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FDA-approved

Investigational

Vicriviroc  Audio icon

Other Names: SCH-417690, SCH-D, VCV, vicriviroc maleate
Drug Class: Entry and Fusion Inhibitors
Molecular Formula: C28 H38 F3 N5 O2
Registry Number: 306296-47-9 (CAS)
Chemical Name: (4,6-dimethylpyrimidin-5-yl)-[4-[(3S)-4-[(1R)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl]-3-methyl-piperazin-1-yl]-4-methyl-1-piperidyl]methanone
Chemical Class: Pyrimidines
Phase of Development: Phase III (discontinued)
Chemical Image:
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vicriviroc
vicriviroc
Molecular Weight: 533.6352
(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and National AIDS Treatment Advocacy Project [NATAP] website3)
Patent Version Content

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


The study of vicriviroc as an entry inhibitor HIV medicine was discontinued in 2010. The company developing the drug announced that this decision was based on data from one Phase II trial in treatment-naive adults and two Phase III trials in treatment-experienced adults. In these trials, vicriviroc failed to show improved efficacy over currently approved HIV medicines already in use.3-5


Pharmacology


Mechanism of Action: HIV-1 entry inhibitor. Vicriviroc is a reversible, small-molecule CCR5 co-receptor antagonist that prevents viral entry by binding to a domain of CCR5 and subsequently inhibiting the interaction between HIV-1 gp120 and CCR5.6-8

Half-life (T½): 28 hours (vicriviroc 50 mg twice daily in HIV-infected individuals).6

Metabolism/Elimination: Vicriviroc is primarily metabolized by cytochrome P450 (CYP) 3A4 and, to a lesser extent, by CYP3A5 and CYP2C9.6 When healthy participants received a single 14C-radiolabeled dose of vicriviroc, approximately 47% was excreted in urine and 45% was excreted in feces.9

Resistance: Isolates from treatment-experienced participants experiencing virologic failure in two Phase III trials were analyzed. Analysis included only those participants with R5-tropic virus detected at baseline. Seventy-one out of 486 vicriviroc-treated participants met the protocol-defined virologic failure criteria after 48 weeks of treatment. Of those virologic failures, 10% were determined to have dual-mixed/X4 virus at the time of failure. Resistance to vicriviroc was identified in 1% of treated participants (4 out of 486). Clonal analysis identified 2 to 5 amino acid substitutions in the V3 loop associated with vicriviroc resistance; changes outside the V3 loop were also seen in resistant clones; however, no consistent pattern was observed.10

In vitro studies have described reduced susceptibility to vicriviroc that is associated with changes in the HIV-1 gp120 V4 loop and the gp41 fusion peptide.11,12
 


Dosing in Clinical Trials


Study Identifiers: P04875; NCT0055101813
Phase: II
Study Purpose: Safety and efficacy study comparing vicriviroc to emtricitabine/tenofovir DF (Truvada)
Study Population: HIV-infected, treatment-naive adults with CCR5-tropic HIV
Dosing: Vicriviroc 30 mg administered once daily versus emtricitabine 200 mg/tenofovir DF 300mg, each in combination with ritonavir-boosted atazanavir.5,13
(See references cited above for information on study results.)

Study Identifiers: P04405AM5 and P04889AM8; VICTOR-E3 and VICTOR-E4; NCT00523211 and NCT0047437014,15
Phase: III
Study Purpose: VICTOR-E3 and VICTOR-E4 were two identically designed Phase III safety and efficacy trials that compared vicriviroc  to placebo. 
Study Population: HIV-infected, treatment-experienced adults with CCR5-tropic HIV and who had resistance to two antiretroviral (ARV) drug classes or had at least 6 months of ARV therapy
Dosing: Vicriviroc 30 mg administered once daily versus placebo, each in combination with optimized background therapy containing a ritonavir-boosted protease inhibitor plus two fully active ARV drugs.4,14-16
(See references cited above for information on study results.)
 


Adverse Events


In the Phase III trials VICTOR-E3 and VICTOR-E4, vicriviroc was comparable to placebo in terms of adverse events, with no significant differences in new AIDS diagnoses, malignancies, or other major adverse events. Study discontinuations due to adverse events occurred in 14% of participants receiving vicriviroc and in 8% of participants receiving placebo.16

In the Phase II trial (Study P04875), a greater proportion of vicriviroc participants than emtricitabine/tenofovir DF participants discontinued treatment because of adverse events. There were no predominant adverse events among vicriviroc-treated participants. Laboratory abnormalities were comparable between both groups.5
 


Drug Interactions


Vicriviroc is a substrate of CYP3A4; however, it is neither a CYP3A4 inhibitor nor inducer.17

If carbamazepine or rifabutin (CYP3A4 inducers) are co-administered with vicriviroc in a regimen containing a ritonavir-boosted protease inhibitor, the ritonavir dose should be increased. Rifampin (CYP3A4 inducer) co-administered with vicriviroc is not recommended.17

No vicriviroc dosage adjustments are required when vicriviroc is co-administered with most ritonavir-boosted protease inhibitors.6

There are no significant drug interactions between vicriviroc and the drugs lamivudine, zidovudine, or tenofovir. Efavirenz significantly increases the metabolism of vicriviroc; however, the addition of ritonavir in the regimen attenuates the inductive effects.6

Vicriviroc alone has minimal effects on the pharmacokinetics of ethinyl estradiol (EE) or norethindrone (NET). Ritonavir administered alone or with vicriviroc, however, is associated with decreases in EE and NET exposure.18
 


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/306296-47-9. Last accessed on September 13, 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 September 13, 2014.
  3. Dunkle LM. Merck Research Laboratories. Vicriviroc Discontinued Investigator Letter. National AIDS Treatment Advocacy Project (NATAP): News Updates; 2010. Available at: http://www.natap.org/2010/newsUpdates/071510_02.htm. Last accessed on September 13, 2014.
  4. Caseiro MM, Nelson M, Diaz RS, et al. Vicriviroc plus optimized background therapy for treatment-experienced subjects with CCR5 HIV-1 infection: final results of two randomized phase III trials. J Infect. 2012 Oct;65(4):326-35. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22634184. Last accessed on September 13, 2014.
  5. Dunkle LM, Gathe J, Zhou H, McCarthy M. Antiviral Effect of Vicriviroc (VCV) plus Ritonavir-Boosted Atazanavir (ATV/r) Similar to Tenofovir/emtricitabine (TEM) + ATV/r but Efficacy (%<50c/mL) Inferior as Initial Therapy. Abstract presented at: 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 12-15, 2010; Boston, MA. Abstract H-938a. Available at: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=d89fb4da-4268-4d6b-88ee-4f4ebcd548de&cKey=bb11cf2f-7e42-4aa1-bffa-d364f8cc3e6d&mKey=%7b93AEED6A-54D4-4EF6-99BD-A9B3CE9FACD9%7d. Last accessed on September 13, 2014.
  6. Brown KC, Paul S, Kashuba AD. Drug Interactions with New and Investigational Antiretrovirals. Clin Pharmacokinet. 2009;48(4):211-41. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2857544/. Last accessed on September 13, 2014.
  7. Emmelkamp JM, Rockstroh JK. CCR5 antagonists: comparison of efficacy, side effects, pharmacokinetics and interactions--review of the literature. Eur J Med Res. 2007 Oct 15;12(9):409-17. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17933722. Last accessed on September 13, 2014.
  8. Strizki JM, Tremblay C, Xu S, et al. Discovery and Characterization of Vicriviroc (SCH 417690), a CCR5 Antagonist with Potent Activity against Human Immunodeficiency Virus Type 1. Antimicrob Agents Chemother. 2005 Dec;49(12):4911-9. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1315929/. Last accessed on September 13, 2014.
  9. Kasserra C, O'Mara E. Pharmacokinetic Interaction of Vicriviroc with Other Antiretroviral Agents: Results from a Series of Fixed-Sequence and Parallel-Group Clinical Trials. Clin Pharmacokinet. 2011 Apr;50(4):267-80. Available at: http://www.problemsinanes.com/pt/re/merck/pdfhandler.00003088-201150040-00005.pdf;jsessionid=Tf6W1CL9Jv1rvpvRqy2sbJwpNWr5YjbJymq19Nny07dCTvTMXtwh!1026220615!181195628!8091!-1. Last accessed on September 13, 2014.
  10. McNicholas P, Vilchez RA, Greaves W, et al. Detection of HIV-1 CXCR4 tropism and resistance in treatment experienced subjects receiving CCR5 antagonist-Vicriviroc. J Clin Virol. 2012 Oct;55(2):134-9. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22824230. Last accessed on September 13, 2014.
  11. Asin-Milan O, Chamberland A, Wei Y, Haidara A, Sylla M, Tremblay CL. Mutations in variable domains of the HIV-1 envelope gene can have a significant impact on maraviroc and vicriviroc resistance. AIDS Res Ther. 2013 Jun 7;10(1):15. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3700831/. Last accessed on September 13, 2014.
  12. Anastassopoulou CG, Ketas TJ, Sanders RW, Klasse PJ, Moore JP. Effects of sequence changes in the HIV-1 gp41 fusion peptide on CCR5 inhibitor resistance. Virology. 2012 Jul 5;428(2):86-97. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22520838. Last accessed on September 13, 2014.
  13. Merck Sharp & Dohme Corp. Efficacy and Safety of VICRIVIROC in HIV-Infected Treatment-Naïve Subjects. Bethesda (MD): National Library of Medicine (US). Registered on October 29, 2007. NLM Identifier: NCT00551018. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00551018. Last accessed on September 13, 2014.
  14. Merck Sharp & Dohme Corp. Vicriviroc in Combination Treatment With an Optimized ART Regimen in HIV-Infected Treatment-Experienced Subjects (VICTOR-E3). Bethesda (MD): National Library of Medicine (US). Registered on August 30, 2007. NLM Identifier: NCT00523211. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00523211. Last accessed on September 13, 2014.
  15. Merck Sharp & Dohme Corp. Vicriviroc in Combination Treatment With an Optimized ART Regimen in HIV-Infected Treatment-Experienced Subjects (VICTOR-E4). Bethesda (MD): National Library of Medicine (US). Registered on May 15, 2007. NLM Identifier: NCT00474370. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00474370. Last accessed on September 13, 2014.
  16. Mascolini M. Vicriviroc Does Not Outdo Placebo Regimen in Phase 3 Trials. 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_12.htm. Last accessed on September 13, 2014.
  17. Kasserra C, O’Mara E, Lisbon E. Assessment of Pharmacokinetic and Safety Interactions Between Vicriviroc and CYP3A4 Substrates, Inhibitors, and Inducers. Abstract presented at: 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 12-15, 2009; San Francisco, CA. Abstract H-230. Available at: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=60346ac8-4819-4613-8f61-0e36f03f9155&cKey=12d32cce-fb9e-4eea-9a73-f8ef11f6ecaf&mKey=%7b14EBFE7E-6F65-4D97-8CB6-F64F4347C38A%7d. Last accessed on September 13, 2014.
  18. Kasserra C, Li J, March B, O'Mara E. Effect of vicriviroc with or without ritonavir on oral contraceptive pharmacokinetics: a randomized, open-label, parallel-group, fixed-sequence crossover trial in healthy women. Clin Ther. 2011 Oct;33(10):1503-14. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22015327. Last accessed on September 13, 2014.
 


Last Reviewed: September 13, 2014

Last Updated: September 13, 2014


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