Model-based evaluation of adherence to bedaquiline and clofazimine in adults with drug-resistant TB.

<sec><title>BACKGROUND</title>There is a need for objective measures of adherence to fully-oral bedaquiline-based regimens for rifampicin- and multidrug-resistant tuberculosis (RR/MDR-TB). Due to their prolonged half-lives, bedaquiline (BDQ) and clofazimine CFZ) are appropriate for evaluating long-term treatment adherence using a model-based approach.</sec><sec><title>METHODS</title>We enrolled adults initiating a 9-month regimen that included BDQ and CFZ for RR/MDR-TB. Dried blood spot samples were taken at intervals and assayed for BDQ and CFZ concentrations. Demographic and clinical factors were used to predict drug concentrations using known pharmacokinetic models, assuming full adherence. Individual observed concentrations were compared to model-predicted values (1000 simulations). Observations were ranked, with those below the 5th percentile of simulated concentrations, indicating possible poor adherence.</sec><sec><title>RESULTS</title>Adherence worsened over time, especially for BDQ (11, 21, 26, and 35% of the observations below the 5th percentile in the first, second, fourth, and sixth month respectively). CFZ observations under the 5th percentile were 10, 9, 7.5, 14, and 23% at months 1, 2, 4, 6, and 9.</sec><sec><title>CONCLUSION</title>Concentrations of BDQ and CFZ below the 5th percentile increased over time and this trend was more marked with BDQ. We hypothesise that the complexity of the thrice-weekly BDQ regimen increases the risk of suboptimal adherence.</sec>.