Pharmacokinetic Interactions Between Antiretroviral Agents and Antimalarial Drug Combinations

HIV Infections Clinical Trial

Official title:

Pharmacokinetic Interactions Between Antiretroviral Agents, Lopinavir/Ritonavir and Efavirenz and Antimalarial Drug Combinations, Artesunate/Amodiaquine and Artemether/Lumefantrine.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00697892
• Other study ID #: H6930-27654
• Status: Completed
• Phase: Phase 1
• First received: June 2, 2008
• Last updated: June 4, 2013
• Start date: July 2005
• Est. completion date: December 2010

Study information

• Verified date: May 2013
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 38
• Est. completion date: December 2010
• Est. primary completion date: December 2008
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 21 Years to 60 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• HIV Infections
• Malaria

Intervention

Drug:
• lopinavir/ritonavir
Two tablets of lopinavir 200mg / ritonavir 50mg orally twice daily with food for 26 days
• efavirenz
One 600mg tablet orally once daily before bedtime on an empty stomach for 26 days
• 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.

Locations

Country	Name	City	State
United States	San Francisco General Hospital	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Fran Aweeka

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	AUC (zero to infinity) of the antimalarial agent		Each 3-day antimalarial treatment course throughout study	No