Effects of concurrent administration of nevirapine on the disposition of quinine in healthy volunteers

Soyinka, Julius O.; Onyeji, Cyprian O.; Omoruyi, Sharon I.; Owolabi, Adegbenga Rotimi; Sarma, P. V. V. Srirama; Cook, James M.

doi:10.1211/jpp.61.04.0004

Cited by 26 publications

(16 citation statements)

References 23 publications

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“…Interaction with one or more reported concomitant drugs (stavudine, lamivudine, or zidovudine) in this study is possible but unlikely because none of these drugs is involved in CYPP450 metabolism25 or shares significant overlapping metabolic pathways with quinine. Our finding is consistent with previous reports of quinine–antiretroviral drug interaction in healthy volunteers,13,14 and quinine–rifampin interaction in non-pregnant adults with acute falciparum malaria 12. However, CYP3A4-mediated interactions between antimalarial and antiretroviral drugs may be deleterious or beneficial.…”

supporting

confidence: 93%

“…Quinine is predominantly metabolized by CYP3A enzymes to its major active metabolite 3-hydroxyquinine,10 and subjected to clinically significant interactions with drugs that inhibit11 or induce12 this enzyme, including antiretroviral drugs 13,14. Inadequate quinine concentrations increase the risk of malaria treatment failure, and it is recommended that the trough level of total quinine be kept within 5–15 mg/L 12,15…”

mentioning

confidence: 99%

“…Quinine is primarily biotransformed to 3-hydroxyquinine by CYP3A4,10 and nevirapine is a potent inducer of this enzyme 24. The activation of the CYP3A family has been proposed for the interactions12,14 but clear mechanisms need further elucidation. Interaction with one or more reported concomitant drugs (stavudine, lamivudine, or zidovudine) in this study is possible but unlikely because none of these drugs is involved in CYPP450 metabolism25 or shares significant overlapping metabolic pathways with quinine.…”

mentioning

confidence: 99%

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Preliminary Study of Quinine Pharmacokinetics in Pregnant Women with Malaria-HIV Co-Infection

Kayentao¹,

Guirou²,

Doumbo³

et al. 2014

The American Society of Tropical Medicine and Hygiene

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Pregnant women bear the greatest burden of malaria–human immunodeficiency virus co-infection. Previous studies suggest that interaction with antiretroviral drugs may compromise antimalarial pharmacokinetics and treatment outcomes. We conducted a preliminary clinical study to assess quinine pharmacokinetics in Malian pregnant women with acute malaria who reported taking nevirapine-based antiretroviral therapy. Of seven women, six had stable concentrations of nevirapine in the plasma and one had none. Quinine concentrations were lower, and its metabolite 3-hydroxyquinine higher, in the six women with nevirapine than in the one without, and quinine concentrations were below the recommended therapeutic range in 50% of the women. This preliminary observation warrants further research to understand the impact of long-term antiretroviral therapy on the treatment of acute malaria.

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supporting

confidence: 93%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Preliminary Study of Quinine Pharmacokinetics in Pregnant Women with Malaria-HIV Co-Infection

Kayentao¹,

Guirou²,

Doumbo³

et al. 2014

The American Society of Tropical Medicine and Hygiene

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“…Ritonavir indeed is both a substrate and inhibitor of P-gp, therefore interaction at this level may explain the increase in Q concentration [52, 53]. After rifampicin, nevirapine and lopinavir co-administration, Q blood plasma concentrations were decreased [49, 54–56]. Rifampicin interacts with P-gp as substrate, inhibitor and inducer, and lopinavir has been found to inhibit P-gp [57–59].…”

Section: Discussionmentioning

confidence: 99%

Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity

Rijpma

Heuvel

Velden

et al. 2014

Malar J

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BackgroundTherapeutic blood plasma concentrations of anti-malarial drugs are essential for successful treatment. Pharmacokinetics of pharmaceutical compounds are dependent of adsorption, distribution, metabolism, and excretion. ATP binding cassette (ABC) transport proteins are particularly involved in drug deposition, as they are located at membranes of many uptake and excretory organs and at protective barriers, where they export endogenous and xenobiotic compounds, including pharmaceuticals. In this study, a panel of well-established anti-malarial drugs which may affect drug plasma concentrations was tested for interactions with human ABC transport proteins.MethodsThe interaction of chloroquine, quinine, artemisinin, mefloquine, lumefantrine, atovaquone, dihydroartemisinin and proguanil, with transport activity of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP) and multidrug resistance-associated proteins (MRP) 1–4 were analysed. The effect of the anti-malarials on the ATP-dependent uptake of radio-labelled substrates was measured in membrane vesicles isolated from HEK293 cells overexpressing the ABC transport proteins.ResultsA strong and previously undescribed inhibition of BCRP-mediated transport by atovaquone with a 50% inhibitory concentration (IC50) of 0.23 μM (95% CI 0.17-0.29 μM) and inhibition of P-gp-mediated transport by quinine with an IC50 of 6.8 μM (95% CI 5.9-7.8 μM) was observed. Furthermore, chloroquine and mefloquine were found to significantly inhibit P-gp-mediated transport. BCRP transport activity was significantly inhibited by all anti-malarials tested, whereas BSEP-mediated transport was not inhibited by any of the compounds. Both MRP1- and MRP3-mediated transport were significantly inhibited by mefloquine.ConclusionsAtovaquone and quinine significantly inhibit BCRP- and P-gp- mediated transport at concentrations within the clinically relevant prophylactic and therapeutic range. Co-administration of these established anti-malarials with drugs that are BCRP or P-gp substrates may potentially lead to drug-drug interactions.

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“…[18] A case report in a single patient observed increased P . falciparum parasitaemia in the presence of quinine in a patient taking nevirapine (attributed to CYP3A4 induction), and switching to atovaquone/proguanil was effective in treating the patient’s malaria.…”

Section: Resultsmentioning

confidence: 99%

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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Effects of concurrent administration of nevirapine on the disposition of quinine in healthy volunteers

Cited by 26 publications

References 23 publications

Preliminary Study of Quinine Pharmacokinetics in Pregnant Women with Malaria-HIV Co-Infection

Preliminary Study of Quinine Pharmacokinetics in Pregnant Women with Malaria-HIV Co-Infection

Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity

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

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