Evaluating tigecycline dosing for hospital-acquired pneumonia patients: insights from physiologically-based pharmacokinetic modeling of lung exposure.

Tigecycline is increasingly used off-label for hospital-acquired pneumonia (HAP), though its efficacy and optimal dosing remain uncertain. Lung exposure to tigecycline may be affected by pulmonary pH changes induced by bacterial infections. This study used a physiologically -based pharmacokinetic (PBPK) model to evaluate the impact of pH shifts on lung exposure and assess the efficacy of various dosing regimens. A lung PBPK model for tigecycline was developed and validated using plasma and lung concentration data from clinical pharmacokinetic studies. Simulations evaluated the impact of pH alterations from 6.6 (healthy) to 5.6 (infection) on lung exposure. Three clinical dosing regimens-standard (100 mg loading dose +50 mg q12h), median (150 mg loading dose +75 mg q12h), and high dose (200 mg loading dose +100 mg q12h)-were assessed by calculating the probability of target attainment (PTA) in lung compartments, including epithelial lining fluid (ELF) and alveolar cells (ACs), across a MIC range of 0.125-32 mg/L. The model reasonably captured tigecycline exposure in plasma and lung. Pulmonary pH alterations had minimal impact on tigecycline AUC in ELF but led to a significant 12.39-fold increase in AUC within ACs at pH 5.6. For pathogens with MIC ≤1 mg/L, all three dosing regimens achieved PTA ≥90% in ELF. However, for MIC >2 mg/L, only the high-dose regimen provided satisfactory PTA. The lung PBPK model provides valuable insights into tigecycline PK in HAP patients and underscores the need to optimize dosing for pneumonia with resistant pathogens.