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Drugs

Vicriviroc

Other Names: MK-4176, MK-4176 IVR, MK-4176 intravaginal ring, MK-7690, SCH-417690, SCH-D, VCV, vicriviroc IVR, vicriviroc intravaginal ring, vicriviroc maleate Drug Class: Entry Inhibitor
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 Organization: Merck & Co., Inc. Phase of Development: Vicriviroc for HIV treatment was previously in Phase III studies but has since been discontinued. Vicriviroc-containing microbicides for HIV prevention are in Phase I studies.

Chemical Image:

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vicriviroc

vicriviroc

Molecular Weight: 533.6352

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 National AIDS Treatment Advocacy Project [NATAP] website,3 and ClinicalTrials.gov4,5)

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): In a study of oral vicriviroc 50 mg twice daily in HIV-infected individuals, the elimination half-life of vicriviroc was 28 hours.6

Metabolism/Elimination: Vicriviroc is primarily metabolized by CYP3A4 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 2 Phase III trials (NCT00523211 and NCT00474370) of oral vicriviroc 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.10-12

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.13,14


Clinical Trials



TREATMENT

Note: The study of oral vicriviroc for HIV treatment was discontinued in 2010. The company developing the drug announced that this decision was based on data from a Phase II trial in treatment-naive adults and 2 Phase III trials in treatment-experienced adults. In these trials, vicriviroc failed to show improved efficacy over currently approved HIV medicines already in use.3,15,16 

Study Identifiers: P04875; NCT00551018
Sponsor: Merck Sharp & Dohme Corp.
Phase: II
Study Purpose: The purpose of this open-label study was to evaulate the safety and effectiveness of vicriviroc as compared to emtricitabine/tenofovir DF (Truvada).
Study Population:
  • Participants were treatment-naive adults infected with CCR5-tropic HIV. Participants may have had, at most, 4 weeks of cumulative lifetime ART exposure (with exceptions), but must not have received ART in the 8 weeks prior to randomization.
  • Participants had HIV RNA ≥2,000 copies/mL and CD4 counts ≥100 cells/mm3 at screening.

Dosing: Participants received vicriviroc 30 mg or Truvada 200/300 mg, each administered once daily and in combination with ritonavir-boosted atazanavir over 48 weeks (primary analysis) and up to 96 weeks (final analysis).16,17
Selected Study Results:

Study Identifiers: (1) P04405AM5; VICTOR-E3; NCT00523211 and (2) P04889AM8; VICTOR-E4; NCT00474370
Sponsor: Merck Sharp & Dohme Corp.
Phase: III
Study Purpose: VICTOR-E3 and VICTOR-E4 were 2 identically designed Phase III safety and efficacy trials that compared vicriviroc to placebo.
Study Population:
  • Participants were treatment-experienced adults infected with CCR5-tropic HIV.
  • Participants had HIV RNA >1,000 copies/mL within 60 days of randomization and were either on a stable ART regimen of 3 or more ARVs for at least 4 weeks prior to screening or were not receiving ART for at least 4 weeks prior to screening.
  • Participants had documented resistance to at least 2 ARV drug classes (NRTI, NNRTI, or PI) or had at least 6 months of ARV therapy experience with at least 2 of the following: 1 NRTI, 1 NNRTI, or 2 PIs (excluding low-dose ritonavir).

Dosing: Participants received vicriviroc 30 mg administered once daily versus placebo, each in combination with optimized background therapy containing a ritonavir-boosted PI plus 2 fully active ARV drugs over 48 weeks (primary analysis).11,12,15,18
Selected Study Results:


PREVENTION

Vicriviroc is being developed into microbicide products to prevent sexually acquired HIV infection in women. Two Phase I studies assessed the safety and pharmacokinetics of intravaginal rings (IVRs) containing vicriviroc in HIV-uninfected women.
  • In a Phase I study (MTN-027; NCT02356302), 3 IVRs were compared to placebo. The 3 active-drug IVRs tested included a ring containing vicriviroc alone, a ring containing MK-2048 (an investigational INI) alone, and a ring containing a combination of vicriviroc and MK-2048. (The combination IVR is also known as MK-2048A.)4,19
  • The other Phase I study (MTN-028; NCT02419456) evaluated 2 different dosage strengths of the combination IVR, MK-2048A.5,19


Adverse Events


In the Phase III trials VICTOR-E3 (NCT00523211) and VICTOR-E4 (NCT00474370), oral vicriviroc was comparable to placebo in terms of adverse events (AEs), with no significant differences in new AIDS diagnoses, malignancies, or other major AEs. Study discontinuations due to AEs occurred in 14% of participants receiving vicriviroc and in 8% of participants receiving placebo.18

In the Phase II trial (NCT00551018), a greater proportion of participants receiving oral vicriviroc than participants receiving emtricitabine/tenofovir DF discontinued treatment because of AEs. There were no predominant AEs among vicriviroc-treated participants. Laboratory abnormalities were comparable between both groups.16


Drug Interactions


Vicriviroc is a substrate of CYP3A4; however, it is neither a CYP3A4 inhibitor nor inducer.20

If carbamazepine or rifabutin (CYP3A4 inducers) are coadministered with vicriviroc in a regimen containing a ritonavir-boosted PI, the ritonavir dose should be increased. Rifampin (CYP3A4 inducer) coadministered with vicriviroc is not recommended.20

No vicriviroc dosage adjustments are required when vicriviroc is coadministered with most ritonavir-boosted PIs.6

There are no significant drug interactions between vicriviroc and the drugs lamivudine, zidovudine, or tenofovir DF. Efavirenz significantly increases the metabolism of vicriviroc; however, the addition of ritonavir in the regimen attenuates the inductive effects.6,21

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.22


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 December 12, 2016.
  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 December 12, 2016.
  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 December 12, 2016.
  4. National Institute of Allergy and Infectious Diseases (NIAID). Phase 1 Safety and Pharmacokinetics Study of MK-2048/Vicriviroc (MK-4176)/MK-2048A Intravaginal Rings. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 2, 2015. NLM Identifier: NCT02356302. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02356302. Last accessed on December 12, 2016.
  5. National Institute of Allergy and Infectious Diseases (NIAID). Phase 1 Pharmacokinetic Trial of Two Intravaginal Rings (IVRs) Containing Different Dose Strengths of Vicriviroc (MK-4176) and MK-2048. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 14, 2015. NLM Identifier: NCT02419456. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02419456. Last accessed on December 12, 2016.
  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 December 12, 2016.
  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 December 12, 2016.
  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 December 12, 2016.
  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 October 15, 2015.
  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 December 12, 2016.
  11. 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 December 12, 2016.
  12. 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 December 12, 2016.
  13. 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 December 12, 2016.
  14. 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: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3353024/. Last accessed on December 12, 2016.
  15. 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 December 12, 2016.
  16. 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 December 12, 2016.
  17. 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 December 12, 2016.
  18. 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 December 12, 2016.
  19. Microbicide Trials Network (MTN) website. Fact Sheet: Ongoing, Planned and Completed Trials of the MTN. Available at: http://www.mtnstopshiv.org/node/873. Last accessed on December 12, 2016.
  20. 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 December 12, 2016.
  21. Emmelkamp JM and 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):409-417. Available at: http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.452.3276&rep=rep1&type=pdf. Last accessed on December 13, 2016.
  22. 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 December 12, 2016.


Last Reviewed: December 12, 2016