Building Optimal Three-Drug Combination Chemotherapy Regimens

Multidrug therapy is often required. Examples include antiviral therapy, nosocomial infections, and, most commonly, anti-Mycobacterium tuberculosis therapy. Our laboratory previously identified a mathematical approach to identify 2-drug regimens with a synergistic or additive interaction using a full factorial study design. Our objective here was to generate a method to identify an optimal 3-drug therapy. We studied M. tuberculosis isolate H37Rv in log-phase growth in flasks. Pretomanid and moxifloxacin were chosen as the base 2-drug regimen. Bedaquiline (plus M2 metabolite) was chosen as the third drug for evaluation. Total bacterial burden and bacterial burden less-susceptible to study drugs were enumerated. A large mathematical model was fit to all the data. This allowed extension to evaluation of the 3-drug regimen by employing a Monte Carlo simulation. Pretomanid plus moxifloxacin demonstrated excellent bacterial kill and suppressed amplification of less-susceptible pathogens. Total bacterial burden was driven to extinction in 3 weeks in 6 of 9 combination therapy evaluations. Only the lowest pretomanid/moxifloxacin exposures in combination did not extinguish the bacterial burden. No combination regimen allowed resistance amplification. Generation of 95% credible intervals about estimates of the interaction parameters α (α_s, α_r-p, and α_r-m) by bootstrapping showed the interaction was near synergistic. The addition of bedaquiline/M2 metabolite was evaluated by forming a 95% confidence interval regarding the decline in bacterial burden. The addition of bedaquiline/M2 metabolite shortened the time to eradication by 1 week and was significantly different. A model-based system approach to evaluating combinations of 3 agents shows promise to rapidly identify the most promising combinations that can then be trialed.