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Investigational

Lersivirine  Audio icon

Other Names: LRV, 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
Company: ViiV Healthcare
Phase of Development: Phase IIb (discontinued)
Chemical Image:
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lersivirine
lersivirine
Molecular Weight: 310.3552
(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 ViiV Healthcare website,3 and Expert Opinion on Investigational Drugs article4)
Patent Version Content

NOTE: The development of lersivirine for HIV treatment has been discontinued.


The study of lersivirine as a non-nucleoside reverse transcriptase inhibitor (NNRTI) HIV medicine was discontinued in 2013. The company developing the drug decided that lersivirine would not provide an improvement over currently approved HIV medicines already in use.4 
 


Pharmacology


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.5

Half-life (T½): 5.83 hours (single oral 500-mg dose in healthy adults) to 6.91 hours (single oral 750-mg dose in healthy adults).6,7

Metabolism/Elimination: Lersivirine is primarily metabolized via UGT2B7 glucuronidation and cytochrome P450 (CYP3A4) oxidation.7 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%).6

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.5

Among lersivirine-treated patients with virologic failure in a Phase IIb study, the M184V resistance mutation emerged in three out of four participants in the 500-mg arm and in one out of five participants in the 750-mg arm. The K103N mutation did not occur in lersivirine treatment failures.8 Lersivirine minority species mutations that were present at screening were not associated with failure.9
 


Dosing in Clinical Trials


Study Identifiers: A5271015; NCT0082442110,11
Phase: IIb
Study Purpose: Safety and efficacy study of lersivirine plus tenofovir DF/emtricitabine compared to efavirenz plus tenofovir DF/emtricitabine
Study Population: HIV-infected, treatment-naive adults
Dosing: Lersivirine 500 mg or 750 mg administered orally and once daily versus efavirenz 600 mg administered orally and once daily, each in combination with tenofovir DF/emtricitabine.10,11
(See references cited above for information on study results.)

Study Identifiers: A5271022; NCT0082397912
Phase: IIb
Study Purpose: Safety and efficacy study of lersivirine plus darunavir/ritonavir plus a nucleoside reverse transcriptase inhibitor (NRTI) compared to etravirine plus darunavir/ritonavir plus NRTI
Study Population: HIV-infected, treatment-experienced patients with evidence of NNRTI-resistant HIV-1
Dosing: Lersivirine 750 mg or 1000 mg administered orally and once daily versus etravirine 200 mg administered twice daily, each in combination with darunavir/ritonavir and one optimized NRTI.
* Study A5271022 was terminated early because of lack of efficacy. Study termination was not because of any safety concerns.12
(See reference cited above for information on study results.)
 


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 participants (three from the 500-mg group and three from the 750-mg group) and in five efavirenz-treated participants. Rash and Grade 3/4 adverse events were less frequent with lersivirine than with efavirenz. Lersivirine was not associated with lipid elevations.10


Drug Interactions


Lersivirine is a weak CYP3A4 inducer, a weak glucuronidation inhibitor, and a P-glycoprotein inhibitor.13 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.13-16

Studies have indicated that when lersivirine is co-administered with the NRTIs zidovudine, tenofovir DF/emtricitabine, or abacavir/lamivudine, the systemic exposures of zidovudine, tenofovir DF, and abacavir are altered. (Emtricitabine pharmacokinetics were not evaluated.) The zidovudine and abacavir increases in exposure were not considered clinically meaningful. Tenofovir exposure also increased (30%); however, the clinical relevance of this effect is unknown.17  

Dose adjustments do not appear necessary when lersivirine is co-administered with raltegravir or maraviroc.18 Methadone dose adjustments are not required when co-administered with lersivirine.19
 


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/473921-12-9. Last accessed on August 11, 2014.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. NIAID ChemDB, HIV Drugs in Development. Available at: http://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on August 11, 2014.
  3. ViiV Healthcare website. Quick Search for lersivirine. Available at: http://viiv-clinicalstudyregister.com/quick-search-list.jsp?item=lersivirine&type=Compound&letterrange=A-Z. Last accessed on August 11, 2014.
  4. Platten M, Fätkenheuer G. Lersivirine - a new drug for HIV infection therapy. Expert Opin Investig Drugs. 2013 Dec;22(12):1687-94. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24128277. Last accessed on August 11, 2014.
  5. 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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944613/. Last accessed on August 11, 2014.
  6. 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. Available at: http://dmd.aspetjournals.org/content/38/5/789/T1.expansion.html. Last accessed on August 11, 2014.
  7. 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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2863683/. Last accessed on August 11, 2014.
  8. 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. Available at: http://pag.ias2011.org/flash.aspx?pid=294. Last accessed on August 11, 2014.
  9. 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. Available at: http://pag.ias2011.org/abstracts.aspx?aid=3892. Last accessed on August 11, 2014.
  10. 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. Available at: http://pag.ias2011.org/abstracts.aspx?aid=3950. Last accessed on August 11, 2014.
  11. 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: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 15, 2009. NLM Identifier: NCT00824421. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00824421. Last accessed on August 11, 2014.
  12. 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: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 15, 2009. NLM Identifier: NCT00823979. Available at:  http://www.clinicaltrials.gov/ct2/show/NCT00823979. Last accessed on August 11, 2014.
  13. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22527351. Last accessed on August 11, 2014.
  14. 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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3403204/. Last accessed on August 11, 2014.
  15. 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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3421562/. Last accessed on August 11, 2014.
  16. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22517413. Last accessed on August 11, 2014.
  17. Vourvahis M, Davis J, Langdon G, et al. Pharmacokinetic interactions between lersivirine and zidovudine, tenofovir disoproxil fumarate/emtricitabine and abacavir/lamivudine. Antivir Ther. 2013;18(6):745-54. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23558061. Last accessed on August 11, 2014.
  18. Vourvahis M, Langdon G, LaBadie RR, et al. Pharmacokinetic Effects of Coadministration of Lersivirine with Raltegravir or Maraviroc in Healthy Subjects. Antimicrob Agents Chemother. 2012 Feb;56(2):887-92. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3264271/. Last accessed on August 11, 2014.
  19. Vourvahis M, Wang R, Gruener DM, Bruce RD, Haider S, Tawadrous M. Effect of lersivirine co-administration on pharmacokinetics of methadone in healthy volunteers. Drug Alcohol Depend. 2012 Nov 1;126(1-2):183-8. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22682979. Last accessed on August 11, 2014.
 


Last Reviewed: August 11, 2014

Last Updated: August 11, 2014


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