Understanding the suitability of established antibiotics for oral inhalation from a pharmacokinetic perspective: an integrated model-based investigation based on rifampicin, ciprofloxacin and tigecycline in vivo data.

Abstract

Treating pulmonary infections by administering drugs via oral inhalation represents an attractive alternative to usual routes of administration. However, the local concentrations after inhalation are typically not known and the presumed benefits are derived from experiences with drugs specifically optimized for inhaled administration. A physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model was developed to elucidate the pulmonary PK for ciprofloxacin, rifampicin and tigecycline and link it to bacterial PK/PD models. An exemplary sensitivity analysis was performed to potentially guide drug optimization regarding local efficacy for inhaled antibiotics. Detailed pulmonary tissue, endothelial lining fluid and systemic in vivo drug concentration-time profiles were simultaneously measured for all drugs in rats after intravenous infusion. Using this data, a PBPK/PD model was developed, translated to humans and adapted for inhalation. Simulations were performed comparing potential benefits of oral inhalation for treating bronchial infections, covering intracellular pathogens and bacteria residing in the bronchial epithelial lining fluid. The PBPK/PD model was able to describe pulmonary PK in rats. Often applied optimization parameters for orally inhaled drugs (e.g. high systemic clearance and low oral bioavailability) showed little influence on efficacy and instead mainly increased pulmonary selectivity. Instead, low permeability, a high epithelial efflux ratio and a pronounced post-antibiotic effect represented the most impactful parameters to suggest a benefit of inhalation over systemic administration for locally acting antibiotics. The present work might help to develop antibiotics for oral inhalation providing high pulmonary concentrations and fast onset of exposure coupled with lower systemic drug concentrations.