Effect of patient genetics on etonogestrel pharmacokinetics when combined with efavirenz or nevirapine ART

Neary, Megan ORCID: 0000-0002-4960-2139, Chappell, Catherine A, Scarsi, Kimberly K, Nakalema, Shadia, Matovu, Joshua, Achilles, Sharon L, Chen, Beatrice A, Siccardi, Marco ORCID: 0000-0002-3539-7867, Owen, Andrew ORCID: 0000-0002-9819-7651 and Lamorde, Mohammed (2019) Effect of patient genetics on etonogestrel pharmacokinetics when combined with efavirenz or nevirapine ART. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 74 (10). pp. 3003-3010.

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Abstract

<h4>Background</h4>We previously demonstrated that etonogestrel concentrations were 82% lower in women using etonogestrel contraceptive implants plus efavirenz-based ART compared with women not receiving ART.<h4>Objectives</h4>To investigate the genetic contribution to this previously observed drug-drug interaction through studying SNPs in genes known to be involved in efavirenz, nevirapine or etonogestrel metabolism in the same group of women.<h4>Patients and methods</h4>Here, we present a secondary analysis evaluating SNPs involved in efavirenz, nevirapine and etonogestrel metabolism and associated etonogestrel pharmacokinetics among 57 women, 19 not receiving ART (control group), 19 receiving efavirenz- (600 mg daily) based ART and 19 receiving nevirapine- (200 mg twice daily) based ART. Associations between patient genotype and etonogestrel pharmacokinetic parameters were determined through univariate and multivariate linear regression. This study was registered at clinicaltrials.gov (NCT02082652).<h4>Results</h4>Within the control group, CYP2B6 983 T>C was associated with 27% higher etonogestrel Cmax and 28% higher AUC0-24weeks. In the efavirenz group CYP2B6 516 G>T was associated with 43% lower etonogestrel Cmin and 34% lower AUC0-24weeks. For participants receiving nevirapine, NR1I2 63396 C>T was associated with 39% lower etonogestrel Cmin and 37% lower AUC0-24weeks.<h4>Conclusions</h4>This study demonstrates the influence of pharmacogenetics on the extent of drug-drug interactions between etonogestrel and efavirenz- or nevirapine-based ART. Efavirenz plus the etonogestrel contraceptive implant results in a detrimental drug-drug interaction irrespective of patient genetics, which is worsened in women possessing variant alleles for these CYP2B6 SNPs.

Item Type:	Article
Uncontrolled Keywords:	Humans, HIV Infections, Benzoxazines, Nevirapine, Desogestrel, Anti-HIV Agents, Drug Interactions, Genotype, Polymorphism, Single Nucleotide, Adult, Female, Young Adult, Cytochrome P-450 CYP2B6
Depositing User:	Symplectic Admin
Date Deposited:	03 Jul 2019 07:24
Last Modified:	19 Jan 2023 00:38
DOI:	10.1093/jac/dkz298
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3048354