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Lersivirine  Audio icon

Other Names: UK-453,061
Drug Class: Non-nucleoside Reverse Transcriptase Inhibitors
Molecular Formula: C17 H18 N4 O2
Registry Number: 473921-12-9 (CAS)
Chemical Name: 5-[3,5-diethyl-1-(2-hydroxyethyl)pyrazol-4-yl]oxybenzene-1,3-dicarbonitrile
Phase of Development: Phase II. The clinical development of lersivirine for the treatment of HIV infection was discontinued in February 2013.
Chemical Image:
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Molecular Weight: 310.3552
(Compound details obtained from ChemIDplus Advanced1, NIAID Therapeutics Database2, and ViiV Healthcare website3)
Patent Version Content


Mechanism of Action: Non-nucleoside reverse transcriptase inhibitor (NNRTI). Lersivirine inhibits the HIV reverse transcriptase enzyme by a mixed noncompetitive mechanism. Lersivirine binds noncovalently to the allosteric, non-nucleoside binding site of recombinant wild-type (wt) HIV-1 reverse transcriptase enzyme, interacting with residues L100, V106, Y181, Y188, F227, W229, Y318, L234, and P236 of the p66 subunit of reverse transcriptase. Lersivirine’s binding mode to the K103N mutant virus reverse transcriptase enzyme is similar to lersivirine’s binding mode to the wt virus reverse transcriptase enzyme. K103N mutant virus is common in patients failng NNRTI therapy.4

: 5.83 hours (single oral 500-mg dose in healthy adults) to 6.91 hours (single oral 750-mg dose in healthy adults).5,6

Metabolism/Elimination: Lersivirine is primarily metabolized via UGT2B7 glucuronidation and cytochrome P450 (CYP3A4) oxidation.6 A radiolabeled single oral 500-mg dose of lersivirine was extensively metabolized after absorption. The lersivirine dose was eliminated by renal (80% of dose) and fecal (23% of dose) routes. Unchanged lersivirine was a minor component in excreta (≤ 1%).5

Resistance: In vitro, lersivirine retains activity against K103N, Y181C, and G190A mutant virus, common in patients failing NNRTI therapy. The pathway to lersivirine resistance appears to be associated with acquisition of V108I mutation.4

Among lersivirine-treated patients with virologic failure in a Phase IIb study, the M184V resistance mutation emerged in 3 out of 4 subjects in the 500-mg arm and in 1 out of 5 subjects in the 750-mg arm. The K103N mutation did not occur in lersivirine treatment failures.7 Lersivirine minority species mutations that were present at screening were not associated with failure.8

Dosing in Clinical Trials

Lersivirine is administered once daily and orally.9,10

Phase IIb (treatment-naive) (Study A5271015):

  • Lersivirine 500 mg or 750 mg versus efavirenz 600 mg, each in combination with tenofovir DF/emtricitabine.11
Phase IIb (treatment-experienced):

  • Lersivirine 750 mg or 1000 mg versus etravirine 200 mg given twice daily, each in combination with an optimized NRTI plus darunavir/ritonavir.10

Adverse Events

The most common adverse events associated with lersivirine (500 mg and 750 mg) in a Phase IIb trial (Study A5271015) were nausea and headache. Discontinuations due to adverse events occurred in six of the lersivirine-treated subjects (three from the 500-mg group and three from the 750-mg group) and in five efavirenz-treated subjects. Rash and grade 3/4 adverse events were less frequent with lersivirine than with efavirenz. Lersivirine was not associated with lipid elevations.11

Drug Interactions

Lersivirine is a weak CYP3A4 inducer, weak glucuronidation inhibitor, and a P-glycoprotein inhibitor.12 Drugs that may interact with lersivirine include ketoconazole, valproic acid, midazolam, oral contraceptives (ethinylestradiol and levonorgestrel), rifampin, rifabutin, lopinavir/ritonavir, darunavir/ritonavir, and atazanavir with/without ritonavir.12,13,14,15


1. United States National Library of Medicine. ChemIDplus Advanced.

2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development.

3. ViiV Healthcare website. February 2013: Lersivirine update. Accessed May 10, 2013.

4. Corbau R, Mori J, Phillips C, et al. Lersivirine, a nonnucleoside reverse transcriptase inhibitor with activity against drug-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother. 2010 Oct;54(10):4451-63.

5. Vourvahis M, Gleave M, Nedderman AN, et al. Excretion and metabolism of lersivirine (5-{[3,5-diethyl-1-(2-hydroxyethyl)(3,5-14C2)-1H-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. 2010 May;38(5):789-800.

6. Vourvahis M, Banerjee S, LaBadie R, Gore D, Mayer H. Lack of a clinically relevant effect of an antacid on the pharmacokinetics of lersivirine. Antimicrob Agents Chemother. 2010 May;54(5):2209-11.

7. Vernazza P, Wang C, Pozniak A, et al. Efficacy and safety of lersivirine vs efavirenz in antiretroviral treatment-naïve HIV-1-infected patients: Week 48 primary analysis results from an ongoing, multicenter, randomized, double-blind, phase 2b trial (Study A5271015). Slides with audio presented at: 6th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention; July 17-20, 2011; Rome, Italy. Abstract TUAB0101.

8. Craig C, Wang C, Cusack N, et al. Minority species resistance present at screening does not affect outcomes at week 48 in lersivirine (UK-453,061) phase IIb study A5271015 in treatment-naive patients. Abstract presented at: 6th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention; July 17-20, 2011; Rome, Italy. Abstract MOPE161.

9. Pfizer. A Phase 2B Multicenter, Randomized, Double-Blind, Comparative Trial Of UK-453,061, In Combination With Tenofovir Df And Emtricitabine Versus Efavirenz In Combination With Tenofovir DF And Emtricitabine For The Treatment Of Antiretroviral-Naive HIV-1 Infected Subjects. In: Bethesda (MD): National Library of Medicine (US). Registered on Jan 15, 2009. NLM Identifier: NCT00824421. Last Accessed: May 8, 2013.

10. Pfizer. A Phase 2B Multicenter, Randomized, Comparative Trial Of UK-453,061 Versus Etravirine In Combination With Darunavir/Ritonavir And A Nucleos(t)Ide Reverse Transcriptase Inhibitor For The Treatment Of Antiretroviral Experienced HIV-1 Infected Subjects With Evidence Of NNRTI Resistant HIV-1. In: Bethesda (MD): National Library of Medicine (US). Registered on Jan 15, 2009. NLM Identifier: NCT00823979. Last Accessed: May 9, 2013.

11. Vernazza P, Wang C, Pozniak A, et al. Efficacy and safety of lersivirine (UK-453,061) vs. efavirenz in antiretroviral treatment-naïve HIV-1-infected patients: week 48 primary analysis results from an ongoing, multicentre, randomised, double-blind, phase IIb trial (study A5271015). Abstract presented at: 6th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention; July 17-20, 2011; Rome, Italy. Abstract TUAB0101.

12. Davis J, Langdon G, Layton G, Chong CL, Ndongo MN, Vourvahis M. The effect of lersivirine, a next-generation NNRTI, on the pharmacokinetics of midazolam and oral contraceptives in healthy subjects. Eur J Clin Pharmacol. 2012 Nov;68(11):1567-72.

13. Langdon G, Davis J, Layton G, Chong CL, Weissgerber G, Vourvahis M. Effects of ketoconazole and valproic acid on the pharmacokinetics of the next generation NNRTI, lersivirine (UK-453,061), in healthy adult subjects. Br J Clin Pharmacol. 2012 May;73(5):768-75.

14. Vourvahis M, Davis J, Wang R, et al. Effect of rifampin and rifabutin on the pharmacokinetics of lersivirine and effect of lersivirine on the pharmacokinetics of rifabutin and 25-O-desacetyl-rifabutin in healthy subjects. Antimicrob Agents Chemother. 2012 Aug;56(8):4303-9.

15. Vourvahis M, Langdon G, Layton G, et al. The pharmacokinetics of lersivirine (UK-453,061) and HIV-1 protease inhibitor coadministration in healthy subjects. J Acquir Immune Defic Syndr. 2012 May 1;60(1):24-32.

Last Reviewed: May 23, 2013

Last Updated: May 23, 2013

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