Lower atovaquone/proguanil concentrations in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir

Luin, Matthijs van; Ende, Marchina E. van der; Richter, Clemens; Visser, Mirjam; Faraj, Diari; Ven, André van der; Gelinck, Luc Ben Stefan; Kroon, F.P.; Wit, Ferdinand W. N. M.; Schaik, Ron H.N. van; Kuks, Paul F. M.; Burger, David M.

doi:10.1097/qad.0b013e3283389129

Cited by 36 publications

(26 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another study demonstrated a significant decrease in ATO plasma concentration when taken in combination with efavirenz, lopinavir/ritonavir or atazanavir/ritonavir therapy [36]. Interaction at the level of metabolism through glucuronidation was proposed.…”

Section: Discussionmentioning

confidence: 99%

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

Rijpma

Heuvel

Velden

et al. 2014

Malar J

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Rijpma

Heuvel

Velden

et al. 2014

Malar J

View full text Add to dashboard Cite

show abstract

“…Efavirenz, through activation of constitutive androstane receptor (CAR) and/or pregnane X receptor (PXR), enhances the expression of multiple enzymes regulated by these nuclear receptors, including CYP2B6, CYP2C19 and CYP3A 5-6) . Therefore, many drug interactions associated with efavirenz at steady state including decreased exposures of methadone 7) , statins 8) , omeprazole 9) , voriconazole 10) , proguanil 11) and etravirine 12) , and protease inhibitors 13) can be primarily explained by the inductive effect of efavirenz. Furthermore, efavirenz enhances its own metabolism (auto-induction) upon repeated administration compared to a single dose 14) , probably through induction of CYP2B6 and other enzymes involved in its metabolism 2-4) .…”

Section: Introductionmentioning

confidence: 99%

In Vitro Analysis and Quantitative Prediction of Efavirenz Inhibition of Eight Cytochrome P450 (CYP) Enzymes: Major Effects on CYPs 2B6, 2C8, 2C9 and 2C19

Desta

2013

Drug Metabolism and Pharmacokinetics

View full text Add to dashboard Cite

Summary In order to quantitatively predict drug interactions associated with efavirenz-based anti-HIV therapy, we evaluated reversible and time-dependent inhibitions of efavirenz on eight cytochrome P450 (CYP) enzymes in vitro. Present study showed that efavirenz was a potent competitive inhibitor of CYP2B6 in HLMs (average Ki = 1.68 μM) and expressed CYP2B6 (Ki = 1.38 μM). Moderate inhibition of CYP2C8 by efavirenz was observed in pooled HLMs (Ki = 4.78 μM) and HLMs with CYP2C8*3/*3 genotype (Ki = 4.80 μM). Efavirenz was a moderate inhibitor of CYP2C9 (Ki= 19.46 μM) and CYP2C19 (Ki= 21.31 μM); and a weak inhibitor of CYP3A (Ki= 40.33 μM). No appreciable inhibition was observed on CYP1A2, CYP2A6 or CYP2D6. No time-dependent inhibition of the CYPs by efavirenz was observed in this study. Quantitative predictions showed that single dose of efavirenz may substantially slow the elimination of drugs predominately cleared by CYP2B6, CYP2C19 or by both enzymes and may also lower the area under the plasma concentration time curve (AUC) of active metabolites of some pro-drugs (e.g. clopidogrel and proguanil ) by up to 30%. Depending on substrates, chronic administration of efavirenz may increase the AUC of CYP2C8 and CYP2C9 substrates about 3.5 ~ 4.4-fold and 1.7 ~ 2.0-fold at steady state.

show abstract

“…A recent study administered a single dose of oral atovaquone/proguanil 250/ 100 mg to 76 participants who had been taking efavirenz 600 mg daily, atazanavir/ritonavir 300/100 mg daily, or lopinavir/ritonavir 400/100 mg twice daily or 800/200 mg once daily for at least 1 month. Compared to healthy volunteers, the AUC of both atovaquone and proguanil was decreased with all three cART regimens (46%-75% for atovaquone and about 40% for proguanil) [35]. The clinical relevance of these findings is unknown, since optimal plasma concentrations for malaria prophylaxis are not determined.…”

Section: Antimalarialsmentioning

confidence: 89%

“…There is a growing body of evidence on interactions with atovaquone/proguanil (Malarone®) and cART, since atovaquone is mainly glucuronidated, while proguanil is partly metabolized by CYP2C19 [35]. A recent study administered a single dose of oral atovaquone/proguanil 250/ 100 mg to 76 participants who had been taking efavirenz 600 mg daily, atazanavir/ritonavir 300/100 mg daily, or lopinavir/ritonavir 400/100 mg twice daily or 800/200 mg once daily for at least 1 month.…”

Section: Antimalarialsmentioning

confidence: 99%

Important Drug-Drug Interactions in HIV-Infected Persons on Antiretroviral Therapy: An Update on New Interactions Between HIV and Non-HIV Drugs

Tseng

Foisy²

2011

Curr Infect Dis Rep

View full text Add to dashboard Cite

Advances in antiretroviral therapy have turned HIV into a chronic, manageable disease. Patients often require treatment for co-morbid conditions as well as HIV, and consequently, pharmacokinetic interactions between antiretrovirals (ARVs) and other drug classes are an increasing concern. Protease inhibitors and non-nucleoside reverse transcriptase inhibitors are involved in the CYP450 or other transporter systems, and may be associated with higher risk of clinically significant drug interactions. One reverse transcriptase inhibitor, abacavir, has demonstrated weak inhibition of CYP3A4, 2D6 and 2C9 in vitro, but is not associated with any clinically significant interactions involving the CYP450 system. The integrase inhibitor raltegravir is not involved in the CYP450 system, and may be a suitable option to use when trying to minimize interactions with other drug classes. This review summarizes recently published data on clinically significant drug interactions between ARVs and other drug classes including antineoplastics, immunosuppressant transplant drugs, directly acting antivirals for hepatitis C, antifungals, antimalarials, corticosteroids, psychotropics, hormonal contraceptives, anticoagulants, drugs for pulmonary hypertension, and herbal products. In situations of suspected or potential interactions, close monitoring is warranted, and dose adjustments or substitutions may be required.

show abstract

Lower atovaquone/proguanil concentrations in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir

Cited by 36 publications

References 9 publications

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

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

In Vitro Analysis and Quantitative Prediction of Efavirenz Inhibition of Eight Cytochrome P450 (CYP) Enzymes: Major Effects on CYPs 2B6, 2C8, 2C9 and 2C19

Important Drug-Drug Interactions in HIV-Infected Persons on Antiretroviral Therapy: An Update on New Interactions Between HIV and Non-HIV Drugs

Contact Info

Product

Resources

About