title: 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.
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey, USA suresh.mallikaarjun@otsuka-us.com.
authors.forename: Suresh
authors.initials: S
authors.lastname: Mallikaarjun
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Wells
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Petersen
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Paccaly
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Shoaf
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey, USA.
authors.forename: Shiva
authors.initials: S
authors.lastname: Patil
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Geiter
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D048588:Benzoxazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D003521:Cyclopropanes; D004338:Drug Combinations; D004347:Drug Interactions; D004977:Ethambutol / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007538:Isoniazid / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010080:Oxazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011718:Pyrazinamide / Q000493:pharmacokinetics / Q000627:therapeutic use; D012293:Rifampin / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D004338:Drug Combinations; D009593:Nitroimidazoles; C516022:OPC-67683; D010080:Oxazoles; C087181:isoniazid, pyrazinamide, rifampin drug combination; D011718:Pyrazinamide; D004977:Ethambutol; C098320:efavirenz; D007538:Isoniazid; D012293:Rifampin