Figure 4

PK-PD Monte-Carlo simulations of clinical Mtb response based on concentration-kill rate dynamics derived from in vitro models of intracellular and extracellular Mtb. (a) Predicted dynamics of total TB in patients receiving HRZE combination for 6 months based on extracellular kill rates only. (b) Predicted dynamics of total TB in patients receiving HRZE combination for 6 months based on intracellular kill rates only. (c) Predicted dynamics of total TB in patients receiving HRZE combination for 6 months based on the assumption that extracellular TB constitutes 95% and intracellular 5% of total TB (1-month view). (d) Predicted dynamics of total TB in patients receiving HRZE combination for 6 months based on the assumption that extracellular TB constitutes 95% and intracellular 5% of total TB (6-month view). (e) Probability of sputum sample conversion to Mtb culture-positive status over time as observed in TB patients receiving standard HRZE treatment in a previous clinical study⁷ (solid black line) compared to the predicted probabilities over time using our novel PK-PD model (dashed red line). Dashed green line shows our PK-PD prediction when using a standard HRZE regimen but with an elevated dose of RIF (35 mg/kg). The comparison assumes that the limit of detection for positive culture conversion is 10 CFU/mL when using Löwenstein–Jensen medium culture assays⁶⁷ which have been implemented in the comparator clinical study. (f) Predicted dynamics of total TB in patients receiving HRZE with a high dose of RIF (35 mg/kg) for 3 months on the assumption that extracellular TB constitutes 95% and intracellular 5% of total TB (6-month view).