A modeling-based framework to evaluate forgiveness of tuberculosis treatment in a BALB/c relapsing mouse model

ABSTRACT Tuberculosis (TB) remains a leading cause of death due to an infectious agent. Adherence to long and complex TB treatments is supported by methods including directly observed therapy. The negative impact of missed drug doses on clinical outcomes is well established, highlighting both the importance of adherence support and methods to quantify the ability of a regimen to continue exerting a biologic effect during gaps in dosing known as treatment “forgiveness.” To explore the value of the BALB/c relapsing mouse model of TB in evaluating treatment forgiveness, we assessed the impact of weekend dose holidays on the bactericidal efficacy, including CFU and RS ratio reduction and sterilizing efficacy, of RHZE/RH and BPaMZ. The cure/relapse data from this study, plus multiple historical studies, were used to identify a nonlinear mixed-effects Emax model that was then used to estimate time to cure 50% and derive time to cure 90% of mice (T90). The expected time-dependent bactericidal activity and reductions in RS ratio were observed for both treatments, with more rapid decreases for the BPaMZ groups. The weekend dosing holiday significantly decreased reductions in lung CFU and RS ratio earlier in RHZE/RH treatment, but no such effect was observed for BPaMZ. Similarly, the predicted T90 was significantly greater for RHZE/RH (but not BPaMZ), with weekend doses omitted. No major drug exposure difference was observed between the two dosing schedules. Our results suggest that BPaMZ is more forgiving of missed doses than RHZE/RH and demonstrate the utility of this methodology to support the evaluation of TB treatment forgiveness.