Dose optimization of inhaled tigecycline in humans to overcome inherent adverse events and maximize bacterial clearance using a physiologically-based pharmacokinetic modeling approach.

Introduction: Intrapulmonary delivery of tigecycline has been highlighted as an optimal strategy for enhancing local drug concentrations at the site of infection in the treatment of Methods: The PBPK model developed to predict plasma and target-site exposure of inhaled tigecycline and to relate these exposures to adverse event thresholds was derived from plasma and tissue concentration-time courses of Results: Using model-based simulations, we predicted the longitudinal exposure profiles of tigecycline in the systemic circulation, the epithelial lining fluid (ELF) in the lungs as site of antibacterial activity, and other major organs following inhalation under clinically relevant conditions. Intrapulmonary aerosol dosing using the currently approved intravenous dose of tigecycline was predicted to result in significantly lower plasma exposure compared to the gastrointestinal adverse event threshold reported in the literature (AUC Discussion: Our findings indicate that compared to conventional intravenous infusion, inhaled tigecycline offers an improved safety margin and enhances bacterial killing. Based on simulations for multiple dosing scenarios in humans, a dose of 135 mg given every third day by intrapulmonary delivery would result in ELF, bone and plasma exposures that effectively balance efficacy and safety.