Pharmacokinetic Interactions Between Antiretroviral Agents and Antimalarial Drug Combinations
Condition: HIV Infections; Malaria
MeSH terms: HIV Infections; Malaria
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of the study is to determine in healthy volunteers whether certain anti-HIV
      medications (lopinavir/ritonavir and efavirenz) affect the drug levels of certain
      anti-malarial medications (artesunate/ amodiaquine and artemether/ lumefantrine) and vice
      versa. Since these drugs are degraded using overlapping pathways in the liver, it is
      predicted that changes in both drug level and overall drug exposure will be observed.
    

Detailed description: 
      HIV and malaria are two of the most pernicious diseases facing developing countries. Malaria
      affects 300 to 500 million individuals annually in developing countries and it is estimated
      that 25.8 million people in Africa live with HIV. Current therapy recommended by the World
      Health Organization includes the use of artemisinin derivatives, such as artesunate and
      artemether. To minimize the risk of resistance, these drugs are used in combination with
      older drugs with longer half-lives including amodiaquine and lumefantrine.

      Treatment of malaria is further complicated by the increasing availability of antiretroviral
      (ARV) medications for HIV in that clinically important drug-drug interactions may occur in
      co-infected patients. Protease inhibitor (e.g. lopinavir and ritonavir) and non-nucleoside
      reverse transcriptase (e.g. efavirenz) based treatment commonly affects pharmacokinetic
      exposure of drugs metabolized by cytochrome P450 (CYP) metabolic pathways.

      Artemether is metabolized by the CYP3A4 to active dihydroartemisinin (DHA), while artesunate
      is hydrolyzed to DHA. Lumefantrine is an active compound that is metabolized by CYP3A4.
      Amodiaquine is an active "prodrug" that is quickly metabolized to an active metabolite
      N-desethylamodiaquine (DEAQ) by CYP2C8. In addition, these antimalarial drugs may also affect
      the metabolism of CYP substrates, such as ARVs.

      The primary objective of this study is to investigate the effects of ARV agents (ritonavir/
      lopinavir (Kaletra) and efavirenz) on the pharmacokinetics of antimalarial drug combinations
      [artesunate/ amodiaquine and their active metabolites, and artemether/ lumefantrine
      (Coartem®) and their active metabolites]. The secondary objective is to investigate the
      effects of antimalarial drug combinations [artesunate/amodiaquine and artemether/lumefantrine
      (Coartem®)] on the pharmacokinetics of ARV drugs [lopinavir/ritonavir (Kaletra®) and
      efavirenz].

      If clinically important interactions occur, net effects may include improved or diminished
      antimalarial activity (as activity is attributed to both the parent drug and the active
      metabolite(s)) and drug toxicity. The study in HIV negative healthy volunteers will allow
      rapid assessment of these potential interactions and will provide essential data for
      optimizing a future clinical study and the use of ARVs and antimalarials for children and
      adults in Uganda.

      Currently the components of the study involving the impact of ARVs on artesunate/amodiaquine
      are not being pursued (and recruitment for those arms was conducted separately), so there are
      only two groups in the presently-approved trial: one in which the effects of
      lopinavir/ritonavir on artemether/lumefantrine are studied and another in which the effects
      of efavirenz on artemether/lumefantrine are studied.
    

Intervention name(s): lopinavir/ritonavir; efavirenz; artemether/lumefantrine
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Two tablets of lopinavir 200mg / ritonavir 50mg orally twice daily with food for 26 days; One 600mg tablet orally once daily before bedtime on an empty stomach for 26 days; 4 tablets of artemether 20mg/lumefantrine 120mg twice daily with food. 2 three-day courses will be administered (with washout in between) during the duration of the trial.
Other intervention name(s): Kaletra; Sustiva; Coartem
Intervention MeSH terms: Ritonavir; Lopinavir; Efavirenz; Lumefantrine; Artemether; Artemether, Lumefantrine Drug Combination
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Human Immunodeficiency Virus; Drug Interactions