Phase I Safety, Pharmacokinetics, and Pharmacogenetics Study of the Anti-Tuberculosis Drug PA-824 with Concomitant Lopinavir/Ritonavir, Efavirenz, or Rifampin. There is an urgent need for new anti-tuberculosis (TB) drugs, including agents that are safe and effective with concomitant antiretrovirals (ARV) and first-line TB drugs. PA-824 is a novel anti-tuberculosis nitroimidazole in late-phase clinical development. Cytochrome P450 (CYP) 3A, which can be induced or inhibited by ARV and anti-tuberculosis drugs, is a minor (∼20%) metabolic pathway for PA-824. In a Phase I clinical trial, we characterized interactions between PA-824 and efavirenz (Arm 1), lopinavir/ritonavir (Arm 2), and rifampin (Arm 3) in healthy, HIV-uninfected volunteers without TB disease. Participants in Arms 1 and 2 were randomized to receive drugs via Sequence 1 (PA-824 alone, washout, ARV, ARV plus PA-824) or Sequence 2 (ARV, ARV with PA-824, washout, PA-824 alone). In Arm 3, participants received PA-824, then rifampin, then both. Pharmacokinetic sampling occurred at the end of each dosing period. Fifty-two individuals participated.
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