Mechanism of Action: HIV-1 entry inhibitor. Cenicriviroc is a small-molecule CCR5 coreceptor antagonist that prevents viral entry by binding to a domain of CCR5 and subsequently inhibiting the interaction between HIV-1 gp120 and CCR5.3,4 Cenicriviroc is also a CCR2 antagonist.5
T½: 11.3 to 12.8 hours (once daily oral administration of 100-mg and 200-mg doses, respectively, in HIV-infected subjects, using a 50-mg tablet formulation).6
Metabolism/Elimination: Oxidative metabolism was primarily via CYP3A4 and CYP2C8 in rats, dogs, and monkeys. Cenicriviroc had no inhibitory effects on CYP-mediated activities and no inductive effects on CYP3A4 in human hepatocytes. In animals, elimination of cenicriviroc was primarily as unchanged drug (minor amounts of metabolites) into feces via the hepatobilliary route.7
Resistance: In a study of a cenicriviroc-resistant clinical isolate, several amino acid changes in not only the V3 region but also in other Env regions were required for R5 HIV-1 to develop complete resistance to cenicriviroc.8
In a Phase I/II 10-day monotherapy dose-escalating study of treatment-experienced, CCR5-naive HIV-infected patients, shifts in viral tropism were not detected (except in one subject who was found to have a tropism shift from CCR5 to CXCR4 coreceptor at baseline and was excluded from efficacy analysis).5
Cenicriviroc is administered once daily and orally.5,6
Phase I/II (treatment-experienced, CCR5 antagonist-naive):
- Cenicriviroc doses ranging from 25 mg to 150 mg (25-mg tablet formulation, except for the 100-mg dosing group, which was given a 100-mg tablet formulation) versus placebo.5
Phase IIb (treatment-naive) (Study 202):
- Cenicriviroc 100 mg or 200 mg (50-mg tablet formulation) versus efavirenz, each in combination with emtricitabine/tenofovir DF.6
The most common adverse events associated with cenicriviroc in a Phase I/II trial of five dose levels ranging from 25 mg to 150 mg were headache, nausea, constipation, diarrhea, and sinusitis. Adverse events were generally considered mild. No grade 4 or serious events occurred. There were no deaths or study discontinuations due to adverse events.5
Cenicriviroc has no inhibitory effects on CYP-mediated activities and no inductive effects on CYP3A4 in human hepatocytes.7
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. Baba M, Takashima K, Miyake H, et al. TAK-652 inhibits CCR5-mediated human immunodeficiency virus type 1 infection in vitro and has favorable pharmacokinetics in humans. Antimicrob Agents Chemother. 2005 Nov;49(11):4584-91.
4. Briz V, Poveda E, Soriano V. HIV entry inhibitors: mechanisms of action and resistance pathways. J Antimicrob Chemother. 2006 Apr;57(4):619-27.
5. Marier JF, Trinh M, Pheng LH, Palleja SM, Martin DE. Pharmacokinetics and pharmacodynamics of TBR-652, a novel CCR5 antagonist, in HIV-1-infected, antiretroviral treatment-experienced, CCR5 antagonist-naïve patients. Antimicrob Agents Chemother. 2011 Jun;55(6):2768-74.
6. Martin D, Beliveau M, Marier JF, Driz R, Palleja S. Pharmacokinetics (PK) of Cenicriviroc (CVC) Following 100 or 200 mg Once-Daily Dosing with Open-Label Tenofovir / Emtricitabine (TDF/FTC) in HIV-1–Infected Subjects Enrolled in a Phase 2b Study. Poster presented at: 19th Conference on Retroviruses and Opportunistic Infections (CROI); March 5-8, 2012; Seattle, WA. Poster 600.
7. Martin DE, Kawase M, Asahi S, et al. Cenicriviroc (CVC, TBR-652) Absorption, Distribution, Metabolism, and Excretion Profile in Rats, Dogs, Monkeys, and Humans. Poster presented at: 18th Conference on Retroviruses and Opportunistic Infections (CROI); February 27-March 2, 2011; Boston, MA. Poster N-101.
8. Baba M, Miyake H, Wang X, Okamoto M, Takashima K. Isolation and characterization of human immunodeficiency virus type 1 resistant to the small-molecule CCR5 antagonist TAK-652. Antimicrob Agents Chemother. 2007 Feb;51(2):707-15.
Last Reviewed: May 10, 2013
Last Updated: May 10, 2013