Clinical Relevance of CYP3A5 Genotype on Maraviroc Exposures

Vourvahis, Manoli; McFadyen, Lynn; Heera, Jayvant; Clark, Andrew

doi:10.1124/dmd.115.063321

Cited by 7 publications

(4 citation statements)

References 14 publications

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“…This has been shown in the clinic wherein CYP3A5 EM subjects have been shown to have between 26% and 41% lower exposure to MVC and a higher (1S,2S)-2-OH-MVC to MVC exposure ratio, consistent with estimates made from the in vitro data (M. Vourvahis, manuscript in preparation; Lu et al, 2014). However, it is also the observation that these lower exposures are still in excess of exposures associated with near-maximal MVC virologic efficacy, which may explain why there was no observation of decreased efficacy in CYP3A5 EM patients in the phase 3 efficacy trials of MVC (McFadyen et al, 2008;Vourvahis et al, 2015). Additionally, it should be noted that in clinical practice, many HIV patients receive MVC in the presence of CYP3A-inhibiting protease inhibitors.…”

Section: Discussionsupporting

confidence: 72%

Biosynthesis and Identification of Metabolites of Maraviroc and Their Use in Experiments to Delineate the Relative Contributions of Cytochrome P4503A4 versus 3A5

et al. 2018

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Maraviroc (MVC) is a CCR5 coreceptor antagonist indicated in combination with other antiretroviral agents for the treatment of CCR5-tropic human immunodefinciency virus-1 infection. In this study, the metabolism of MVC was investigated in human liver microsomes to delineate the relative roles of CYP3A4 and CYP3A5. MVC is metabolized to five hydroxylated metabolites, all of which were biosynthesized and identified using mass and NMR spectroscopy. The sites of metabolism were the 2- and 3-positions of the 4,4-difluorocyclohexyl moiety and the methyl of the triazole moiety. Absolute configurations were ultimately ascertained by comparison to authentic standards. The biosynthesized metabolites were used for quantitative in vitro experiments in liver microsomes using cyp3cide, a selective inactivator of CYP3A4. (1,2)-2-OH-MVC was the main metabolite representing approximately half of the total metabolism, and CYP3A5 contributed approximately 40% to that pathway in microsomes from CYP3A5*1/*1 donors. The other four metabolites were almost exclusively metabolized by CYP3A4. (1,2)-2-hydroxylation also correlated to T-5 -oxidation, a CYP3A5-specific activity. These data are consistent with clinical pharmacokinetic data wherein CYP3A5 extensive metabolizer subjects showed a modestly lower exposure to MVC.

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Section: Discussionsupporting

confidence: 72%

Biosynthesis and Identification of Metabolites of Maraviroc and Their Use in Experiments to Delineate the Relative Contributions of Cytochrome P4503A4 versus 3A5

et al. 2018

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“…We appreciate the comments by Vourvahis et al (2015). We agree, and we believe that it goes without saying, that there are several variables that affect the pharmacokinetics of any drug, including maraviroc.…”

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confidence: 84%

Response to “Clinical Relevance of CYP3A5 Genotype on Maraviroc Exposures”

Fuchs

Hendrix

et al. 2015

Drug Metab Dispos

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Section: Understanding Clearance Mechanismsmentioning

confidence: 99%

“…It should be noted that the differences in the systemic exposure of maraviroc did not translate into dose adjustments due to diminished efficacy in the poor vs extensive metabolizer groups as the concentrations achieved in the extensive metabolizer group were still in excess of exposures needed for virologic efficiency. 28 However, this example underscores the importance of understanding the complete metabolic profile of a drug and the potential for its clearance to be mediated by polymorphic enzymes. If the liability is identified in early discovery, rational chemical intervention strategies can be potentially implemented to remove the liability (eliminating or blocking sites of metabolism by polymorphic enzymes) or a decision can be made to move on to new lead chemical matter.…”

Section: ■ Introductionmentioning

confidence: 99%

Effective Application of Metabolite Profiling in Drug Design and Discovery

et al. 2020

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At one time, biotransformation was a descriptive activity in pharmaceutical development, viewed simply as structural elucidation of drug metabolites, completed only once compounds entered clinical development. Herein, we present our strategic approach using structural elucidation to enable chemistry design/ SAR development. The approach considers four questions that often present themselves to medicinal chemists optimizing their compounds for candidate selection: (1) What are the important clearance mechanisms that mediate the disposition of my molecule? (2) Can metabolic liabilities be modulated in a favorable way? (3) Does my compound undergo bioactivation to a reactive metabolite? (4) Do any of the metabolites possess activity, either on-or off-target? An additional question necessary to support compound development relates to metabolites in safety testing (MIST) and our approach also addresses this question. The value in structural elucidation is derived from its application to better design molecules, guide their clinical development, and underwrite patient safety.

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Clinical Relevance of CYP3A5 Genotype on Maraviroc Exposures

Cited by 7 publications

References 14 publications

Biosynthesis and Identification of Metabolites of Maraviroc and Their Use in Experiments to Delineate the Relative Contributions of Cytochrome P4503A4 versus 3A5

Biosynthesis and Identification of Metabolites of Maraviroc and Their Use in Experiments to Delineate the Relative Contributions of Cytochrome P4503A4 versus 3A5

Response to “Clinical Relevance of CYP3A5 Genotype on Maraviroc Exposures”

Effective Application of Metabolite Profiling in Drug Design and Discovery

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