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.

Population Pharmacokinetic Modeling as a Tool To Characterize the Decrease in Ciprofloxacin Free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats

“…In the model, the lung compartment is connected to the venous compartment and returns to the arterial compartment (Fig. 2), as suggested previously in physiologically based pharmacokinetic models (24)(25)(26). Initially, lung data were modeled as a single compartment, but this approach resulted in a poor fit.…”

Development of an Adult Physiologically Based Pharmacokinetic Model of Solithromycin in Plasma and Epithelial Lining Fluid

“…Because these compounds are basic, they may accumulate in the acidic compartments of phagocytes within AM cells . Supporting this assumption, a previously published PBPK model used sensitivity analysis to show that decreasing the pH in ELF may account for the underprediction of basic macrolide drugs in ELF . The presence of drug transporters, such as P‐gp, in the lung epithelial cells has also been postulated to cause increased distribution of macrolides into intrapulmonary fluid .…”

“…8 Supporting this assumption, a previously published PBPK model used sensitivity analysis to show that decreasing the pH in ELF may account for the underprediction of basic macrolide drugs in ELF. 37 The presence of drug transporters, such as P-gp, in the lung epithelial cells has also been postulated to cause increased distribution of macrolides into intrapulmonary fluid. 38,39 Finally, lysis of AM cells in the collected bronchoalveolar lavage fluid, and other technical errors in the measurement Figure 4 Population simulations for plasma concentrations for the 800 mg on day 1 followed by 400 mg orally daily regimen for the phase I population in healthy adults (a) and the phase II population in patients with community-acquired bacterial pneumonia (b).…”

Translational PK/PD of anti-infective therapeutics

“…Tissue distribution of antibiotics may be predicted using physiologically-based pharmacokinetic (PBPK) modelling [26,27]. Recently, a PBPK model incorporating a multi-compartment permeability-limited lung model was used to simulate the pharmacokinetics of anti-tuberculosis agents in plasma, lungs and its sub-compartments where the mycobacteria reside in the host [28]. This model also provides a framework for predicting the lung concentrations of novel anti-tuberculosis agents.…”