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 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…
Read the paper
Related studies
- Synthesis, In Vitro and In Silico Molecular Docking Studies of Novel Phthalimide–Pyrimidine Hybrid Analogues to Thalidomide as Potent Antitubercular Agents
- Exploring the inhibitory performance of expired moxifloxacin and norfloxacin on copper corrosion in saline environment
- Molecular investigation of antimicrobial peptides against Helicobacter pylori proteins using a peptide-protein docking approach
- Screening of novel narrow-spectrum benzofuroxan derivatives for the treatment of multidrug-resistant tuberculosis through in silico, in vitro, and in vivo approaches
- Synthesis, Characterization, Anticancer, Antioxidant, and In Silico Evaluation of Semicarbazides and Thiosemicarbazides
- Fast and accurate prediction of drug induced proarrhythmic risk with sex specific cardiac emulators
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.