- ICH GCP
- 미국 임상 시험 레지스트리
- 임상시험 NCT00619944
Drug Interaction Study Between Lumefantrine and Lopinavir/Ritonavir
Lumefantrine Pharmacokinetics When Administered as a Fixed Dose Combination With Artemether in HIV Positive Patients on Lopinavir/Ritonavir
연구 개요
상태
정황
상세 설명
In 2004 there were an estimated 40 million people living with HIV, 95% of whom live in the developing world. It is estimated that 5-6 million of these require antiretroviral therapy (ARV) now, and this number will continue to rise. At the recent G8 summit in Gleneagles, Scotland, a unanimous commitment to Universal Access to ARV by 2010 was made. This will result in an unprecedented number of individuals, predominantly in the developing world, commencing lifelong therapy with ARV. Currently the recommended second-line therapy for ARV is a combination of two nucleoside reverse-transcriptase inhibitors (NRTI) and a protease inhibitor (PI). The most widely recommended PI at this time in sub-Saharan Africa is Kaletra (Abbott Laboratories) which is a combination of lopinavir, a PI, and ritonavir, a PI that is a potent enzyme inhibitor and acts as a pharmacokinetic enhancer for lopinavir. Although Kaletra is highly effective in the treatment of HIV, it is a drug that has significant potential for drug-drug interactions. These are largely due to ritonavir's, and to a lesser extent lopinavir's, potent inhibition of Cytochrome P450 3A4 (CYP 3A4), which can result in dramatically raised levels of any co-administered drug metabolised by this same route.
Unfortunately these same people are also the constant victims of the malaria pandemic. There are at least 300 million acute cases of malaria each year globally, resulting in more than a million deaths, 90% of which occur in Africa. Increasing resistance to anti-malarials such as chloroquine, amodiaquine, fansidar, sulphadoxine-pyrimethamine (SP) 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. By 2004, fourteen countries in sub-Saharan Africa had adopted this as official policy, with the WHO applying pressure on the rest to follow as part of its Roll Back Malaria Campaign. The WHO's recommendations however makes no specific reference to the use of artemether-lumefantrine in HIV positive patients, particularly in patients who are being treated with ARV, although in it's document "Malaria and HIV/AIDS Interactions and Implications: Conclusions of a Technical Consultation Convened by WHO, 23-25 June, 2004" it states that "additional research on interactions between antiretroviral and antimalarial drugs is urgently needed." Coartem is already being used in sub-Saharan Africa as treatment for malaria in HIV-positive individuals on ARV, and this trend is likely to continue given the lack of explicit guidelines on their concomitant administration.
Lumefantrine and artemether are both extensively metabolized by CYP 3A4. To date, no data exist with regard to the potential interactions of these drugs with PI. This gives rise for concern, in particular in the case of lumefantrine, that patients administered both drugs concurrently are likely to have elevated lumefantrine levels with potential for associated toxicity. Lumefantrine, unlike its predecessor halofantrine, does not seem to prolong the QT interval (which can lead to adverse cardiac events), however there is no data with regard to the potential for adverse events when administered with PI. Given the unknown potential for interactions when co-administered with PI, in association with the massive roll out that is occurring of both these drugs across sub-Saharan Africa and their concomitant use in patients, it is essential that these issues be addressed to inform policy as a matter of urgency.
Preliminary or supportive data:
Artemether is metabolized via CYP 3A4 to dihydroartemisinin (although both compounds have antimalarial activity, dihydroartemisinin has greater potency). Inhibition of CYP 3A4 would reduce dihydroartemisinin but increase artemether and potentially increase the short half-life of artemether (1 - 2 hours). The effects of PI and NNRTI are unclear.
Lumefantrine and halofantrine are extensively metabolized by CYP 3A4. Inhibition of halofantrine metabolism could potentially prolong QT interval; given the narrow therapeutic index of this drug, combination with PI is contraindicated and NVP and EFV should be used with caution. Lumefantrine does not seem to prolong the QT interval and is much safer than halofantrine. In a single-dose study in combination with ketoconazole, a potent inhibitor of CYP 3A4, lumefantrine Cmax and AUC were doubled but no clinically significant QT effects were noted. Nevertheless, the Novartis Drug Monograph for Coartem lists CYP 3A4 inhibitors, including Ketoconazole and PI, under precautions/contraindications, despite stating in the same document that "dose adjustment of coartemether appears to be unnecessary when administered in association with ketoconazole or another potent inhibitor of CYP 3A4 activity." No studies however exist in the literature or are listed in the product monograph addressing the important potential interaction with PI. The WHO and a recent editorial in AIDS identify an urgent need for interaction data and state that studies should be prioritized to address this gap in knowledge. Currently in practice, coartem is being administered to patients in sub-Saharan Africa and WHO policy and guidelines do not address this issue.
Significance of the study:
As outlined in the background, this study is of urgent public health importance in the developing world where ARV and anti-malarials are used concomitantly. There are increasing numbers of HIV patients in Uganda moving on to second-line therapy with Kaletra and these are already being treated with coartem where they can afford it. The consequences of prescribing these drugs concomitantly have not been elucidated. The WHO has made no recommendations to guide treatment in this situation and there are no study data available to guide policy. Data generated by this study would help address this important gap which has been identified by WHO and others as meriting urgent investigation.
Hypothesis:
That administration of the lumefantrine and artemether-containing antimalarial combination therapy (Coartem) to HIV-positive patients receiving lopinavir/ritonavir (Kaletra) results in increased exposure to lumefantrine and/or artemether thus putting the patient at increased risk of toxicity from these drugs.
연구 유형
등록 (예상)
단계
- 4단계
연락처 및 위치
연구 장소
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Kampala, 우간다, 22418
- Infectious Diseases Institute, Faculty of Medicine, Makerere University
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참여기준
자격 기준
공부할 수 있는 나이
건강한 자원 봉사자를 받아들입니다
연구 대상 성별
설명
Inclusion Criteria:
- Age over eighteen
- Ability to provide full informed written consent
- Confirmed diagnosis of HIV infection
Exclusion Criteria:
- Haemoglobin < 8 g/dl
- HIV RNA (Viral Load) > 400 c/ml (if on antiretroviral therapy)
- Malaria Parasitaemia
- Liver and renal function tests > 3 times the upper limit of normal
- Pregnancy
- Use of known inhibitors or inducers of cytochrome P450 or P-glycoprotein
- Use of herbal medications
- QTc (Rate adjusted QT interval) > 450 ms (men) or > 470 ms (women)
- Intercurrent illness including malaria
공부 계획
연구는 어떻게 설계됩니까?
디자인 세부사항
- 주 목적: 기초 과학
- 할당: 무작위화되지 않음
- 중재 모델: 병렬 할당
- 마스킹: 없음(오픈 라벨)
무기와 개입
참가자 그룹 / 팔 |
개입 / 치료 |
---|---|
실험적: 1
Lumefantrine lopinavir drug interaction arm
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Lumefantrine 480 mg co-formulated with artemether 80 mg administered as single dose to HIV-positive adults receiving lopinavir/ritonavir 400 mg/100 mg twice daily
다른 이름들:
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활성 비교기: 2
lumefantrine only arm
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Lumefantrine 480 mg co-formulated with artemether 80 mg administered as a single dose to antiretroviral naive HIV-positive patients
다른 이름들:
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연구는 무엇을 측정합니까?
주요 결과 측정
결과 측정 |
기간 |
---|---|
12 hour pharmacokinetics profile of lumefantrine in HIV-positive patients receiving lopinavir/ritonavir
기간: 11 months
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11 months
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2차 결과 측정
결과 측정 |
기간 |
---|---|
Safety and tolerability of lumefantrine/artemether in HIV-positive Ugandan patients receiving lopinavir/ritonavir
기간: 11 months
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11 months
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공동 작업자 및 조사자
수사관
- 수석 연구원: Concepta A. Merry, PhD, University of Dublin, Trinity College
간행물 및 유용한 링크
일반 간행물
- Hoglund RM, Byakika-Kibwika P, Lamorde M, Merry C, Ashton M, Hanpithakpong W, Day NP, White NJ, Abelo A, Tarning J. Artemether-lumefantrine co-administration with antiretrovirals: population pharmacokinetics and dosing implications. Br J Clin Pharmacol. 2015 Apr;79(4):636-49. doi: 10.1111/bcp.12529.
- Byakika-Kibwika P, Lamorde M, Okaba-Kayom V, Mayanja-Kizza H, Katabira E, Hanpithakpong W, Pakker N, Dorlo TP, Tarning J, Lindegardh N, de Vries PJ, Back D, Khoo S, Merry C. Lopinavir/ritonavir significantly influences pharmacokinetic exposure of artemether/lumefantrine in HIV-infected Ugandan adults. J Antimicrob Chemother. 2012 May;67(5):1217-23. doi: 10.1093/jac/dkr596. Epub 2012 Feb 8.
연구 기록 날짜
연구 주요 날짜
연구 시작
기본 완료 (실제)
연구 완료 (실제)
연구 등록 날짜
최초 제출
QC 기준을 충족하는 최초 제출
처음 게시됨 (추정)
연구 기록 업데이트
마지막 업데이트 게시됨 (추정)
QC 기준을 충족하는 마지막 업데이트 제출
마지막으로 확인됨
추가 정보
이 연구와 관련된 용어
추가 관련 MeSH 약관
기타 연구 ID 번호
- CPR 003
이 정보는 변경 없이 clinicaltrials.gov 웹사이트에서 직접 가져온 것입니다. 귀하의 연구 세부 정보를 변경, 제거 또는 업데이트하도록 요청하는 경우 register@clinicaltrials.gov. 문의하십시오. 변경 사항이 clinicaltrials.gov에 구현되는 즉시 저희 웹사이트에도 자동으로 업데이트됩니다. .
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