Pharmacometrics to advance novel regimens for drug-resistant tuberculosis (PandrTB)
Wellcome Trust
Institute of Tropical Medicine Antwerp
PandrTB is a study of the pharmacokinetics(PK) and pharmacodynamics(PD) of bedaquiline, delamanid, clofazimine, linezolid, moxifloxacin, levofloxacin and pyrazinamide used in novel combinations to treat multidrug-resistant tuberculosis(MDR-TB). PandrTB is nested in the endTB trial, a randomized study that will evaluate five 9-month, injectable-sparing regimens that could transform the treatment of MDR-TB. Nonlinear mixed-effects models will describe the population PK of the drugs and treatment response of Mycobacterium tuberculosis(Mtb) load over time. Recursive partitioning methods will evaluate baseline MICs and PK measures as drivers of treatment response (PD model parameters, time to culture conversion, longer-term outcomes, acquisition of phenotypic resistance). Thus the key drugs and drug exposure thresholds for activity will be defined, and exposure-dependent synergy or antagonism identified. Toxicities will be assessed and the risks of toxicity estimated, by drug exposure and important comorbidity (including HIV infection). To advance the understanding of drug penetration, we will develop approaches to measure free drug plasma concentrations. Drug-drug interactions will be described. Simulations will predict optimal doses. Thus PandrTB will inform how best to use these new and repurposed drugs in combination, to create the most effective and least toxic regimens while minimizing the development of further drug resistance.
5.1 Pharmaceuticals