title: Development of a Multicompartment Permeability-Limited Lung PBPK Model and Its Application in Predicting Pulmonary Pharmacokinetics of Antituberculosis Drugs.
abstract: 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.
authors.affiliation: Simcyp Limited (a Certara company) Sheffield, United Kingdom.
authors.forename: L
authors.initials: L
authors.lastname: Gaohua
authors.affiliation: Simcyp Limited (a Certara company) Sheffield, United Kingdom.
authors.forename: J
authors.initials: J
authors.lastname: Wedagedera
authors.affiliation: Simcyp Limited (a Certara company) Sheffield, United Kingdom.
authors.forename: B G
authors.initials: BG
authors.lastname: Small
authors.affiliation: Simcyp Limited (a Certara company) Sheffield, United Kingdom.
authors.forename: L
authors.initials: L
authors.lastname: Almond
authors.affiliation: Critical Path Institute Tucson, Arizona, USA.
authors.forename: K
authors.initials: K
authors.lastname: Romero
authors.affiliation: Certara USA, Inc. Princeton, New Jersey, USA.
authors.forename: D
authors.initials: D
authors.lastname: Hermann
authors.affiliation: Critical Path Institute Tucson, Arizona, USA.
authors.forename: D
authors.initials: D
authors.lastname: Hanna
authors.affiliation: Simcyp Limited (a Certara company) Sheffield, United Kingdom.
authors.forename: M
authors.initials: M
authors.lastname: Jamei
authors.affiliation: Simcyp Limited (a Certara company) Sheffield, United Kingdom.
authors.forename: I
authors.initials: I
authors.lastname: Gardner