Drug Interaction Between Coartem® and Nevirapine, Efavirenz or Rifampicin in HIV Positive Ugandan Patients
Verified December 2010
Health Research Board, Ireland
Information provided by (Responsible Party)
First received: February 7, 2008
Last updated: December 3, 2010
Last Verified: December 2010
History of Changes
There are increasing numbers of HIV-infected patients in sub-Saharan Africa receiving
antiretroviral drugs and/or rifampicin based antituberculous therapy. HIV infected patients
are at an increased risk of contracting malaria. Increasing resistance to anti-malarials such
as chloroquine, amodiaquine, fansidar, sulphadoxine-pyrimethamine in East and West Africa has
led the WHO to recommend artemether-lumefantrine (Coartem®- Novartis) as first line therapy
for malaria for adults and children. As early as 2004, fourteen countries in sub-Saharan
Africa had adopted this guideline as national policy.
There are no data on the interaction between Coartem® and any of the antiretroviral agents. Both components of Coartem® are substrates for the 3A4 isoform of cytochrome P450. Despite the lack of data, antiretroviral drugs and/or antituberculous drugs in addition to Coartem® are of necessity co-prescribed daily in the African setting. Nevirapine, efavirenz and rifampicin are known inducers of cytochrome P450 3A4. A technical consultation convened by WHO in June, 2004 concluded that additional research on interactions between antiretroviral and antimalarial drugs is urgently needed.
We propose to perform a suite of pharmacokinetic studies to evaluate these interactions in HIV infected Ugandan patients. The aim of these studies is to evaluate the pharmacokinetic interaction between Coartem® and commonly co-prescribed inducers of 3A4 i.e. nevirapine, efavirenz and rifampicin.
- Comparison of steady state pharmacokinetics of Coartem® in HIV-infected patients prior to commencement of nevirapine and at nevirapine steady state
- Comparison of steady state pharmacokinetics of Coartem® in HIV-infected patients prior to commencement of efavirenz and at efavirenz steady state
- Comparison of steady state pharmacokinetics of Coartem® in Ugandan patients at
Drug : Lumefantrine-artemether and nevirapine
Drug : lumefantrine-artemether and efavirenz
Drug : Lumefantrine-artemether and rifampicin
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||Pharmacokinetic Interaction Between Coartem® and Either Nevirapine, Efavirenz or Rifampicin in HIV Positive Ugandan Patients|
Further study details as provided by Makerere University:
Primary Outcome Measures
- Pharmacokinetics of lumefantrine in patients receiving either nevirapine, efavirenz or rifampicin [ Time Frame: 11 months ]
|Study Start Date:||February 2008|
|Estimated Study Completion Date:||July 2011|
|Estimated Primary Completion Date:||July 2011 (Final data collection date for primary outcome measure)|
Lumefantrine-artemether and nevirapine
Administration of lumefantrine 480mg co-formulated with artemether 80mg twice daily for three days to HIV positive patients receiving nevirapine 200mg twice daily as part of their antiretroviral treatment
lumefantrine-artemether and efavirenz
Administration of lumefantrine 480mg co-formulated with artemether 80mg twice daily for three days to HIV positive adults receiving efavirenz tablets 600mg once daily
Lumefantrine-artemether and rifampicin
Administration of lumefantrine 480mg co-formulated with artemether 80mg twice daily for three days to patients receiving rifampicin as part of fixed dose combination therapy for tuberculosis
Other Name: Coartem
Coartem® is the combination of artemether and lumefantrine used for the treatment of
uncomplicated falciparum malaria 1. This oral combination seems to be well-tolerated and is
useful for treatment of multi-drug resistant Plasmodium falciparum. This unique anti-malarial
agent combines the fast, but short-acting artemether with a less potent, but longer-acting
lumefantrine. Original studies with the combination demonstrated safety and efficacy in
adults and children with uncomplicated falciparum malaria. 2,3 Additional studies showed
superiority with respect to parasite clearance time versus halofantrine,4 chloroquine5, and
mefloquine6. Coartem® also demonstrated a faster reduction in parasite burden after 24-hours
versus halofantrine4, chloroquine5 (in adults), chloroquine (in children) 7, and mefloquine6.
Various other studies have shown artemether-lumefantrine to have a superior 28-day cure rate,
as well as time to fever resolution compared to other antimalarial agents.1 Both components
of Coartem® were discovered in China. Artemether was isolated from sweet wormwood, Atemisia
annua, which has been used in traditional Chinese medicine for over 2000 years 1.
Lumefantrine is a synthetic compound, which has structural and physiochemical
characteristics; and a mode of action similar to other antimalarials, including quinine,
mefloquine, and halofantrine 8. In vitro, the two antimalarial agents show synergistic
activity against P.falciparum. Based on both in vitro and in vivo studies, a 1:6 ratio of
artemether to lumefantrine has been described as optimal. Thus, the tablets are manufactured
as 20mg artemether and 120mg lumefantrine. 8 Currently there are two recommended dosing
regimen for adults and children above 35 kg; or 12 years of age or older. In partially immune
patients, a 4-dose regimen is recommended. Four tablets as a single dose should be taken at
time of diagnosis and then again at 8, 24, and 48 hours post-initial dose. A different
regimen is recommended for either non-immune patients or patients in areas where multi-drug
resistance to falciparum malaria is a problem. This is a 3-day regimen consisting of 4
tablets as a single dose given at the time of diagnosis, 8 hours later and then twice daily
for the following two days. 1
Antimalarial Activity and Mechanism of Action: 1, 8 The antimalarial activity of artemether and that of its active metabolite, dihydroartemisinin (DHA) have been extensively studied in vitro. These are very potent antimalarial compounds. The IC50 of artemether ranges from 0.1 to 20 nmol/L and the IC50 for DHA ranges from 0.1 to 15 nmol/L. In vitro studies have shown artemether to be 2 to 3 times less active than its metabolite, DHA.
The exact mechanisms of action of artemether and lumefantrine are unknown, but both agents appear to act on the parasite's organelles. Artemether's action depends on its endoperoxide bridge, which interacts with heme iron to cause free radical damage to the malaria parasite. Lumefantrine most likely interferes with heme polymerization, which is a critical detoxifying pathway for the malaria parasite. Both agents may have secondary actions that include inhibition of parasite nucleic acid and protein synthesis; however, these actions have not been well-described.
The varied pharmacokinetic profiles of the two antimalarial agents appear to create a synergistic effect. Artemether works rapidly to decrease the parasite load and improve patients' clinical symptoms. Lumefantrine is long-acting and appears to prevent recrudescence (reappearance of the disease after inadequate or failed drug therapy). The different actions of the two agents may also reduce the emergence of resistance. Artemether and DHA have been shown to decrease parasite burden by about 104 per asexual life cycle in about 2 days. Thus, the 3-day course of the combination therapy can potentially decrease the parasite burden by about 108.
Drug Interactions Pharmacokinetic and electrocardiographic interactions between artemether-lumefantrine and the mefloquine were studied in 42 healthy volunteers. Like artemether-lumefantrine, mefloquine is a substrate for CYP 3A4; however, it is also a potential CYP 3A4 inhibitor. Pharmacokinetic parameters for artemether, DHA, and mefloquine were unchanged; however, lumefantrine concentrations decreased by 30-40% when given with mefloquine. The clinical significance of this interaction is not known. Co-administration of the antimalarial agents resulted in no increased adverse effects. 13
An additional study evaluated the effects of concomitant administration with ketoconazole, a potent CYP 3A4 inhibitor, and artemether-lumefantrine. The study was carried out in 16 healthy volunteers who received single doses of artemether-lumefantrine either alone or in combination with multiple doses of ketoconazole. Artemether, DHA, and lumefantrine pharmacokinetics were altered by ketoconazole. AUC and Cmax increased for all three compounds and terminal half-life increased for artemether and DHA. None of the changes in PK parameters were greater than those changes observed in healthy volunteers taking artemether-lumefantrine with a high fat meal (i.e. a 16-fold increase in AUC). There was no increase in observed side effects or electrocardiographic changes. Dosage adjustments do not appear to be necessary with concomitant ketoconazole administration.14
A study of 42 healthy Caucasian volunteers was conducted to investigate pharmacokinetic or electrocardiographic effects of concomitant administration of IV quinine and artemether-lumefantrine. QTc prolongation was not associated with artemether-lumefantrine administration alone; however transient increases in QTc interval were noted in the combination groups. PK variables for lumefantrine and quinine were unchanged, but artemether and DHA plasma concentrations decreased with concomitant quinine administration. The exact mechanism for this decrease could not be explained for the results of this study.15
Artemether is metabolized via CYP 3A4 to dihydroartemisinin (although both compounds have antimalarial activity, dihydroartemisinin has greater potency). Induction of CYP 3A4 would increase dihydroartemisinin but decrease artemether.
Study objectives General objective To evaluate the pharmacokinetic interaction between Coartem® and commonly co-prescribed inducers of 3A4 i.e. nevirapine, efavirenz and rifampicin in HIV positive patients.
- To compare the steady state pharmacokinetics of Coartem® in HIV-infected patients prior to commencement of nevirapine and at nevirapine steady state
- To compare the steady state pharmacokinetics of Coartem® in HIV-infected patients prior to commencement of efavirenz and at efavirenz steady state
- To compare the steady state pharmacokinetics of Coartem® in Ugandan patients at
|Ages Eligible for Study:||18 Years to 60 Years|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- Age over eighteen years
- Ability to provide full written informed consent
- Confirmed diagnosis of HIV infection
- Haemoglobin < 8g/dl
- Liver and renal function tests > 3 times the upper limit of normal
- Use of known inhibitors or inducers of cytochrome P450 or P-glycoprotein.
- Use of herbal medications (information will be obtained from patients' medication history through interview with the patient)
- Abnormal EKG ie QTc (Rate adjusted QT interval) >450ms (men) or >470ms (women)
- Intercurrent Illness including malaria
- Known hypersensitivity to artemisinin-derivatives, halofantrine or lumefantrine
- History of cardiac disease
Contacts and LocationsChoosing to participate in a study is an important personal decision.Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.For general information, see Learn About Clinical Studies.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00620438
Locations Show More
|Infectious Diseases Institute, Makerere University|
|Kampala, Uganda, 22418|
Sponsors and CollaboratorsMakerere University
Health Research Board, Ireland
|Principal Investigator:||Concepta Merry, PhD||Trinity Colleg Dublin|
|Responsible Party:||Concepta Merry, Infectious Diseases Institute, Makerere University|
|ClinicalTrials.gov Identifier:||NCT00620438 History of Changes|
|Other Study ID Numbers:||CPR 005|
|Study First Received:||February 7, 2008|
|Last Updated:||December 3, 2010|
Keywords provided by Makerere University:Lumefantrine
Additional relevant MeSH terms:
ClinicalTrials.gov processed this data on March 21, 2018
This information is provided by ClinicalTrials.gov.