Data Sheet 1_Dose optimization of inhaled tigecycline in humans to overcome inherent adverse events and maximize bacterial clearance using a physiologically-based pharmacokinetic modeling approach.pdf

IntroductionIntrapulmonary delivery of tigecycline has been highlighted as an optimal strategy for enhancing local drug concentrations at the site of infection in the treatment of Mycobacterium abscessus pulmonary infections. Therefore, determining an appropriate inhaled dose is imperative to optimize therapeutic use of tigecycline. In this study, we aimed at establishing a human dose rationale for inhaled tigecycline by leveraging various preclinical experimental datasets through physiologically-based pharmacokinetic (PBPK) modeling.
MethodsThe 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 in vivo mouse studies. Following inter-species scaling, the predictive performance of the model was qualified by comparing model-based simulations with experimental data in rats and literature reports in humans, thereby demonstrating its applicability across species. The final human PBPK model was utilized to predict tigecycline exposure in plasma and major organs of interest, thereby establishing the clinical utility of tigecycline inhaled dosing.
ResultsUsing 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 (AUC0−24 6.87 mg·h/L). Additionally, simulated steady-state bone concentrations remained below a threshold which has been previously defined as a steady-state trough concentration leading to bone toxicity in rats. For efficacy, intrapulmonary aerosol administration produced markedly higher peak concentrations in ELF than intravenous dosing, and the simulated exposure in ELF exceeded effective exposure levels identified in murine infection models of Mycobacterium abscessus.
DiscussionOur 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.