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)
  • Infectious Diseases
  • Pharmacology (medical)

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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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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

Y1 - 2019/10/1

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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