skip navigation

Skip Nav

AIDSinfo Drug Database

AIDSinfo Drugs

Drugs by class

FDA-approved

Investigational

Elvucitabine  Audio icon

Other Names: ACH-126443, beta-L-Fd4C, ELV, L-F-D4C, l(−)Fd4C
Drug Class: Nucleoside Reverse Transcriptase Inhibitors
Molecular Formula: C9 H10 F N3 O3
Registry Number: 181785-84-2 (CAS)
Chemical Name: 4-amino-5-fluoro-1-[(2S,5R)-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl]pyrimidin-2-one
Chemical Class: Pyrimidine Nucleosides
Company: Achillion Pharmaceuticals
Phase of Development: II (The company developing elvucitabine has reported that it is out-licensing elvucitabine and looking to work with partner companies to focus elvucitabine’s development in regions outside the United States.)
Chemical Image:
Click image to enlarge
elvucitabine
elvucitabine
Molecular Weight: 227.194
(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and Achillion Pharmaceuticals 2009 Annual Report3)
Patent Version Content

Pharmacology


Mechanism of Action: Nucleoside reverse transcriptase inhibitor. Elvucitabine, an L-cytosine nucleoside analog, is intracellularly phosphorylated to its active 5′-triphosphate metabolite, which has an intracellular half-life of at least 20 hours.4,5 Elvucitabine triphosphate inhibits the activity of HIV reverse transcriptase by competing with natural substrates and by causing DNA chain termination after incorporation into viral DNA.6,7 Elvucitabine has also demonstrated in vitro and in vivo activity against HBV.8,9

Half-life (T½): Approximately 100 hours (in a 21-day study of elvucitabine 5 mg or 10 mg daily or 20 mg every 48 hours, in combination with lopinavir/ritonavir, in HIV-infected adults).5

Metabolism/Elimination: Elvucitabine is not metabolized by cytochrome P450 (CYP) enzymes. Elvucitabine is eliminated renally, primarily unchanged in the urine.5

Resistance: In vitro selection experiments have isolated virus that is resistant to elvucitabine and is associated with mutations at codon 184 (M to I or V).10 Additionally, elvucitabine has been shown to have less in vitro activity against HIV with the K65R mutation than against wild-type (wt) virus.11

In a study of HIV-infected adults, elvucitabine—at doses of 50 mg and 100 mg daily—demonstrated potent activity against multidrug-resistant HIV, including lamivudine-resistant virus (associated with the M184V mutation). The 100-mg dose level, however, was associated with myelosuppression.12 A study of a lower dose—10 mg  of elvucitabine—has been conducted in a similar patient population, one that harbors the M184V mutation.13

In a study of HIV-infected, treatment-naive adults receiving either elvucitabine 10 mg daily or lamivudine 300 mg daily, each combined with efavirenz and tenofovir DF, a total of five virologic failures occurred in the elvucitabine arm versus seven in the lamivudine arm through 96 weeks. No documented resistance to elvucitabine occurred after 96 weeks of treatment.14


Dosing in Clinical Trials


Study Identifiers: ACH443-015; NCT0035027215
Phase: II
Study Purpose: Safety and efficacy study comparing elvucitabine with lamivudine
Study Population: HIV-infected, treatment-naive adults
Dosing: Elvucitabine 10 mg once daily versus lamivudine 300 mg once daily, each in combination with efavirenz and tenofovir DF. Treatments were administered over 12 weeks (primary endpoint analysis) and for up to a total of 96 weeks (secondary endpoint analysis).4,14,15 
* A 48-week open-label extension study was conducted for participants completing 96 weeks of elvucitabine treatment in ACH443-015.16
(See references cited above for information on study results.)

Study Identifiers: ACH443-014A; NCT0031203913
Phase: II
Study Purpose: Safety and efficacy study comparing elvucitabine with lamivudine in participants with the M184V HIV resistance mutation
Study Population: HIV-infected, treatment-experienced adults with documented M184V mutation 
Dosing: Elvucitabine 10 mg once daily versus lamivudine 300 mg once daily, each in combination with background antiretroviral therapy (ART), administered over 14 days.13
* A 48-week open-label extension study was conducted for participants completing 14 days of elvucitabine treatment in ACH443-014A.17 Beyond the initial 48-week extension study, an additional extension was provided through study protocol NCT00675844.16


Adverse Events


In ACH443-015, drug-related adverse events associated with elvucitabine occurring in 5% or more of participants were nausea, dizziness, fatigue, diarrhea, vomiting, dyspepsia, and asthenia. The incidence, type, and severity of adverse events were similar between the elvucitabine and lamivudine treatment groups. One participant discontinued elvucitabine because of severe neutropenia. Twenty-five serious adverse events occurred (13 in the elvucitabine group; 12 in the lamivudine group), none of which were considered to be related to the study drug.4,14


Drug Interactions


Elvucitabine is neither an inducer nor an inhibitor of cytochrome P450 (CYP) enzymes.5

When co-administered in a single-dose drug interaction study, ritonavir significantly reduced the bioavailability of elvucitabine.18



References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/181785-84-2. Last accessed on October 22, 2014.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: http://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on October 22, 2014.
  3. Achillion Pharmaceuticals. Achillion Pharmaceuticals 2009 Annual Report. Available at:  http://files.shareholder.com/downloads/ACHN/3406700524x0x368900/1A85086D-BD5F-4384-B5F9-960A5E379C48/ACHL_09AR_4.26.10.pdf. Last accessed on October 22, 2014.
  4. DeJesus E, Saple D, Morales-Ramirez J, et al. Elvucitabine vs Lamivudine with Tenofovir and Efavirenz in Antiretroviral-Treatment-Naïve HIV-1 Infected Patients: 96 Week Final Results. Poster presented at: 17th Conference on Retroviruses and Opportunistic Infections (CROI); February 16-19, 2010; San Francisco, CA. Paper 511. Available at: http://www.retroconference.org/2010/PDFs/511.pdf. Last accessed on May 22, 2013.
  5. Colucci P, Pottage JC, Robison H, et al. Multiple-Dose Pharmacokinetic Behavior of Elvucitabine, a Nucleoside Reverse Transcriptase Inhibitor, Administered over 21 Days with Lopinavir-Ritonavir in Human Immunodeficiency Virus Type 1-Infected Subjects. Antimicrob Agents Chemother. 2009 Feb;53(2):662-9. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2630663/. Last accessed on October 22, 2014.
  6. Dutschman GE, Bridges EG, Liu SH, et al. Metabolism of 2',3'-Dideoxy-2',3'-Didehydro-beta-L(-)-5-Fluorocytidine and Its Activity in Combination with Clinically Approved Anti-Human Immunodeficiency Virus beta-D(+) Nucleoside Analogs In Vitro. Antimicrob Agents Chemother. 1998 Jul;42(7):1799-804. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC105686/. Last accessed on October 22, 2014.
  7. Esposito F, Corona A, Tramontano E. HIV-1 Reverse Transcriptase Still Remains a New Drug Target: Structure, Function, Classical Inhibitors, and New Inhibitors with Innovative Mechanisms of Actions. Mol Biol Int. 2012;Volume 2012:Article ID 586401. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3388302/. Last accessed on October 22, 2014.
  8. Zhu YL, Dutschman DE, Liu SH, Bridges EG, Cheng YC. Anti-Hepatitis B Virus Activity and Metabolism of 2',3'-Dideoxy-2',3'-Didehydro-beta-L(-)-5-Fluorocytidine. Antimicrob Agents Chemother. 1998 Jul;42(7):1805-10. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC105687/. Last accessed on October 22, 2014.
  9. DeJesus E, Saple D, Morales-Ramirez J, et al. Elvucitabine Phase II 48 Week Interim Results Show Safety and Efficacy Profiles Similar to Lamivudine in Treatment Naive HIV-1 Infected Patients with a Unique Pharmacokinetic Profile. 48th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)/46th Infectious Diseases Society of America (IDSA) Meeting; October 25-28. 2008; Washington DC. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2008. Available at: http://www.natap.org/2008/ICAAC/ICAAC_22.htm. Last accessed on October 22, 2014.
  10. Hammond JL, Parikh UM, Koontz DL, et al. In Vitro Selection and Analysis of Human Immunodeficiency Virus Type 1 Resistant to Derivatives of beta-2',3'-Didehydro-2',3'-Dideoxy-5-Fluorocytidine. Antimicrob Agents Chemother. 2005 Sep;49(9):3930-2. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1195387/. Last accessed on October 22, 2014.
  11. Parikh UM, Koontz DL, Chu CK, Schinazi RF, Mellors JW. In Vitro Activity of Structurally Diverse Nucleoside Analogs Against Human Immunodeficiency Virus Type 1 with the K65R Mutation in Reverse Transcriptase. Antimicrob Agents Chemother. 2005 Mar;49(3):1139-44. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC549267/. Last accessed on October 22, 2014.
  12. Dunkle LM, Gathe JC, Pedevillano DE, Robison HG, Rice WG, Pottage JC. Elvucitabine: potent antiviral activity demonstrated in multidrug-resistant HIV infection. Abstract presented at: 12th International HIV Drug Resistance Workshop: Basic Principles & Clinical Implications; June 10-14, 2003; Los Cabos, Mexico. Abstract 2. Available at: http://www.intmedpress.com/serveFile.cfm?sUID=759f6f9d-a638-47c3-be71-7d7aaa2efb7d. Last accessed on October 22, 2014.
  13. Achillion Pharmaceuticals. A 14 Day Randomized, Double Blind, Study of Once Daily Elvucitabine Versus Lamivudine in Subjects With a Documented M184V Mutation. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 5, 2006. NLM Identifier: NCT00312039. Last accessed: May 13, 2013. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00312039. Last accessed on October 22, 2014.
  14. Mascolini M. Elvucitabine Versus 3TC in First-Line Regimens for 96 Weeks - see slides from poster below. Conference Reports for National AIDS Treatment Advocacy Project (NATAP): 17th Conference on Retroviruses and Opportunistic Infections (CROI); February 16-19, 2010; San Francisco, CA. Available at: http://www.natap.org/2010/CROI/croi_60.htm. Last accessed on October 22, 2014.
  15. Achillion Pharmaceuticals. A Randomized, Blinded, 12-week Comparison of Elvucitabine/Efavirenz/Tenofovir Versus Lamivudine/Efavirenz/Tenofovir in HIV-1 Infected, Treatment Naive Subjects. There is a 36 Week, Open Label, Extension Phase for Eligible Subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 6, 2006. NLM Identifier: NCT00350272. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00350272. Last accessed on October 22, 2014.
  16. Achillion Pharmaceuticals. An Open Label Treatment Protocol to Provide Continued Elvucitabine Treatment for 48-Weeks in Subjects Who Have Completed 96 -Weeks of Elvucitabine Therapy in Protocol ACH443-015 or 48 Weeks of Therapy in Protocol ACH443-018. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 8, 2008. NLM Identifier: NCT00675844. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00675844. Last accessed on October 22, 2014.
  17. Achillion Pharmaceuticals. An Open-Label,48 Week Extension Study of Elvucitabine Administered In Combination With Background Antiretroviral Agents in Subjects Who Have Completed 14 Days of Treatment in Protocol ACH443-014A. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 21, 2006. NLM Identifier: NCT00380159. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00380159. Last accessed on October 22, 2014.
  18. Colucci P, Pottage JC, Robison H, Turgeon J, Ducharme MP. Effect of a Single Dose of Ritonavir on the Pharmacokinetic Behavior of Elvucitabine, a Nucleoside Reverse Transcriptase Inhibitor, Administered in Healthy Volunteers. Antimicrob Agents Chemother. 2009 Feb;53(2):646-50. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2630647/. Last accessed on October 22, 2014.
 


Last Reviewed: October 22, 2014

Last Updated: October 22, 2014


Back to Top