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

Megan Neary, Catherine A. Chappell, Kimberly K Scarsi, Shadia Nakalema, Joshua Matovu, Sharon L. Achilles, Beatrice A. Chen, Marco Siccardi, Andrew Owen, Mohammed Lamorde

Research output: Contribution to journalArticle

Abstract

BACKGROUND: 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. OBJECTIVES: 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. PATIENTS AND METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Original languageEnglish (US)
Pages (from-to)3003-3010
Number of pages8
JournalThe Journal of antimicrobial chemotherapy
Volume74
Issue number10
DOIs
StatePublished - Oct 1 2019

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efavirenz
Nevirapine
Pharmacokinetics
Drug Interactions
Single Nucleotide Polymorphism
Contraceptive Agents
etonogestrel
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology
  • Microbiology (medical)
  • Pharmacology (medical)
  • Infectious Diseases

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Effect of patient genetics on etonogestrel pharmacokinetics when combined with efavirenz or nevirapine ART. / Neary, Megan; Chappell, Catherine A.; Scarsi, Kimberly K; Nakalema, Shadia; Matovu, Joshua; Achilles, Sharon L.; Chen, Beatrice A.; Siccardi, Marco; Owen, Andrew; Lamorde, Mohammed.

In: The Journal of antimicrobial chemotherapy, Vol. 74, No. 10, 01.10.2019, p. 3003-3010.

Research output: Contribution to journalArticle

Neary, M, Chappell, CA, Scarsi, KK, Nakalema, S, Matovu, J, Achilles, SL, Chen, BA, Siccardi, M, Owen, A & Lamorde, M 2019, 'Effect of patient genetics on etonogestrel pharmacokinetics when combined with efavirenz or nevirapine ART', The Journal of antimicrobial chemotherapy, vol. 74, no. 10, pp. 3003-3010. https://doi.org/10.1093/jac/dkz298
Neary, Megan ; Chappell, Catherine A. ; Scarsi, Kimberly K ; Nakalema, Shadia ; Matovu, Joshua ; Achilles, Sharon L. ; Chen, Beatrice A. ; Siccardi, Marco ; Owen, Andrew ; Lamorde, Mohammed. / Effect of patient genetics on etonogestrel pharmacokinetics when combined with efavirenz or nevirapine ART. In: The Journal of antimicrobial chemotherapy. 2019 ; Vol. 74, No. 10. pp. 3003-3010.
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title = "Effect of patient genetics on etonogestrel pharmacokinetics when combined with efavirenz or nevirapine ART",
abstract = "BACKGROUND: 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. OBJECTIVES: 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. PATIENTS AND METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.",
author = "Megan Neary and Chappell, {Catherine A.} and Scarsi, {Kimberly K} and Shadia Nakalema and Joshua Matovu and Achilles, {Sharon L.} and Chen, {Beatrice A.} and Marco Siccardi and Andrew Owen and Mohammed Lamorde",
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T1 - Effect of patient genetics on etonogestrel pharmacokinetics when combined with efavirenz or nevirapine ART

AU - Neary, Megan

AU - Chappell, Catherine A.

AU - Scarsi, Kimberly K

AU - Nakalema, Shadia

AU - Matovu, Joshua

AU - Achilles, Sharon L.

AU - Chen, Beatrice A.

AU - Siccardi, Marco

AU - Owen, Andrew

AU - Lamorde, Mohammed

PY - 2019/10/1

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N2 - BACKGROUND: 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. OBJECTIVES: 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. PATIENTS AND METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

AB - BACKGROUND: 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. OBJECTIVES: 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. PATIENTS AND METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

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