- ICH GCP
- Registro degli studi clinici negli Stati Uniti
- Sperimentazione clinica 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
Panoramica dello studio
Stato
Condizioni
Intervento / Trattamento
Descrizione dettagliata
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.
Tipo di studio
Iscrizione (Anticipato)
Fase
- Fase 4
Contatti e Sedi
Luoghi di studio
-
-
-
Kampala, Uganda, 22418
- Infectious Diseases Institute, Faculty of Medicine, Makerere University
-
-
Criteri di partecipazione
Criteri di ammissibilità
Età idonea allo studio
Accetta volontari sani
Sessi ammissibili allo studio
Descrizione
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
Piano di studio
Come è strutturato lo studio?
Dettagli di progettazione
- Scopo principale: Scienza basilare
- Assegnazione: Non randomizzato
- Modello interventistico: Assegnazione parallela
- Mascheramento: Nessuno (etichetta aperta)
Armi e interventi
Gruppo di partecipanti / Arm |
Intervento / Trattamento |
---|---|
Sperimentale: 1
Lumefantrine lopinavir drug interaction arm
|
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
Altri nomi:
|
Comparatore attivo: 2
lumefantrine only arm
|
Lumefantrine 480 mg co-formulated with artemether 80 mg administered as a single dose to antiretroviral naive HIV-positive patients
Altri nomi:
|
Cosa sta misurando lo studio?
Misure di risultato primarie
Misura del risultato |
Lasso di tempo |
---|---|
12 hour pharmacokinetics profile of lumefantrine in HIV-positive patients receiving lopinavir/ritonavir
Lasso di tempo: 11 months
|
11 months
|
Misure di risultato secondarie
Misura del risultato |
Lasso di tempo |
---|---|
Safety and tolerability of lumefantrine/artemether in HIV-positive Ugandan patients receiving lopinavir/ritonavir
Lasso di tempo: 11 months
|
11 months
|
Collaboratori e investigatori
Sponsor
Collaboratori
Investigatori
- Investigatore principale: Concepta A. Merry, PhD, University of Dublin, Trinity College
Pubblicazioni e link utili
Pubblicazioni generali
- 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.
Studiare le date dei record
Studia le date principali
Inizio studio
Completamento primario (Effettivo)
Completamento dello studio (Effettivo)
Date di iscrizione allo studio
Primo inviato
Primo inviato che soddisfa i criteri di controllo qualità
Primo Inserito (Stima)
Aggiornamenti dei record di studio
Ultimo aggiornamento pubblicato (Stima)
Ultimo aggiornamento inviato che soddisfa i criteri QC
Ultimo verificato
Maggiori informazioni
Termini relativi a questo studio
Parole chiave
Termini MeSH pertinenti aggiuntivi
- Infezioni da virus a RNA
- Malattie virali
- Infezioni
- Infezioni a trasmissione ematica
- Malattie trasmissibili
- Malattie sessualmente trasmissibili, virali
- Malattie trasmesse sessualmente
- Infezioni da lentivirus
- Infezioni da retroviridae
- Sindromi da deficit immunologico
- Malattie del sistema immunitario
- Infezioni da HIV
- Meccanismi molecolari dell'azione farmacologica
- Agenti antinfettivi
- Agenti antivirali
- Inibitori enzimatici
- Agenti anti-HIV
- Agenti antiretrovirali
- Inibitori della proteasi
- Inibitori del citocromo P-450 CYP3A
- Inibitori dell'enzima del citocromo P-450
- Agenti antiprotozoici
- Agenti antiparassitari
- Inibitori della proteasi dell'HIV
- Inibitori virali della proteasi
- Antimalarici
- Ritonavir
- Lopinavir
- Lumefantrina
- Artemetere, combinazione di farmaci Lumefantrina
Altri numeri di identificazione dello studio
- CPR 003
Queste informazioni sono state recuperate direttamente dal sito web clinicaltrials.gov senza alcuna modifica. In caso di richieste di modifica, rimozione o aggiornamento dei dettagli dello studio, contattare register@clinicaltrials.gov. Non appena verrà implementata una modifica su clinicaltrials.gov, questa verrà aggiornata automaticamente anche sul nostro sito web .
Prove cliniche su Infezioni da HIV
-
University of MinnesotaRitiratoInfezioni da HIV | HIV/AIDS | HIV | AIDS | Problema di Aids/Hiv | AIDS e infezioniStati Uniti
-
Erasmus Medical CenterNon ancora reclutamentoInfezioni da HIV | HIV | Infezione da HIV-1 | Infezione da HIV IOlanda
-
Helios SaludViiV HealthcareSconosciutoHIV | Infezione da HIV-1Argentina
-
ANRS, Emerging Infectious DiseasesHopital Universitaire Robert-Debre; Institut de Recherche pour le Developpement; Centre Pasteur du Cameroun e altri collaboratoriSconosciutoHIV | Bambini non infetti da HIV | Bambini esposti all'HIVCamerun
-
University of MinnesotaCompletatoInfezioni da HIV | HIV | ImmunodeficienzaStati Uniti
-
Midway Specialty Care CenterNon ancora reclutamentoInfezioni da HIV | HIV | Infezione da HIV-1Stati Uniti
-
Allegheny Singer Research Institute (also known...Attivo, non reclutanteInfezioni da HIV | Infezione da HIV-1 | Infezione da HIV IStati Uniti
-
University of California, DavisCompletato
-
University of ChicagoUniversity of Athens; National Development and Research Institutes, Inc.Completato
-
University of ZimbabweCompletato
Prove cliniche su Lumefantrine - lopinavir/ritonavir drug interaction
-
Drugs for Neglected DiseasesUniversity of Cape Town; Medecins Sans Frontieres, Netherlands; UBS Optimus Foundation e altri collaboratoriCompletatoSindrome da immunodeficienza acquisita | TubercolosiSud Africa
-
AbbottCompletato
-
University College, LondonLifeArcCompletato
-
University of California, San DiegoAbbottCompletato
-
Fundacion SEIMC-GESIDAAbbottCompletatoInfezioni da HIV | Infezione da HIV | LipodistrofiaSpagna
-
Fundacion SEIMC-GESIDAAbbottCompletatoInfezioni da HIV | Coinfezione HIV/HCVSpagna
-
Institut National de la Santé Et de la Recherche...FUJIFILM Toyama Chemical Co., Ltd.ReclutamentoMalattia infettiva | FarmacologiaFrancia
-
St Stephens Aids TrustCompletato
-
Germans Trias i Pujol HospitalFundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción...Completato