Abstract
Delamanid is a medicinal product approved for treatment of multidrug-resistant tuberculosis. Three studies were conducted to evaluate the potential drug-drug interactions between delamanid and antiretroviral drugs, including ritonavir, a strong inhibitor of CYP3A4, and selected anti-TB drugs, including rifampin, a strong inducer of cytochrome P450 (CYP) isozymes. Multiple-dose studies were conducted in parallel groups of healthy subjects. Plasma samples were analyzed for delamanid, delamanid metabolite, and coadministered drug concentrations, and pharmacokinetic (PK) parameters were determined. The magnitude of the interaction was assessed by the ratio of the geometric means and 90% confidence intervals. Coadministration of delamanid with tenofovir or efavirenz did not affect the PK characteristics of delamanid. Coadministration of Kaletra (lopinavir/ritonavir) with delamanid resulted in an approximately 25% higher delamanid area under the concentration-time curve from time 0 to the end of the dosing interval (AUCτ). Tenofovir, efavirenz, lopinavir, and ritonavir exposure were not affected by delamanid. Coadministration of delamanid with the TB drugs (ethambutol plus Rifater [rifampin, pyrazinamide, and isoniazid]) resulted in lower delamanid exposures (47 and 42% for the AUCτ and Cmax [maximum concentration of a drug in plasma] values, respectively), as well as decreased exposure of three primary metabolites (approximately 30 to 50% lower AUCτ values). Delamanid did not affect rifampin, pyrazinamide, and isoniazid exposure; the ethambutol AUCτ and Cmax values were about 25% higher with delamanid coadministration. The lack of clinically significant drug-drug interactions between delamanid and selected antiretroviral agents (including the strong CYP inhibitor ritonavir) and a combination of anti-TB drugs was demonstrated. Although there was a decrease in the delamanid concentrations when coadministered with ethambutol plus Rifater, this is likely related to decreased delamanid absorption and not to CYP induction.
Highlights
Multidrug-resistant tuberculosis (MDR-TB), or tuberculosis resistant to two first-line drugs, isoniazid and rifampin, has emerged over the past 3 decades to greatly complicate efforts to control the disease
We report here the results using two broad categories of medications evaluated for potential drug-drug interactions in the delamanid development program: first-line anti-TB drugs and antiretroviral drugs used in HIV-infected patients and the strong CYP3A4 inhibitor ritonavir
The greater than planned number of subjects, as well as the imbalance in the number randomized per group, reflects the decision to replace 16 subjects who either withdrew due to a generalized rash (18) or who were withdrawn by the investigator because of a suspected decrease in visual acuity, which was shown on further investigation to be a false-positive event
Summary
Multidrug-resistant tuberculosis (MDR-TB), or tuberculosis resistant to two first-line drugs, isoniazid and rifampin, has emerged over the past 3 decades to greatly complicate efforts to control the disease. In the combined treatment of TB patients and MDR-TB patients coinfected with HIV, the risk of clinically significant drugdrug interactions increases, especially when considering the number of commonly coadministered anti-TB and antiretroviral medications that are either inducers or inhibitors of CYP, including newer anti-TB drugs such as bedaquiline and PA-824 (9, 10). We report here the results using two broad categories of medications evaluated for potential drug-drug interactions in the delamanid development program: first-line anti-TB drugs (including the strong CYP3A4 and other CYP450 isoenzymes inducer rifampin) and antiretroviral drugs used in HIV-infected patients (including the moderate CYP3A4 inducer efavirenz) and the strong CYP3A4 inhibitor ritonavir
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