CYP2B6*6 genotype and high efavirenz plasma concentration but not nevirapine are associated with low lumefantrine plasma exposure and poor treatment response in HIV-malaria-coinfected patients

Maganda, Betty A; Minzi, Omary; Ngaimisi, Eliford; Kamuhabwa, Appolinary; Aklillu, Eleni

doi:10.1038/tpj.2015.37

Cited by 43 publications

(44 citation statements)

References 39 publications

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“…The overall lower lumefantrine exposure may be due in part to a decrease in oral bioavailability resulting from increased intestinal P-glycoprotein or CYP3A4 expression or to the 30-to 60-min delay in food intake in the nevirapine-based ART group (23). While reported studies were all conducted with adults, there were differences in study design (parallel groups, crossover, or historical controls), pharmacokinetic analysis (intensive sampling, population modeling, or day 7 sampling only), sample size, patient characteristics (malaria infection status, race, ethnicity, and gender), and food intake that may underlie these differences (8,10,11,13,14,22,24).A significant limitation of our study is the use of healthy historical controls as the comparator group. While the sampling protocols were nearly identical and assays were conducted in the same laboratory, differences in demographic features, ethnicity, and HIV status between subjects enrolled in the control and nevirapine-based ART groups are important (16,18,25).…”

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“…The control group received artemether-lumefantrine alone, following the same schedule but with food provided immediately postdose (16). Blood samples for quantification of artemether, DHA, lumefantrine, and nevirapine were collected around the sixth (last) dose on day 3, predose and 0.5, 1, 1.5, 2, 3, 4,6,8,10,12,24,48,72, and 96 h postdose. Pharmacokinetic sampling was identical for the control group, although samples were collected through 296 h. Plasma was stored at Ϫ80°C within 30 min after collection.…”

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Artemether-Lumefantrine Exposure in HIV-Infected Nigerian Subjects on Nevirapine-Containing Antiretroviral Therapy

Parikh

Fehintola

Huang

et al. 2015

Antimicrob Agents Chemother

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i Coadministration of nevirapine-based antiretroviral therapy (ART) and artemether-lumefantrine is reported to result in variable changes in lumefantrine exposure. We conducted an intensive pharmacokinetic study with 11 HIV-infected adults who were receiving artemether-lumefantrine plus nevirapine-based ART, and we compared the results with those for 16 HIV-negative adult historical controls. Exposure to artemether and lumefantrine was significantly lower and dihydroartemisinin exposure was unchanged in subjects receiving nevirapine-based ART, compared with controls. Nevirapine exposure was unchanged before and after artemether-lumefantrine administration. Malaria and HIV affect millions of children and adults in subSaharan Africa, and drug-drug interactions between antiretroviral therapy (ART) and antimalarial agents are clinically important to characterize. Nevirapine-based ART represents 50% of first-line ART in regions where malaria coinfection occurs (1). Artemether-lumefantrine, an artemisinin derivative combined with a longer-acting partner drug, represents the most common antimalarial therapy (2, 3). Metabolism of these HIV and antimalarial agents occurs primarily via cytochrome P450 (CYP) enzymes. Artemether is metabolized to an active metabolite, dihydroartemisinin (DHA), predominately by CYP3A4/5 and to a lesser extent by CYP2B6, CYP2C9, and CYP2C19 (4). DHA undergoes glucuronidation by uridine diphosphoglucuronosyltransferases. Lumefantrine is metabolized by CYP3A4 into active desbutyl-lumefantrine (2, 4, 5). Nevirapine is metabolized by CYP3A4 and CYP2B6 while inducing CYP3A4 (6, 7). Studies report reduced artemisinin exposure in the presence of nevirapinebased ART, but the effects on lumefantrine concentrations are variable, with studies showing increased, decreased, or unchanged concentrations (8)(9)(10)(11)(12)(13)(14). Importantly, reduced antimalarial levels have been associated with therapeutic failure (12,13,15). The primary objective of this study was to evaluate the pharmacokinetics of artemether, DHA, and lumefantrine in HIV-infected Nigerian adults without clinical malaria who were receiving nevirapine-based ART.(Data were presented at the 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, Washington, DC, 19 May 2014.) HIV-infected subjects (Ն18 years of age) who had been receiving nevirapine-based ART for Ն4 weeks (nevirapine-based ART group) were eligible after informed consent was obtained. Exclusion criteria were current pregnancy; intolerance to study drugs; use of antimalarials or CYP substrates, inducers, or inhibitors within 4 weeks; and clinical symptoms of malaria. The historical control group included healthy adults (n ϭ 16). The same laboratory analyzed all plasma drug concentrations (16). The University College Hospital Ethics Committee approved this study (protocol NHREC/05/01/2008a).Participants received coformulated nevirapine-zidovudinelamivudine (200/300/150 mg; Aurobindo Pharma, India) twice daily. On day 0, participants underwent venou...

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Artemether-Lumefantrine Exposure in HIV-Infected Nigerian Subjects on Nevirapine-Containing Antiretroviral Therapy

Parikh

Fehintola

Huang

et al. 2015

Antimicrob Agents Chemother

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“…In the absence of concomitant EFV, CYP2B6*6 genotype had no significant influence on lumefantrine plasma exposure. [44] Patients with CYP2B6*6 genotype are at increased risk of QT interval prolongation[45], so monitoring is warranted when co-administering EFV with lumefantrine.…”

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Development of an evidence evaluation and synthesis system for drug-drug interactions, and its application to a systematic review of HIV and malaria co-infection

et al. 2017

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BackgroundIn all settings, there are challenges associated with safely treating patients with multimorbidity and polypharmacy. The need to characterise, understand and limit harms resulting from medication use is therefore increasingly important. Drug-drug interactions (DDIs) are prevalent in patients taking antiretrovirals (ARVs) and if unmanaged, may pose considerable risk to treatment outcome. One of the biggest challenges in preventing DDIs is the substantial gap between theory and clinical practice. There are no robust methods published for formally assessing quality of evidence relating to DDIs, despite the diverse sources of information. We defined a transparent, structured process for developing evidence quality summaries in order to guide therapeutic decision making. This was applied to a systematic review of DDI data with considerable public health significance: HIV and malaria.Methods and findingsThis was a systematic review of DDI data between antiretrovirals and drugs used in prophylaxis and treatment of malaria. The data comprised all original research in humans that evaluated pharmacokinetic data and/or related adverse events when antiretroviral agents were combined with antimalarial agents, including healthy volunteers, patients with HIV and/or malaria, observational studies, and case reports. The data synthesis included 36 articles and conference presentations published via PubMed and conference websites/abstract books between 1987-August 2016. There is significant risk of DDIs between HIV protease inhibitors, or NNRTIs and artemesinin-containing antimalarial regimens. For many antiretrovirals, DDI studies with antimalarials were lacking, and the majority were of moderate to very low quality. Quality of evidence and strength of recommendation categories were defined and developed specifically for recommendations concerning DDIs.ConclusionsThere is significant potential for DDIs between antiretrovirals and antimalarials. The application of quality of evidence and strength of recommendation criteria to DDI data is feasible, and allows the assessment of DDIs to be robust, consistent, transparent and evidence-based.

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“…Few recent studies have investigated the pharmacogenetics of antimalarial drugs and its relevance for antiretroviral and antimalarial drug interaction in HIV–malaria coinfected patients receiving dual therapy in Africa . Lumefantrine, a long‐acting antimalarial drug, is metabolized by CYP3A4, an enzyme inducible by efavirenz .…”

Section: African Pharmacogenomics Research Consortium: Focus On Hiv mentioning

confidence: 99%

Conference report: pharmacogenomics in special populations at WCP2018

Suarez‐Kurtz

Aklillu

Saito

et al. 2019

Brit J Clinical Pharma

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The 18th World Congress of Basic and Clinical Pharmacology (WCP2018), coordinated by IUPHAR and hosted by the Japanese Pharmacological Society and the Japanese Society of Clinical Pharmacology and Therapeutics, was held in July 2018 at the Kyoto International Conference Center, in Kyoto, Japan. Having as its main theme ‘Pharmacology for the Future: Science, Drug Development and Therapeutics’, WCP2018 was attended by over 4500 delegates, representing 78 countries. The present report is an overview of a symposium at WCP2018, entitled Pharmacogenomics in Special Populations, organized by IUPHAR´s Pharmacogenetics/Genomics (PGx) section. The PGx section congregates distinguished scientists from different continents, covering expertise from basic research, to clinical implementation and ethical aspects of PGx, and one of its major activities is the coordination of symposia and workshops to foster exchange of PGx knowledge (https://iuphar.org/sections-subcoms/pharmacogenetics-genomics/). The symposium attracted a large audience to listen to presentations covering various areas of research and clinical adoption of PGx in Oceania, Africa, Latin America and Asia.

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CYP2B6*6 genotype and high efavirenz plasma concentration but not nevirapine are associated with low lumefantrine plasma exposure and poor treatment response in HIV-malaria-coinfected patients

Cited by 43 publications

References 39 publications

Artemether-Lumefantrine Exposure in HIV-Infected Nigerian Subjects on Nevirapine-Containing Antiretroviral Therapy

Artemether-Lumefantrine Exposure in HIV-Infected Nigerian Subjects on Nevirapine-Containing Antiretroviral Therapy

Development of an evidence evaluation and synthesis system for drug-drug interactions, and its application to a systematic review of HIV and malaria co-infection

Conference report: pharmacogenomics in special populations at WCP2018

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