A Clinical Overview of Elvucitabine

Other Names: ACH-126443, L-F-D4C
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
Molecular Weight: 227.194
(Compound details obtained from ChemIDplus Advanced¹ and NIAID Therapeutics Database²)

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.³˒⁴ 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.⁵˒⁶

T½: Approximately 100 hours (in a 21-day study of elvucitabine 5 or 10 mg daily or 20 mg every 48 hours, in combination with lopinavir/ritonavir, in HIV-infected adults).⁴

Metabolism/Elimination: Elvucitabine is not metabolized by cytochrome P450 (CYP) enzymes. Elvucitabine is eliminated renally, primarily unchanged in the urine.⁴

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).⁷ Additionally, elvucitabine has been shown to have less in vitro activity against HIV with the K65R mutation than against wild-type (wt) virus.⁸

In a study of HIV-infected adults, elvucitabine -- at doses of 50 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.⁹ A study of a lower dose -- 10 mg of elvucitabine -- has been conducted in a similar patient population, one that harbors the M184V mutation.¹⁰

Dosing

Elvucitabine is administered once daily and orally.³˒¹⁰

Phase II (treatment-naive):

• Elvucitabine 10 mg versus lamidvudine 300 mg, each in combination with efavirenz and tenofovir DF.³

Phase II (treatment-experienced with M184V mutation):

• Elvucitabine 10 mg versus lamivudine 300 mg, each in combination with a background regimen.¹⁰

Adverse Events

In a 96-week Phase II trial of treatment-naive adults, drug-related adverse events associated with elvucitabine occurring in 5% or more of subjects 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 subject 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.³

Drug Interactions

Elvucitabine is neither an inducer nor an inhibitor of CYP enzymes.⁴

When co-administered in a single-dose drug interaction study, ritonavir significantly reduced the bioavailability of elvucitabine.¹¹

References

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. DeJesus E, Saple D, Morales-Ramirez J, et al. Elvucitabine vs Lamivudine with Tenofovir and Efavirenz in Antiretroviral-Treatment-Naive 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/Abstract K-131.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.