Intracellular PD Modelling (PD_i) for the Prediction of Clinical Activity of Increased Rifampicin Dosing

Increasing rifampicin (RIF) dosages could significantly reduce tuberculosis (TB) treatment durations. Understanding the pharmacokinetic-pharmacodynamics (PK-PD) of increasing RIF dosages could inform clinical regimen selection. We used intracellular PD modelling (PD_i) to predict clinical outcomes, primarily time to culture conversion, of increasing RIF dosages. PD_i modelling utilizes in vitro-derived measurements of intracellular (macrophage) and extracellular Mycobacterium tuberculosis sterilization rates to predict the clinical outcomes of RIF at increasing doses. We evaluated PD_i simulations against recent clinical data from a high dose (35 mg/kg per day) RIF phase II clinical trial. PD_i-based simulations closely predicted the observed time-to-patient culture conversion status at eight weeks (hazard ratio: 2.04 (predicted) vs. 2.06 (observed)) for high dose RIF-based treatments. However, PD_i modelling was less predictive of culture conversion status at 26 weeks for high-dosage RIF (99% predicted vs. 81% observed). PD_i-based simulations indicate that increasing RIF beyond 35 mg/kg/day is unlikely to significantly improve culture conversion rates, however, improvements to other clinical outcomes (e.g., relapse rates) cannot be ruled out. This study supports the value of translational PD_i-based modelling in predicting culture conversion rates for antitubercular therapies and highlights the potential value of this platform for the improved design of future clinical trials.