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Pharmacokinetic Interactions Between Antiretroviral Agents and Antimalarial Drug Combinations

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00697892
Recruitment Status : Completed
First Posted : June 16, 2008
Last Update Posted : June 6, 2013
Sponsor:
Information provided by (Responsible Party):
Fran Aweeka, University of California, San Francisco

Study Description
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Brief 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.

Condition or disease Intervention/treatment Phase
HIV Infections Malaria Drug: lopinavir/ritonavir Drug: efavirenz Drug: artemether/lumefantrine Phase 1

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 38 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pharmacokinetic Interactions Between Antiretroviral Agents, Lopinavir/Ritonavir and Efavirenz and Antimalarial Drug Combinations, Artesunate/Amodiaquine and Artemether/Lumefantrine.
Study Start Date : July 2005
Actual Primary Completion Date : December 2008
Actual Study Completion Date : December 2010

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Group A4
healthy volunteers assigned to the efavirenz with artemether/lumefantrine intervention
 Drug: efavirenz
One 600mg tablet orally once daily before bedtime on an empty stomach for 26 days
Other Name: Sustiva

Drug: artemether/lumefantrine
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 Name: Coartem
Experimental: Group A3
healthy volunteers assigned to the lopinavir/ritonavir with artemether/lumefantrine intervention
 Drug: lopinavir/ritonavir
Two tablets of lopinavir 200mg / ritonavir 50mg orally twice daily with food for 26 days
Other Name: Kaletra

Drug: artemether/lumefantrine
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 Name: Coartem


Outcome Measures
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Primary Outcome Measures :
  1. AUC (zero to infinity) of the antimalarial agent [ Time Frame: Each 3-day antimalarial treatment course throughout study ]

Eligibility Criteria
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Ages Eligible for Study:   21 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Absence of HIV infection prior to study entry
  • Male or female aged 21-60 who are able to provide informed consent
  • Subject is within 20% (+/-) of ideal body weight and weighs at least 50 kg.
  • Healthy, without evidence of acute or chronic illness including diabetes, hypertension, CAD, psychiatric illnesses, renal or hepatic impairment.
  • Screening laboratory tests that are normal or deemed not clinically significant by the study physician.
  • Female subjects of reproductive potential must agree to the use of two forms of birth control methods for at least one month prior to study enrollment and for 6 weeks following study completion
  • Female subjects must have a negative pregnancy test within 24 hours before receiving any study drugs.

Exclusion Criteria:

  • Use of illicit drugs or alcohol that could interfere with the completion of the study
  • Use of any over-the-counter or prescribed drugs unless approved by the principal investigator or study physician
  • Use of drugs that are known to inhibit/induce CYP450 isozymes or are substrates of CYP3A4, CYP2D6, CYP2C8 enzymes (use of hormonal contraceptives is permitted).
  • Pregnant or breastfeeding
  • History of acute or chronic illnesses, such as diabetes, hypertension, CAD, psychiatric illnesses, renal or hepatic impairment.
  • Evidence of acute illness
  • Family history of congenital prolongation of QTc interval or with any conditions known to prolong QTc interval such as cardiac arrhythmias, bradycardia, or severe heart disease
  • History of hypokalemia, hypomagnesemia, or hypercholesteremia
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00697892


Locations
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United States, California
San Francisco General Hospital
San Francisco, California, United States, 94110
Sponsors and Collaborators
Fran Aweeka
Investigators
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Principal Investigator: Francesca T Aweeka, PharmD University of California, San Francisco
More Information
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Responsible Party: Fran Aweeka, Sponsor-Investigator, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT00697892    
Other Study ID Numbers: H6930-27654
First Posted: June 16, 2008    Key Record Dates
Last Update Posted: June 6, 2013
Last Verified: May 2013
Keywords provided by Fran Aweeka, University of California, San Francisco:
Human Immunodeficiency Virus
Drug Interactions
Additional relevant MeSH terms:
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HIV Infections
Malaria
Blood-Borne Infections
Communicable Diseases
Infections
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Genital Diseases
Urogenital Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
 Protozoan Infections
Parasitic Diseases
Vector Borne Diseases
Ritonavir
Lopinavir
Efavirenz
Lumefantrine
Artemether
Artemether, Lumefantrine Drug Combination
HIV Protease Inhibitors
Viral Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents