Prediction of moxifloxacin concentrations in tuberculosis patient populations by physiologically-based pharmacokinetic modeling

Moxifloxacin has an important role in the treatment of tuberculosis (TB). Unfortunately, co-administration with the cornerstone TB drug rifampicin results in sub-optimal plasma exposure. We aimed to gain insight into the moxifloxacin pharmacokinetics and the interaction with rifampicin. Moreover, we provided a mechanistic framework to understand moxifloxacin pharmacokinetics. We developed a physiologically-based pharmacokinetic (PBPK) model in Simcyp version 19, with available and newly generated in vitro and in vivo data, to estimate PK parameters of moxifloxacin alone and when administered with rifampicin. By combining these strategies, we illustrate that the role of P-gp in moxifloxacin transport is limited and implicate MRP2 as transporter of moxifloxacin-glucuronide followed by rapid hydrolysis in the gut. Simulations of multiple dose area under the plasma concentration-time curves (AUC) of moxifloxacin (400 mg QD) with and without rifampicin (600 mg QD) were in accordance with clinically observed data (predicted/observed (P/O) ratio of 0.87 and 0.80, respectively). Importantly, increasing the moxifloxacin dose to 600 mg restored the plasma exposure both in actual TB patients as well as in our simulations. Furthermore, we extrapolated the single dose model to pediatric populations (P/O AUC ratios 1.04-1.52) and the multiple dose model to children with TB (P/O AUC ratio 1.51). In conclusion, our combined approach resulted in new insights into moxifloxacin PK and accurate simulations of moxifloxacin exposure with and without rifampicin. Finally, various knowledge gaps were identified, which may be considered as avenues for further PBPK refinement. This article is protected by copyright. All rights reserved.