Achilles, Sharon

Chappell, Catherine

Chen, Beatrice

Lamorde, Mohammed

Matovu, Joshua

Nakalema, Shadia

Neary, MG

Owen, Andrew

Scarsi, Kimberly

Siccardi, Marco

University of Liverpool Repository

GG GT TT0100020003000CYP2B6 516G>T (rs3745274)Etonogestrel AUC0-24weeks (pg*week/mL)CC CT TT05000100001500020000NR1I2 63396C>T (rs2472677)Etonogestrel AUC0-24weeks (pg*week/mL)TT CT0100020003000CYP2B6 983T>C (rs28399499)Etonogestrel AUC0-24weeks (pg*week/mL)AAAGGG05000100001500020000CYP3A4 293A>G (rs2740574)Etonogestrel AUC0-24weeks (pg*week/mL)A) B)C) D)Difference in ENG AUC for each statistically significant SNP.Values represented as mean (standard deviation)ENG and EFV pharmacokinetics for each statistically significant genotype.Values given as median (interquartile range)CYP2B6 Variants Alter Etonogestrel Pharmacokinetics When Combined With EfavirenzINTRODUCTIONCONCLUSIONSMETHODSRESULTSMegan Neary, Catherine Chappell, Kimberly K. Scarsi, Shadia Nakalema, Joshua Matovu, Sharon L. Achilles, Beatrice A. Chen, Marco Siccardi, Andrew Owen, Mohammed Lamorde466Corresponding author: mneary@liv.ac.ukCYP2B6 516G>T was associated with:• 43% lower log10 ENG Cmin (P=0.003, β=-0.102) in TT compared to GG patients• 34% lower log10 ENG AUC0-24 weeks (P=0.008, β=-0.106) in TT compared to GG patientsCYP2B6 983T>C was associated with:• 37% lower log10 ENG Cmax (P=0.003, β=-0.237) in CT compared to TT patients• 20% lower log10 ENG AUC0-24 weeks (P=0.016, β=-0.158) in CT compared to TT patientsEFV plasma concentration (C12-14hrs) was:• 76% higher in TT patients for CYP2B6 516G>T compared to GG patients• 69% higher in CT patients for CYP2B6 983T>C compared to TT patients- The etonogestrel (ENG) implant is an effective hormonal contraceptive methodcommonly used in sub-Saharan Africa.- Drug-drug interactions between contraceptive progestins and antiretrovirals,specifically efavirenz (EFV), continue to be a significant barrier to contraceptiveuse among women living with HIV.- ENG concentrations were previously demonstrated to be 82% lower at week24 in women receiving efavirenz (EFV) based antiretroviral therapy (ART)compared to women not receiving ART. (1)- We investigated a genetic contribution to this previously observed drug-druginteraction through studying the following SNPs in the same group of women:CYP2B6 516G>T, 983T>C and 15582C>T, CYP3A4 293A>G, NR1I2 63396C>T,ABCB1 4036A>G and 3435C>T.- CYP2B6 is the primary metaboliser of EFV and CYP3A4 is the primarymetabolizer of ENG. NR1I2 encodes the pregnane X receptor, a transcriptionalregulator of multiple CYPs including CYP2B6 and CYP3A4. ABCB1 encodes theP-glycoprotein receptor a membrane bound transporter of many endogenoussubstrates and xenobiotics, including EFV.Patient characteristics and genotype frequencies for each SNP.Values given as median (interquartile range) or % This study demonstrates a relationship between CYP2B6polymorphisms and alterations in ENG pharmacokinetics whenENG implants are combined with EFV.We hypothesize that this relationship is mediated by anindirect effect of reduced EFV metabolism by CYP2B6, resultingin higher EFV concentrations. Supratherapeutic EFVconcentrations may induce CYP3A4 to a greater extent,resulting in lower ENG exposure.These results are consistent with previously observedassociations between SNPs in CYP2B6 and lower levonorgestrelimplant pharmacokinetics when combined with EFV. (4)Further study is required to confirm the mechanism of actionof this association.(1) Chappell et al. 2017. AIDS (2) Moser et al. 2012. Anal Bioanal Chem (3) Almond LM et al. 2005. J Antimicrob Chemother (4)Neary et al. 2017. Clin Pharmacol TherEthics: All study procedures approved by the University of Pittsburgh (PRO14010195), theJoint Clinical Research Centre, and Uganda National Council of Science and Technology (HS1618). This study followed the Declaration of Helsinki and was registered at clinicaltrials.gov(NCT02082652).Study Population: 19 patients receiving EFV (600mg daily) based ART. Exclusionary criteriaincluded but was not limited to HIV RNA >400 copies/mL and participants receiving anymedication that was contraindicated for use with ENG or EFV. Participants in the EFV grouphad a copper intrauterine device inserted prior to study initiation to minimise the risk ofunintended pregnancy in the event of ENG contraceptive failure.Sample Collection: Study visits occurred at 1, 4, 12 and 24 weeks post implant placement.Blood samples were taken in order to determine ENG concentration at each study visit. ForEFV a single timed blood sample was taken twice before implant insertion and 4, 12 and 24weeks post implant insertion.Pharmacokinetic Parameters: Pharmacokinetic parameters included in this analysis were areaunder the concentration time curve from entry to 24 weeks for ENG (AUC0-24wk), maximumENG concentration (Cmax) and minimum ENG concentration (Cmin). AUC was calculated usingthe trapezoidal rule. EFV concentrations were taken 12-14 hours post dose (C12-14h).ENG/EFV Concentration Quantification: ENG concentrations were quantified usingHPLC/mass spectrometry, EFV concentrations were quantified using HPLC, utilising validatedmethods. (2)(3)Genotyping: Genotyping was performed by allelic discrimination real-time PCR usingTaqMan® SNP Genotyping assays for selected candidate SNPs.Statistical Analysis: Univariate linear regression analysis was conducted with a P ≤ 0.20classed as significant. All variables significant in univariate analysis were included in amultivariate backwards linear regression analysis P ≤ 0.05.Statistically significant associations between variables and ENG pharmacokinetic parameters.

CYP2B6 variants alter etonogestrel pharmacokinetics when combined with efavirenz.

http://livrepository.liverpool.ac.uk/3033579/1/CROI%20ENG%202018.pdf

CYP2B6 variants alter etonogestrel pharmacokinetics when combined with efavirenz.

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