Toward optimal moxifloxacin dosing in tuberculous meningitis: A translational physiologically based pharmacokinetic modeling approach

Abstract Background: Tuberculous meningitis (TBM) is a severe central nervous system (CNS) infection with high mortality. Moxifloxacin shows potent anti-mycobacterial activity and favorable CNS penetration. However, optimal dosing remains uncertain, particularly with rifampicin, which markedly reduces moxifloxacin exposure. This study aimed to determine optimal moxifloxacin dosing for TBM by accounting for regional CNS pharmacokinetics (PK) and rifampicin co-administration using a cross-species translational physiologically based pharmacokinetic (PBPK) model. Methods A PBPK model was developed using high-resolution plasma and CNS microdialysis data from pigs to capture CNS physiology and moxifloxacin distribution. The model was translated to humans using literature-derived physiological parameters and allometric scaling and validated with plasma and CNS PK data from healthy subjects and TBM patients. Simulations of once-daily moxifloxacin doses (400 to 1000 mg), with and without rifampicin, were evaluated using the unbound fAUC0-24/MIC target of 53. Results The model accurately reproduced observed moxifloxacin concentrations in porcine and human CNS compartments. Simulations showed regional PK differences, with highest concentrations in the subarachnoid space and cisterna magna and lowest in brain extracellular fluid. Rifampicin reduced mean CNS exposure by 26%. Without rifampicin, target attainment was achieved at 800 mg once daily, while no simulated regimen reached target levels with rifampicin co-administration. Conclusion These results suggest that an 800 mg once-daily moxifloxacin regimen may provide adequate CNS exposure in TBM patients not receiving rifampicin. For patients treated with rifampicin, a higher dose might be necessary to achieve therapeutic targets.