Increasing rifampicin (RIF) dosages could significantly reduce tuberculosis (TB) treatment\ndurations. Understanding the pharmacokinetic-pharmacodynamics (PK-PD) of increasing RIF\ndosages could inform clinical regimen selection. We used intracellular PD modelling (PDi)\nto predict clinical outcomes, primarily time to culture conversion, of increasing RIF dosages.\nPDi modelling utilizes in vitro-derived measurements of intracellular (macrophage) and extracellular\nMycobacterium tuberculosis sterilization rates to predict the clinical outcomes of RIF at increasing doses.\nWe evaluated PDi simulations against recent clinical data from a high dose (35 mg/kg per day) RIF\nphase II clinical trial. PDi-based simulations closely predicted the observed time-to-patient culture\nconversion status at eight weeks (hazard ratio: 2.04 (predicted) vs. 2.06 (observed)) for high dose\nRIF-based treatments. However, PDi modelling was less predictive of culture conversion status at\n26 weeks for high-dosage RIF (99% predicted vs. 81% observed). PDi-based simulations indicate that\nincreasing RIF beyond 35 mg/kg/day is unlikely to significantly improve culture conversion rates,\nhowever, improvements to other clinical outcomes (e.g., relapse rates) cannot be ruled out. This study\nsupports the value of translational PDi-based modelling in predicting culture conversion rates for\nantitubercular therapies and highlights the potential value of this platform for the improved design\nof future clinical trials.
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