Development of a Multicompartment Permeability‐Limited Lung PBPK Model and Its Application in Predicting Pulmonary Pharmacokinetics of Antituberculosis Drugs. (9th October 2015)

• Record Type: Journal Article
• Authors: Gaohua, L; Wedagedera, J; Small, BG; Almond, L; Romero, K; Hermann, D; Hanna, D; Jamei, M; Gardner, I
• Is Part Of: CPT: pharmacometrics & systems pharmacology. Volume 4:Number 10(2015:Oct.)
• Page Start: 605
• Page End: 613
• Publication Date: 2015-10-09
• Subjects: Pharmacokinetics -- Periodicals; Pharmacology -- Periodicals; Pharmacokinetics; Periodicals; 615.05
• DOI: 10.1002/psp4.12034
• Languages: English
• ISSNs: 2163-8306

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 <italic>in vitro‐in vivo</italic> 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.</p> </abstract>