagedera J,
Small BG,
Almond L,
Romero K,
Hermann D,
Hanna D,
Jamei M,
Gardner I
Publication year - 2015
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12034
Subject(s) - pharmacokinetics , ethambutol , pharmacology , physiologically based pharmacokinetic modelling , pyrazinamide , rifampicin , lung , in vivo , medicine , isoniazid , nonmem , tuberculosis , pathology , biology , microbiology and biotechnology
Achieving sufficient concentrations of antituberculosis (TB) drugs in pulmonary tissue at the optimum time is still a challenge in developing therapeutic regimens for TB. A physiologically based pharmacokinetic model incorporating a multicompartment permeability‐limited lung model was developed and used to simulate plasma and pulmonary concentrations of seven drugs. Passive permeability of drugs within the lung was predicted using an in vitro‐in vivo extrapolation approach. Simulated epithelial lining fluid (ELF):plasma concentration ratios showed reasonable agreement with observed clinical data for rifampicin, isoniazid, ethambutol, and erythromycin. For clarithromycin, itraconazole and pyrazinamide the observed ELF:plasma ratios were significantly underpredicted. Sensitivity analyses showed that changing ELF pH or introducing efflux transporter activity between lung tissue and ELF can alter the ELF:plasma concentration ratios. The described model has shown utility in predicting the lung pharmacokinetics of anti‐TB drugs and provides a framework for predicting pulmonary concentrations of novel anti‐TB drugs.