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

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 fAUC₀₂₄/MIC target of 53.

RESULTS: The model reasonably described 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 in most CNS compartments, except brain extracellular fluid, at 800 mg once daily, while even doses up to 1000 mg did not reach target levels in most CNS compartments with rifampicin co-administration.

CONCLUSION: These results suggest that higher doses might be needed to ensure PK target attainment in TBM, regardless of whether moxifloxacin is combined with rifampicin. The safety of regimens exceeding 800 mg must be rigorously established in clinical trials.