Abstract
Efavirenz is a non-nucleoside reverse transcriptase inhibitor used as first-line therapy for the treatment of HIV infection. Cytochrome P450 (CYP) CYP2B6 G516T (rs3745274) is a well-known predictor of efavirenz disposition. Dose adjustment based on G516T variant has been shown to be beneficial. However, this variant cannot explain the entire variability of efavirenz pharmacokinetics. In this study, we evaluated the influence of 11 single-nucleotide polymorphisms (SNPs) in CYP2B6, CYP2A6, CYP3A and ABCB1 (ATP-binding cassette sub-family B member 1) on the pharmacokinetics and safety of efavirenz after single oral dose administration to 47 healthy volunteers. We designed and validated a CYP2B6 activity score model based on two CYP2B6 SNPs (G516T and rs4803419) that predicted efavirenz disposition better than G516T alone.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 print issues and online access
$259.00 per year
only $43.17 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Duarte H, Cruz JP, Aniceto N, Ribeiro AC, Fernandes A, Paixão P, et al. Population approach to efavirenz therapy. J Pharm Sci. 2017;106:3161–6.
Siberry GK, Abzug MJ, Nachman S, Brady MT, Dominguez KL, Handelsman E, et al. Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children: Recommendations from the National Institutes of Health, Centers for Disease Control and Prevention, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics. Pediatr Infect Dis J. 2013;32:i.
FDA. Efavirenz 600mg. FDA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/091471Orig1s000lbl.pdf.
Ogburn ET, Jones DR, Masters AR, Xu C, Guo Y, Desta Z. Efavirenz primary and secondary metabolism in vitro and in vivo: identification of novel metabolic pathways and cytochrome P450 2A6 as the principal catalyst of efavirenz 7-hydroxylation. Drug Metab Dispos. 2010;38:1218–29.
Ngaimisi E, Mugusi S, Minzi OM, Sasi P, Riedel K-D, Suda A, et al. Long-term efavirenz autoinduction and its effect on plasma exposure in HIV patients. Clin Pharm Ther. 2010;88:676–84.
Bienczak A, Cook A, Wiesner L, Olagunju A, Mulenga V, Kityo C, et al. The impact of genetic polymorphisms on the pharmacokinetics of efavirenz in African children: efavirenz pharmacogenomics in African children. Br J Clin Pharmacol. 2016;82:185–98.
Sinxadi PZ, Leger PD, McIlleron HM, Smith PJ, Dave JA, Levitt NS, et al. Pharmacogenetics of plasma efavirenz exposure in HIV-infected adults and children in South Africa. Br J Clin Pharmacol. 2015;80:146–56.
Desta Z, Gammal RS, Gong L, Whirl‐Carrillo M, Gaur AH, Sukasem C, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz‐Containing Antiretroviral Therapy. Clin Pharm Ther. 2019;106:726–33. https://onlinelibrary.wiley.com/doi/abs/10.1002/cpt.1477.
Dobrinas M, Crettol S, Oneda B, Lahyani R, Rotger M, Choong E, et al. Contribution of CYP2B6 alleles in explaining extreme (S)-methadone plasma levels: a CYP2B6 gene resequencing study. Pharmacogenet Genom. 2013;23:84–93.
Pitarque M, von Richter O, Oke B, Berkkan H, Oscarson M, Ingelman-Sundberg M. Identification of a single nucleotide polymorphism in the TATA box of the CYP2A6 gene: impairment of its promoter activity. Biochem Biophys Res Commun. 2001;284:455–60.
Csajka C. Population pharmacokinetics and effects of efavirenz in patients with human immunodeficiency virus infection. Clin Pharm Ther. 2003;73:20–30.
Csajka C, Marzolini C, Fattinger K, Décosterd LA, Fellay J, Telenti A, et al. Population pharmacokinetics and effects of efavirenz in patients with human immunodeficiency virus infection. Clin Pharm Ther. 2003;73:20–30.
Apostolova N, Blas-Garcia A, Galindo MJ, Esplugues JV. Efavirenz: what is known about the cellular mechanisms responsible for its adverse effects. Eur J Pharmacol. 2017;812:163–73.
Lam TN, Hui KH, Chan DPC, Lee SS. Genotype-guided dose adjustment for the use of efavirenz in HIV treatment. J Infect. 2015;71:607–9.
Caro-Vega Y, Belaunzarán-Zamudio PF, Crabtree-Ramírez BE, Shepherd BE, Grinsztejn B, Wolff M, et al. Durability of efavirenz compared with boosted protease inhibitor-based regimens in antiretroviral-naïve patients in the Caribbean and Central and South America. Open Forum Infect Dis. 2018;5:ofy004. https://academic.oup.com/ofid/article/doi/10.1093/ofid/ofy004/4918638.
The 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature. 2015;526:68.
Burger D, van der Heiden I, la Porte C, van der Ende M, Groeneveld P, Richter C, et al. Interpatient variability in the pharmacokinetics of the HIV non-nucleoside reverse transcriptase inhibitor efavirenz: the effect of gender, race, and CYP2B6 polymorphism. Br J Clin Pharmacol. 2006;61:148–54.
Ofotokun I, Chuck SK, Hitti JE. Antiretroviral pharmacokinetic profile: a review of sex differences. Gend Med. 2007;4:106–19.
Gatanaga H, Hayashida T, Tsuchiya K, Yoshino M, Kuwahara T, Tsukada H, et al. Successful efavirenz dose reduction in HIV type 1-infected individuals with cytochrome P450 2B6 *6 and *26. Clin Infect Dis. 2007;45:1230–7.
Sinxadi PZ, Leger PD, McIlleron HM, Smith PJ, Dave JA, Levitt NS, et al. Pharmacogenetics of plasma efavirenz exposure in HIV-infected adults and children in South Africa: Efavirenz pharmacokinetics in Cape Town. Br J Clin Pharmacol. 2015;80:146–56.
Haas DW, Smeaton LM, Shafer RW, Robbins GK, Morse GD, Labbé L, et al. Pharmacogenetics of long‐term responses to antiretroviral regimens containing efavirenz and/or nelfinavir: an Adult AIDS Clinical Trials Group Study. J Infect Dis. 2005;192:1931–42.
Wyen C, Hendra H, Vogel M, Hoffmann C, Knechten H, Brockmeyer NH, et al. Impact of CYP2B6 983T > C polymorphism on non-nucleoside reverse transcriptase inhibitor plasma concentrations in HIV-infected patients. J Antimicrob Chemother. 2008;61:914–8.
Manosuthi W, Sukasem C, Lueangniyomkul A, Mankatitham W, Thongyen S, Nilkamhang S, et al. Impact of pharmacogenetic markers of CYP2B6, clinical factors, and drug-drug interaction on efavirenz concentrations in HIV/tuberculosis-coinfected patients. Antimicrob Agents Chemother. 2013;57:1019–24.
Ahmad T, Sabet S, Primerano DA, Richards-Waugh LL, Rankin GO. Tell-tale SNPs: the role of CYP2B6 in methadone fatalities. J Anal Toxicol. 2017;41:325–33.
ENCORE1 Study Group, Carey D, Puls R, Amin J, Losso M, Phanupak P, Foulkes S, et al. Efficacy and safety of efavirenz 400mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-controlled, non-inferiority ENCORE1 study. Lancet Infect Dis. 2015;15:793–802. https://www.ncbi.nlm.nih.gov/pubmed/25877963
di Iulio J, Fayet A, Arab-Alameddine M, Rotger M, Lubomirov R, Cavassini M, et al. In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function. Pharmacogenet Genom. 2009;19:300–9.
Swart M, Evans J, Skelton M, Castel S, Wiesner L, Smith PJ, et al. An expanded analysis of pharmacogenetics determinants of efavirenz response that includes 3’-UTR single nucleotide polymorphisms among Black South African HIV/AIDS patients. Front Genet. 2015;6:356.
Störmer E, von Moltke LL, Perloff MD, Greenblatt DJ. Differential modulation of P-glycoprotein expression and activity by non-nucleoside HIV-1 reverse transcriptase inhibitors in cell culture. Pharm Res. 2002;19:1038–45.
Storch CH, Theile D, Lindenmaier H, Haefeli WE, Weiss J. Comparison of the inhibitory activity of anti-HIV drugs on P-glycoprotein. Biochem Pharmacol. 2007;73:1573–81.
Janneh O, Chandler B, Hartkoorn R, Kwan WS, Jenkinson C, Evans S, et al. Intracellular accumulation of efavirenz and nevirapine is independent of P-glycoprotein activity in cultured CD4 T cells and primary human lymphocytes. J Antimicrob Chemother. 2009;64:1002–7.
Elens L, Vandercam B, Yombi J-C, Lison D, Wallemacq P, Haufroid V. Influence of host genetic factors on efavirenz plasma and intracellular pharmacokinetics in HIV-1-infected patients. Pharmacogenomics. 2010;11:1223–34.
Dickinson L, Amin J, Else L, Boffito M, Egan D, Owen A, et al. Comprehensive pharmacokinetic, pharmacodynamic and pharmacogenetic evaluation of once-daily efavirenz 400 and 600 mg in treatment-naïve HIV-infected patients at 96 weeks: results of the ENCORE1 Study. Clin Pharmacokinet. 2016;55:861–73.
Sánchez Martín A, Cabrera Figueroa S, Cruz Guerrero R, Hurtado LP, Hurlé AD-G, Carracedo Álvarez A. Impact of pharmacogenetics on CNS side effects related to efavirenz. Pharmacogenomics. 2013;14:1167–78.
Haas DW, Ribaudo HJ, Kim RB, Tierney C, Wilkinson GR, Gulick RM, et al. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS Lond Engl. 2004;18:2391–400.
Nirogi R, Bhyrapuneni G, Kandikere V, Mudigonda K, Komarneni P, Aleti R, et al. Simultaneous quantification of a non-nucleoside reverse transcriptase inhibitor efavirenz, a nucleoside reverse transcriptase inhibitor emtricitabine and a nucleotide reverse transcriptase inhibitor tenofovir in plasma by liquid chromatography positive ion electrospray tandem mass spectrometry. Biomed Chromatogr. 2009;23:371–81.
Karch FE, Lasagna L. Toward the operational identification of adverse drug reactions. Clin Pharm Ther. 1977;21:247–54.
Apellániz-Ruiz M, Inglada-Pérez L, Naranjo MEG, Sánchez L, Mancikova V, Currás-Freixes M, et al. High frequency and founder effect of the CYP3A4*20 loss-of-function allele in the Spanish population classifies CYP3A4 as a polymorphic enzyme. Pharmacogenomics J. 2015;15:288–92.
Cusato J, Tomasello C, Simiele M, Calcagno A, Bonora S, Marinaro L, et al. Efavirenz pharmacogenetics in a cohort of Italian patients. Int J Antimicrob Agents 2016;47:117–23.
Wang D, Sadee W. CYP3A4 intronic SNPrs35599367 (CYP3A4*22) alters RNA splicing. Pharmacogenet Genomics. 2016;26:40–3.
Hustert E, Haberl M, Burk O, Wolbold R, He YQ, Klein K, et al. The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics. 2001;11:773–9.
Singh AB, Bousman CA, Ng CH, Byron K, Berk M. ABCB1 polymorphism predicts escitalopram dose needed for remission in major depression. Transl Psychiatry. 2012;2:e198.
Gonzalez-Haba E, García MI, Cortejoso L, López-Lillo C, Barrueco N, García-Alfonso P, et al. ABCB1 gene polymorphisms are associated with adverse reactions in fluoropyrimidine-treated colorectal cancer patients. Pharmacogenomics. 2010;11:1715–23.
Funding
PZ is co-financed by Consejería de Educación, Juventud y Deporte from Comunidad de Madrid and European Social Fund.
Author information
Authors and Affiliations
Contributions
PZ performed the genotyping tests. PZ, MS-R and FA-S wrote the manuscript. FA-S, DO, MR, GM and SM-V supervised and coordinated the clinical trials.
Corresponding author
Ethics declarations
Conflict of interest
FA-S and DO have been consultant or investigator in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Chemo, Cinfa, FAES, Farmalíder, Ferrer, GlaxoSmithKline, Galenicum, Gilead, Janssen-Cilag, Kern, Normon, Novartis, Servier, Silverpharma, Teva and Zambon. The other authors declare that they have no conflicts of interest.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Zubiaur, P., Saiz-Rodríguez, M., Ochoa, D. et al. Influence of CYP2B6 activity score on the pharmacokinetics and safety of single dose efavirenz in healthy volunteers. Pharmacogenomics J 20, 235–245 (2020). https://doi.org/10.1038/s41397-019-0103-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41397-019-0103-3
This article is cited by
-
Metabolic ratios and SNPs implicated in tramadol-related deaths
International Journal of Legal Medicine (2023)
-
Effect of Sex, Use of Pantoprazole and Polymorphisms in SLC22A1, ABCB1, CES1, CYP3A5 and CYP2D6 on the Pharmacokinetics and Safety of Dabigatran
Advances in Therapy (2020)