European Journal of Clinical Pharmacology

, Volume 68, Issue 11, pp 1567–1572 | Cite as

The effect of lersivirine, a next-generation NNRTI, on the pharmacokinetics of midazolam and oral contraceptives in healthy subjects

  • John Davis
  • Grant Langdon
  • Gary Layton
  • Chew Lan Chong
  • Marie-Noella Ndongo
  • Manoli Vourvahis
Short Communication

Abstract

Purpose

Lersivirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with a unique resistance profile that exhibits potent antiretroviral activity against wild-type human immunodeficiency virus and clinically relevant NNRTI-resistant strains. Results from in vitro and in vivo investigations suggest that lersivirine is a cytochrome P450 (CYP3A4) inducer that is metabolized by CYP3A4 and uridine diphosphate glucuronosyltransferase (UGT) 2B7. In order to formally assess the effects of lersivirine on CYP3A4 metabolism and/or glucuronidation, we performed studies aimed at investigating the effects of lersivirine co-administration on the pharmacokinetics (PK) of midazolam, ethinylestradiol and levonorgestrel.

Methods

Two drug–drug interaction studies were performed. Healthy subjects were co-administered (1) single dose midazolam, a prototypical CYP3A4 substrate, followed by 14 days of lersivirine twice daily with single dose midazolam on the final day of lersivirine dosing or (2) 10 days of once-daily (QD) lersivirine and QD oral contraceptives (OCs; ethinylestradiol and levonorgestrel), substrates for CYP3A4, UGT2B7, and/or P-glycoprotein. The effects of co-administration on the PK parameters of midazolam and OCs were assessed.

Results

At clinically relevant lersivirine doses (500–1,000 mg total daily dose), the mean plasma exposure of midazolam was reduced in a dose-dependent manner by 20–36 %. Co-administration of lersivirine 1,000 mg QD with OCs had minor PK effects, increasing ethinylestradiol exposure by 10 % and reducing levonorgestrel exposure by 13 %.

Conclusions

These data further support previous observations that lersivirine is a weak CYP3A4 inducer, a weak inhibitor of glucuronidation, and a P-glycoprotein inhibitor. In both studies, lersivirine appeared to have a good safety and tolerability profile.

Keywords

Lersivirine UK-453,061 Pharmacokinetics Midazolam Oral contraceptives 

Notes

Acknowledgements

Both studies (A5271005 and A5271007) were funded by Pfizer Inc. Editorial support was provided by Dr Bethan Hahn at Complete Medical Communications and was funded by ViiV Healthcare.

Conflict of interest

Manoli Vourvahis, Gary Layton and Marie-Noella Ndongo are all employees of and hold stock options in Pfizer Inc. John Davis, Grant Langdon and Chew Lan Chong were employees of and held stock options in Pfizer Inc. when the studies were performed. Both studies (A5271005 and A5271007) were funded by Pfizer Inc. Lersivirine is under development by Pfizer Inc. and ViiV Healthcare.

Supplementary material

228_2012_1287_MOESM1_ESM.doc (120 kb)
ESM 1 (DOC 120 kb)

References

  1. 1.
    Mori J, Corbau R, Lewis D, Ellery S, Mayer H, Perros M, Westby M (2008) Characterization of a NNRTI, UK-453,061 in vitro. In: 15th Conf Retroviruses and Opportunistic Infections (abstract 728). BostonGoogle Scholar
  2. 2.
    Vernazza P, Wang C, Pozniak A, Weil E, Pulik P, Cooper DA, Kaplan R, Lazzarin A, Valdez H, Goodrich J, Craig C, Mori J, Tawadrous M (2011) Efficacy and safety of lersivirine vs efavirenz in antiretroviral treatment-naive HIV-1-infected patients: Week 48 primary analysis results from an ongoing multicentre, randomised, double-blind, Phase IIIb trial (Study A5271015). In: 16th Int AIDS Conf on HIV Pathogenesis, Treatment and Prevention (abstract TUAB0101). RomeGoogle Scholar
  3. 3.
    Vourvahis M, Gleave M, Nedderman ANR, Hyland R, Gardner I, Howard M, Kempshall S, Collins C, Labadie R (2010) Excretion and metabolism of lersivirine (5-([3,5-diethyl-1-(2-hydroxyethyl)(3,5-14C2)-1 H-pyrazol-4-yl]oxy)benzene-1,3-dicarbonitrile), a next-generation non-nucleoside reverse transcriptase inhibitor, after administration of [14C]Lersivirine to healthy volunteers. Drug Metab Dispos 38:789–800PubMedCrossRefGoogle Scholar
  4. 4.
    Davis J, Langdon G, Layton G, Chong C, Ndongo M-N, Weissgerber G, Vourvahis M (2008) The effect of UK-453,061, a next-generation NNRTI, on the steady state pharmacokinetics of zidovudine, midazolam and contraceptive steroids. In: 9th Int Workshop on Clinical Pharmacology of HIV Therapy (poster P25). New OrleansGoogle Scholar
  5. 5.
    European Medicines Agency (2010) Guideline on the investigation of drug interactions. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/05/WC500090112.pdf
  6. 6.
    Schöller-Gyüre M, Kakuda TN, Raoof A, de Smedt G, Hoetelmans RM (2009) Clinical pharmacokinetics and pharmacodynamics of etravirine. Clin Pharmacokinet 48:561–574PubMedCrossRefGoogle Scholar
  7. 7.
    Gerber JG, Rosenkranz SL, Fichtenbaum CJ, Vega JM, Yang A, Alston BL, Brobst SW, Segal Y, Aberg JA (2005) Effect of efavirenz on the pharmacokinetics of simvastatin, atorvastatin, and pravastatin: results of AIDS Clinical Trials Group 5108 Study. J Acquir Immune Defic Syndr 39:307–312PubMedCrossRefGoogle Scholar
  8. 8.
    Imai H, Kotegawa T, Tsutsumi K, Morimoto T, Eshima N, Nakano S, Ohashi K (2008) The recovery time-course of CYP3A after induction by St John's wort administration. Br J Clin Pharmacol 65:701–707PubMedCrossRefGoogle Scholar
  9. 9.
    Wang Z, Gorski JC, Hamman MA, Huang SM, Lesko LJ, Hall SD (2001) The effects of St John's wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther 70:317–326PubMedGoogle Scholar
  10. 10.
    Dresser GK, Schwarz UI, Wilkinson GR, Kim RB (2003) Coordinate induction of both cytochrome P4503A and MDR1 by St John's wort in healthy subjects. Clin Pharmacol Ther 73:41–50PubMedCrossRefGoogle Scholar
  11. 11.
    Crauwels HM, Van Heeswijk RPG, Cornelis L, McNeeley D, Buelens A, Clark A, Boven K, Hoetelmans RMW (2009) Pharmacokinetic interaction study between TMC278, an NNRTI, and the contraceptives norethindrone plus ethinylestradiol. HIV Med 10:82Google Scholar
  12. 12.
    Bristol-Myers Squibb Pharmaceuticals Ltd (2010) Sustiva 600 mg film-coated tablets, Summary of Product Characteristics. Electronic Medicines Compendium. Available at: http://www.medicines.org.uk/EMC/medicine/11284/SPC/Sustiva+600+mg+Film-Coated+Tablets/. Accessed 29 Oct 2010
  13. 13.
    Schöller-Gyüre M, Kakuda TN, Woodfall B, Aharchi F, Peeters M, Vandermeulen K, Hoetelmans RM (2009) Effect of steady-state etravirine on the pharmacokinetics and pharmacodynamics of ethinylestradiol and norethindrone. Contraception 80:44–52PubMedCrossRefGoogle Scholar
  14. 14.
    Langdon G, Davis J, Layton G, Ndongo M-N, Vourvahis M (2008) The effect of UK-453,061, a next-generation NNRTI, on the steady-state pharmacokinetics of maraviroc, a CCR5 antagonist. In: 9th Int Workshop on Clinical Pharmacology of HIV Therapy (abstract). Rev Antiviral Ther 3:P27Google Scholar
  15. 15.
    ViiV Healthcare (2009) Selzentry (maraviroc) prescribing information. Available at: http://www.selzentry.com/. Accessed 24 June 2011
  16. 16.
    Sidhu J, Job S, Singh S, Philipson R (2006) The pharmacokinetic and pharmacodynamic consequences of the co-administration of lamotrigine and a combined oral contraceptive in healthy female subjects. Br J Clin Pharmacol 61:191–199PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • John Davis
    • 1
    • 5
  • Grant Langdon
    • 1
    • 6
  • Gary Layton
    • 1
  • Chew Lan Chong
    • 2
    • 7
  • Marie-Noella Ndongo
    • 3
  • Manoli Vourvahis
    • 4
  1. 1.Pfizer Global Research and DevelopmentSandwichUK
  2. 2.Pfizer Clinical Research UnitRaffles HospitalSingaporeSingapore
  3. 3.Pfizer Research ClinicAnderlecht, BrusselsBelgium
  4. 4.Pfizer Global Research and DevelopmentNew YorkUSA
  5. 5.Genentech IncSan FranciscoUSA
  6. 6.PTx Solutions LtdDealUK
  7. 7.Lilly-NUS Centre for Clinical Pharmacology Pte LtdSingaporeSingapore

Personalised recommendations