Abstract
BACKGROUND: Physiologically-based pharmacokinetic (PBPK) modeling has received growing interest as a useful tool for the assessment of drug pharmacokinetics by continuous knowledge integration. OBJECTIVE: The objective of this study was to build a ciprofloxacin PBPK model for intravenous and oral dosing based on a comprehensive literature review, and evaluate the predictive performance towards pediatric and geriatric patients. METHODS: The aim of this report was to establish confidence in simulations of the ciprofloxacin PBPK model along the development process to facilitate reliable predictions outside of the tested adult age range towards the extremes of ages. Therefore, mean data of 69 published clinical trials were identified and integrated into the model building, simulation and verification process. The predictive performance on both ends of the age scale was assessed using individual data of 258 subjects observed in own clinical trials. RESULTS: Ciprofloxacin model verification demonstrated no concentration-related bias and accurate simulations for the adult age range, with only 4.8% of the mean observed data points for intravenous administration and 12.1% for oral administration being outside the simulated twofold range. Predictions towards the extremes of ages for the area under the plasma concentration-time curve (AUC) and the maximum plasma concentration (C(max)) over the entire span of life revealed a reliable estimation, with only two pediatric AUC observations outside the 90% prediction interval. CONCLUSION: Overall, this ciprofloxacin PBPK modeling approach demonstrated the predictive power of a thoroughly informed middle-out approach towards age groups of interest to potentially support the decision-making process.