title: Pharmacokinetic interaction between etravirine or darunavir/ritonavir and artemether/lumefantrine in healthy volunteers: a two-panel, two-way, two-period, randomized trial.
abstract: OBJECTIVE
  Etravirine is a substrate and inducer of cytochrome P450 (CYP) 3A and a substrate and inhibitor of CYP2C9 and CYPC2C19. Darunavir/ritonavir is a substrate and inhibitor of CYP3A. Artemether and lumefantrine are primarily metabolized by CYP3A; artemether is also metabolized to a lesser extent by CYP2B6, CYP2C9 and CYP2C19. Artemether has an active metabolite, dihydroartemisinin. The objective was to investigate pharmacokinetic interactions between darunavir/ritonavir or etravirine and arthemether/lumefrantrine.
  
  
  METHODS
  This single-centre, randomized, two-way, two-period cross-over study included 33 healthy volunteers. In panel 1, 17 healthy volunteers received two treatments (A and B) in random order, with a washout period of 4 weeks between treatments: treatment A: artemether/lumefantrine 80/480 mg alone, in a 3-day course; treatment B: etravirine 200 mg twice a day (bid) for 21 days with artemether/lumefantrine 80/480 mg from day 8 (a 3-day treatment course). In panel 2, another 16 healthy volunteers received two treatments, similar to those in panel 1 but instead of etravirine, darunavir/ritonavir 600/100 mg bid was given.
  
  
  RESULTS
  Overall, 28 of the 33 volunteers completed the study. Co-administration of etravirine reduced the area under the plasma concentration-time curve (AUC) of artemether [by 38%; 90% confidence interval (CI) 0.48-0.80], dihydroartemisinin (by 15%; 90% CI 0.75-0.97) and lumefantrine (by 13%; 90% CI 0.77-0.98) at steady state. Co-administration of darunavir/ritonavir reduced the AUC of artemether (by 16%; 90% CI 0.69-1.02) and dihydroartemisinin (by 18%; 90% CI 0.74-0.91) but increased lumefantrine (2.75-fold; 90% CI 2.46-3.08) at steady state. Co-administration of artemether/lumefantrine had no effect on etravirine, darunavir or ritonavir AUC. No drug-related serious adverse events were reported during the study.
  
  
  CONCLUSIONS
  Co-administration of etravirine with artemether/lumefantrine may lower the antimalarial activity of artemether and should therefore be used with caution. Darunavir/ritonavir can be co-administered with artemether/lumefantrine without dose adjustment but should be used with caution.
authors: Janssen Research and Development LLC, Titusville, NJ, USA. tkakuda@its.jnj.com
authors: T N
authors: TN
authors: Kakuda
authors: R
authors: R
authors: DeMasi
authors: Y
authors: Y
authors: van Delft
authors: P
authors: P
authors: Mohammed
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000962:Antimalarials / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077549:Artemether; D037621:Artemisinins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D000069454:Darunavir; D004347:Drug Interactions; D004983:Ethanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005449:Fluorenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006678:HIV / Q000187:drug effects; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy; D064368:Healthy Volunteers; D006801:Humans; D000078102:Lumefantrine; D008288:Malaria / Q000150:complications* / Q000188:drug therapy; D008875:Middle Aged; D009570:Nitriles; D011724:Pyridazines / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D011743:Pyrimidines; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D019380:Anti-HIV Agents; D000962:Antimalarials; D037621:Artemisinins; D004983:Ethanolamines; D005449:Fluorenes; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D013449:Sulfonamides; C451734:etravirine; D000077549:Artemether; D000078102:Lumefantrine; D019438:Ritonavir; D000069454:Darunavir
keywords: HIV; artemether; darunavir; etravirine; lumefantrine; malaria; pharmacokinetics