Phase I Safety, Pharmacokinetics, and Pharmacogenetics Study of the Antituberculosis Drug PA-824 with Concomitant Lopinavir-Ritonavir, Efavirenz, or Rifampin. There is an urgent need for new antituberculosis (anti-TB) drugs, including agents that are safe and effective with concomitant antiretrovirals (ARV) and first-line TB drugs. PA-824 is a novel antituberculosis nitroimidazole in late-phase clinical development. Cytochrome P450 (CYP) 3A, which can be induced or inhibited by ARV and antituberculosis 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, and ARV plus PA-824) or sequence 2 (ARV, ARV with PA-824, washout, and PA-824 alone). In arm 3, participants received PA-824 and then rifampin and then both. Pharmacokinetic sampling occurred at the end of each dosing period. Fifty-two individuals participated.
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