Significant pharmacokinetic interactions between artemether/lumefantrine and efavirenz or nevirapine in HIV-infected Ugandan adults

J Antimicrob Chemother. 2012 Sep;67(9):2213-21. doi: 10.1093/jac/dks207. Epub 2012 Jun 11.

Abstract

Objectives: Co-administration of artemether/lumefantrine with antiretroviral therapy has potential for pharmacokinetic drug interactions. We investigated drug-drug interactions between artemether/lumefantrine and efavirenz or nevirapine.

Methods: We performed a cross-over study in which HIV-infected adults received standard six-dose artemether/lumefantrine 80/480 mg before and at efavirenz or nevirapine steady state. Artemether, dihydroartemisinin, lumefantrine, efavirenz and nevirapine plasma concentrations were measured and compared.

Results: Efavirenz significantly reduced artemether maximum concentration (C(max)) and plasma AUC (median 29 versus 12 ng/mL, P < 0.01, and 119 versus 25 ng · h/mL, P < 0.01), dihydroartemisinin C(max) and AUC (median 120 versus 26 ng/mL, P < 0.01, and 341 versus 84 ng · h/mL, P < 0.01), and lumefantrine C(max) and AUC (median 8737 versus 6331 ng/mL, P = 0.03, and 280 370 versus 124 381 ng · h/mL, P < 0.01). Nevirapine significantly reduced artemether C(max) and AUC (median 28 versus 11 ng/mL, P < 0.01, and 123 versus 34 ng · h/mL, P < 0.01) and dihydroartemisinin C(max) and AUC (median 107 versus 59 ng/mL, P < 0.01, and 364 versus 228 ng · h/mL, P < 0.01). Lumefantrine C(max) and AUC were non-significantly reduced by nevirapine. Artemether/lumefantrine reduced nevirapine C(max) and AUC (median 8620 versus 4958 ng/mL, P < 0.01, and 66 329 versus 35 728 ng · h/mL, P < 0.01), but did not affect efavirenz exposure.

Conclusions: Co-administration of artemether/lumefantrine with efavirenz or nevirapine resulted in a reduction in artemether, dihydroartemisinin, lumefantrine and nevirapine exposure. These drug interactions may increase the risk of malaria treatment failure and development of resistance to artemether/lumefantrine and nevirapine. Clinical data from population pharmacokinetic and pharmacodynamic trials evaluating the impact of these drug interactions are urgently needed.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-HIV Agents / administration & dosage
  • Anti-HIV Agents / pharmacokinetics*
  • Antimalarials / administration & dosage
  • Antimalarials / pharmacokinetics*
  • Artemether, Lumefantrine Drug Combination
  • Artemisinins / administration & dosage
  • Artemisinins / pharmacokinetics*
  • Benzoxazines / administration & dosage
  • Benzoxazines / pharmacokinetics*
  • Cross-Over Studies
  • Drug Combinations
  • Drug Interactions*
  • Ethanolamines / administration & dosage
  • Ethanolamines / pharmacokinetics*
  • Female
  • Fluorenes / administration & dosage
  • Fluorenes / pharmacokinetics*
  • HIV Infections / complications
  • HIV Infections / drug therapy
  • Humans
  • Malaria / complications
  • Malaria / drug therapy
  • Male
  • Nevirapine / administration & dosage
  • Nevirapine / pharmacokinetics*
  • Plasma / chemistry
  • Uganda

Substances

  • Anti-HIV Agents
  • Antimalarials
  • Artemether, Lumefantrine Drug Combination
  • Artemisinins
  • Benzoxazines
  • Drug Combinations
  • Ethanolamines
  • Fluorenes
  • Nevirapine
  • efavirenz