title: The Effect of Gene Variants on Levonorgestrel Pharmacokinetics When Combined With Antiretroviral Therapy Containing Efavirenz or Nevirapine.
abstract: Reduced levonorgestrel concentrations from the levonorgestrel contraceptive implant was previously seen when given concomitantly with efavirenz. We sought to assess whether single nucleotide polymorphisms (SNPs) in genes involved in efavirenz and nevirapine metabolism were linked to these changes in levonorgestrel concentration. SNPs in CYP2B6, CYP2A6, NR1I2, and NR1I3 were analyzed. Associations of participant demographics and genotype with levonorgestrel pharmacokinetics were evaluated in HIV-positive women using the levonorgestrel implant plus efavirenz- or nevirapine-based antiretroviral therapy (ART), in comparison to ART-naïve women using multivariate linear regression. Efavirenz group: CYP2B6 516G>T was associated with lower levonorgestrel log10Cmaxand log10AUC. CYP2B6 15582C>T was associated with lower log10AUC. Nevirapine group: CYP2B6 516G>T was associated with higher log10Cmaxand lower log10Cmin. Pharmacogenetic variations influenced subdermal levonorgestrel pharmacokinetics in HIV-positive women, indicating that the magnitude of the interaction with non-nucleoside reverse transcriptase inhibitors (NNRTIs) is influenced by host genetics.
authors.affiliation: Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: M
authors.initials: M
authors.lastname: Neary
authors.affiliation: Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: M
authors.initials: M
authors.lastname: Lamorde
authors.affiliation: Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria.
authors.forename: A
authors.initials: A
authors.lastname: Olagunju
authors.affiliation: Center for Global Health, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Darin
authors.affiliation: Department of Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: C
authors.initials: C
authors.lastname: Merry
authors.affiliation: Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: P
authors.initials: P
authors.lastname: Byakika-Kibwika
authors.affiliation: Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Back
authors.affiliation: Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: M
authors.initials: M
authors.lastname: Siccardi
authors.affiliation: Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: A
authors.initials: A
authors.lastname: Owen
authors.affiliation: Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: K K
authors.initials: KK
authors.lastname: Scarsi
mesh_terms: D000328:Adult; D000480:Alkynes; D019540:Area Under Curve; D048588:Benzoxazines / Q000008:administration & dosage*; D000090702:Constitutive Androstane Receptor; D003271:Contraceptive Agents, Female / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003521:Cyclopropanes; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D016912:Levonorgestrel / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016014:Linear Models; D015999:Multivariate Analysis; D019829:Nevirapine / Q000008:administration & dosage*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage*
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D000090702:Constitutive Androstane Receptor; D003271:Contraceptive Agents, Female; D003521:Cyclopropanes; C000716327:NR1I3 protein, human; D018894:Reverse Transcriptase Inhibitors; D016912:Levonorgestrel; D019829:Nevirapine; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; C098320:efavirenz