Delamanid Coadministered with Antiretroviral Drugs or Antituberculosis Drugs Shows No Clinically Relevant Drug-Drug Interactions in Healthy Subjects

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.

Outcomes of HIV-infected versus HIV-non-infected patients treated for drug-resistance tuberculosis: Multicenter cohort study

“…More data are needed on the safety and interaction of the bedaquiline and delamanid new anti-TB drugs with the antiretroviral drugs [37][38][39][40][41]. The study also confirms the importance of ART to improve treatment outcomes of DRTB HIV co-infected patients [14].…”

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…Delamanid has few drug-drug interactions and no significant interactions have been seen with the antiretrovirals efavirenz and lopinavirritonavir. 294 Pretomanid (PA-824) is another nitroimidazole agent that is being developed as part of combination therapy for tuberculosis and MDR tuberculosis by the TB Alliance. Pretomanid is in phase 3 testing, and its characteristics are shown in table 7.…”

State‐of‐the‐Art Review of HIV‐TB Coinfection in Special Populations

“…Delamanid is largely metabolized by albumin in serum and is neither an inducer nor an inhibitor of the CYP P450 enzymes, so few clinically relevant DDIs are expected. In healthy volunteer studies of delamanid in adults taking lopinavir–ritonavir, the AUC of delamanid did increase a tad, by 25%, presumably because the modest contribution to its metabolism by CYP 3A4 was inhibited by the PI . It remains to be seen whether this effect is observed among children, and whether there is any attendant toxicity.…”

“…In healthy volunteer studies of delamanid in adults taking lopinavir-ritonavir, the AUC of delamanid did increase a tad, by 25%, presumably because the modest contribution to its metabolism by CYP 3A4 was inhibited by the PI. 58 It remains to be seen whether this effect is observed among children, and whether there is any attendant toxicity. Bedaquiline, which is metabolized by CYP 3A4, can be used with nevirapine (and presumably with raltegravir or dolutegravir).…”