Seminar: Development of a Multicompartment Permeability-Limited Lung PBPK Model and Its Application in Predicting Pulmonary Pharmacokinetics of Antituberculosis Drugs
Speaker: Klaus Romero, Critical Path Institute, Arizona
Date: Friday 15th of January
Time: 12:45 – 13:45
Venue: LG81 (Lucas Room Room) – Keppel Street
A TB themed seminar organised by the Centre for the Mathematical Modelling of Infectious Diseases (CMMID).
”Development of a Multicompartment Permeability-Limited Lung PBPK Model and Its Application in Predicting Pulmonary Pharmacokinetics of Antituberculosis Drugs”
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.
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