Pharmacokinetic Interaction of Ritonavir-Boosted Elvitegravir and Maraviroc

Ramanathan, S.; Abel, Sylvie; Tweedy, Sarah; West, Steve; Hui, James; Kearney, Brian P.

doi:10.1097/qai.0b013e3181ba4536

Cited by 29 publications

(26 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Maraviroc was approved based on the MOTIVATE trials comprised of 85% individuals with European ancestry (Gulick et al, 2008) and most previous maraviroc pharmacokinetic studies were conducted in participants with European ancestry, with the median percentage of participants with European ancestry at 78.5% (Abel et al, 2008a,b,c,d,f;Chan et al, 2008;Pozniak et al, 2008;Dumond et al, 2009;Andrews et al, 2010;Ramanathan et al, 2010;Brown et al, 2011;Kakuda et al, 2011;Gruber et al, 2013;Mora-Peris et al, 2013;Taiwo et al, 2013;Vourvahis et al, 2013). A few studies compared maraviroc concentrations in individuals with African ancestry with individuals with European ancestry and concluded that there were no differences or higher concentrations in individuals with African ancestry (FDA, 2007;Okoli et al, 2012), which may be due to the use of CYP3A inhibitors such as ritonavir in the optimized background therapy in which CYP3A5 activity may have been inhibited in individuals who are carrying CYP3A5*1 allele.…”

Section: Discussionmentioning

confidence: 99%

CYP3A5 Genotype Impacts Maraviroc Concentrations in Healthy Volunteers

Fuchs

Hendrix

et al. 2014

Drug Metabolism and Disposition

View full text Add to dashboard Cite

CYP3A5 plays a prominent role in the metabolism of maraviroc, an approved drug for human immunodeficiency virus (HIV)-1 treatment and a candidate for HIV-1 prevention. We studied the effect of the CYP3A5 genotype on pharmacokinetics of maraviroc and a primary CYP3A5-dependent metabolite of maraviroc denoted as metabolite 1 (M1). Volunteers were screened for health status and CYP3A5 genotype (wild-type allele *1 and dysfunctional alleles *2, *3, *6, and *7) to obtain 24 evaluable subjects in three groups (n = 8 each): homozygous dysfunctional (two dysfunctional alleles), heterozygous (one *1 allele and one dysfunctional allele), and homozygous wild-type (two *1 alleles). Subjects received 300 mg maraviroc orally followed by blood collection for 32 hours. The homozygous wild-type group exhibited lower mean plasma maraviroc concentrations at almost all sampling times. The median (interquartile range) maraviroc area under the plasma concentration-time curves from time 0 to infinity (AUC 0-inf ) were 2099 (1422-2568) ng×h/ml, 1761 (931-2640) ng×h/ml, and 1238 (1065-1407) ng×h/ml for the homozygous dysfunctional, heterozygous, and homozygous wildtype groups, respectively. The homozygous wild-type group had 41% lower maraviroc AUC 0-inf and 66% higher apparent clearance compared with the homozygous dysfunctional group (P = 0.02). The AUC 0-inf ratios of maraviroc to M1 in heterozygous and homozygous wild-type subjects were lower by 51 and 64% relative to the homozygous dysfunctional group, respectively (P < 0.001). In conclusion, the lower maraviroc concentrations in the homozygous wild-type group indicate that maraviroc may be underdosed in people homozygous for the CYP3A5*1 allele, including almost onehalf of African Americans.

show abstract

Section: Discussionmentioning

confidence: 99%

CYP3A5 Genotype Impacts Maraviroc Concentrations in Healthy Volunteers

Fuchs

Hendrix

et al. 2014

Drug Metabolism and Disposition

View full text Add to dashboard Cite

show abstract

“…This is consistent with the clinical observation that the pharmacoenhancement effect of RTV results from inhibition of CYP3A and that it persists beyond the time that the plasma concentrations of RTV are adequately above or close to K i values conferring direct inhibition of the enzymes. [13][14][15] Besides affecting the PKs of HIV PI drugs, RTV has been shown in clinical studies to enhance the PKs of important antiviral drugs that are CYP3A substrates, including the HIV-1 integrase inhibitor elvitegravir, 16 the CCR5 antagonist maraviroc, 17,18 and the HCV PI narlaprevir. 19 Elvitegravir is metabolized primarily by CYP3A4 in the liver and intestine.…”

mentioning

confidence: 99%

Cobicistat (GS-9350): A Potent and Selective Inhibitor of Human CYP3A as a Novel Pharmacoenhancer

Xu¹,

Liu²,

Murray³

et al. 2010

ACS Med. Chem. Lett.

172

165

View full text Add to dashboard Cite

Cobicistat (3, GS-9350) is a newly discovered, potent, and selective inhibitor of human cytochrome P450 3A (CYP3A) enzymes. In contrast to ritonavir, 3 is devoid of anti-HIV activity and is thus more suitable for use in boosting anti-HIV drugs without risking selection of potential drug-resistant HIV variants. Compound 3 shows reduced liability for drug interactions and may have potential improvements in tolerability over ritonavir. In addition, 3 has high aqueous solubility and can be readily coformulated with other agents.

show abstract

“…A minimum sample size of 12 subjects per cohort was planned to provide 90% confidence intervals (CI) for the difference between the treatments on the natural log scale for AUC , C max , and C of Ϯ0.0722, Ϯ0.1705, and Ϯ0.0582, respectively, for MVC; Ϯ0.1049, Ϯ0.1116, and Ϯ0.2542, respectively, for APV; and Ϯ0.079, Ϯ0.1541, and Ϯ0.1723, respectively, for RTV, with 80% coverage probability. These precision values were calculated by using the Clinical Biostatistics Executable Tool (Pfizer, Inc., New York, NY) and assumed the estimated intrasubject standard deviations of natural log AUC , C max , and C to be 0.119, (19). To allow for any subjects who might not complete the study, 14 subjects were recruited for each cohort.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic Interaction between Maraviroc and Fosamprenavir-Ritonavir: an Open-Label, Fixed-Sequence Study in Healthy Subjects

Vourvahis

Plotka

Costa

et al. 2013

Antimicrob Agents Chemother

View full text Add to dashboard Cite

dThis open-label, fixed-sequence, phase 1 study evaluated the pharmacokinetic interaction between maraviroc (MVC) and ritonavir-boosted fosamprenavir (FPV/r) in healthy subjects. In period 1, subjects received 300 mg of MVC twice daily (BID; cohort 1) or once daily (QD; cohort 2) for 5 days. In period 2, cohort 1 subjects received 700/100 mg of FPV/r BID alone on days 1 to 10 and then FPV/r at 700/100 mg BID plus MVC at 300 mg BID on days 11 to 20; cohort 2 subjects received FPV/r at 1,400/100 mg QD alone on days 1 to 10 and then FPV/r at 1,400/100 mg QD plus MVC at 300 mg QD on days 11 to 20. Pharmacokinetic parameters, assessed on day 5 of period 1 and on days 10 and 20 of period 2, included the maximum plasma concentration (C max ), the concentration at end of dosing interval (C ), and the area under the curve over dosing interval (AUC ). Safety and tolerability were also assessed. MVC geometric mean AUC , C max , and C were increased by 149, 52, and 374%, respectively, after BID dosing with FPV/r, and by 126, 45, and 80%, respectively, after QD dosing. Amprenavir (the active form of the prodrug fosamprenavir) and ritonavir exposures were decreased in the presence of MVC with amprenavir AUC , C max , and C decreased by 34 to 36% in the presence of FPV/r plus maraviroc BID and by 15 to 30% with FPV/r plus MVC QD both compared to FPV/r alone. The overall all-causality adverse-event (AE) incidence rate was 96.4%; all AEs were of mild or moderate severity. Commonly reported treatment-related AEs (>20% of patients overall) included diarrhea, fatigue, abdominal discomfort, headache, and nausea. No serious AEs or deaths occurred. In summary, maraviroc exposure increased in the presence of FPV/r, whereas MVC coadministration decreased amprenavir and ritonavir exposures. MVC dosed at 300 mg BID with FPV/r is not recommended due to concerns of lower amprenavir exposures; however, no dose adjustment is warranted with MVC at 150 mg BID in combination with FPV/r based on the available clinical data. MVC plus FPV/r was generally well tolerated; no new safety signals were detected. M araviroc (MVC) is a first-in-class selective chemokine coreceptor type-5 (CCR5) antagonist indicated for the treatment of CCR5-tropic (R5) HIV-1 infection in both treatmentnaive and treatment-experienced patients in the United States (1), as well as treatment-experienced patients in the European Union (2). MVC is primarily metabolized by hepatic and intestinal cytochrome P450 3A4 (CYP3A4) enzymes, with negligible metabolic activity for other CYP enzymes, and is also a substrate for the efflux transport P-glycoprotein (P-gp) (3).As a component of combination regimens, MVC is frequently administered with other antiretroviral agents, including protease inhibitors (PIs) (4, 5). Since the majority of PIs are inhibitors of CYP3A and P-gp, potential exists for drug interactions with MVC. Indeed, MVC exposures have been shown to be increased in the presence of atazanavir, ritonavir (RTV)-boosted atazanavir (atazanavir/r), saquinavir, saquinavir/r, daru...

show abstract

Pharmacokinetic Interaction of Ritonavir-Boosted Elvitegravir and Maraviroc

Abstract: During elvitegravir/r plus maraviroc administration, no elvitegravir or ritonavir dose change and a reduced 150-mg dose of maraviroc are recommended.

Cited by 29 publications

References 14 publications

CYP3A5 Genotype Impacts Maraviroc Concentrations in Healthy Volunteers

CYP3A5 Genotype Impacts Maraviroc Concentrations in Healthy Volunteers

Cobicistat (GS-9350): A Potent and Selective Inhibitor of Human CYP3A as a Novel Pharmacoenhancer

Pharmacokinetic Interaction between Maraviroc and Fosamprenavir-Ritonavir: an Open-Label, Fixed-Sequence Study in Healthy Subjects

Contact Info

Product

Resources

About