|IUPAC Name:||(4,6-dimethylpyrimidin-5-yl)-[4-[(3S)-4-[(1R)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl]-3-methylpiperazin-1-yl]-4-methylpiperidin-1-yl]methanone;2-hydroxybutanedioic acid|
Vicriviroc Malate(cas 541503-81-5) is an inhibitor of CCR5 signaling with an IC50 value of 0.91 nM.
The ﬁrst step of HIV-1 infection is that the viral envelope, gp120, will interact with cellular coreceptor CCR5. As a second CCR5 antagonist, Vicriviroc can block this interaction and has the antivirus potency. In the chemotaxis assay, Vicriviroc can innhibit chemokine-mediated migration of a mouse Ba/F3 cell line stably expressing recombinant human CCR5 with IC50 value below 1 nM. In the calcium ﬂux assay, Vicriviroc inhibit intracellular calcium release induced by receptor stimulation. Vicriviroc is also proved to inhibit GTPgammaS binding induced by RANTES with mean IC50 of 4.2±1.3nM in a GTPgammaS exchange assay. In a PBMC infection assay with 30 R5-tropic HIV-1 isolates, Vicriviroc potently inhibits all the viral isolates with geometric mean EC50s ranging between 0.04 nM and 2.3 nM. Activity of vicriviroc against drug-resistant viruses has also been tested. Vicriviroc is effective against all the viruses with deﬁned RTI, PRI, or fusion inhibitor resistance patterns. Furthermore, engineered viruses containing mutations in the gp41 gene associated with enfuvirtide resistance are completely sensitive to vicriviroc. So far, Vicriviroc has shown good tolerance and partial therapeutic success in phase II clinical trials for HIV.
1. J Clin Virol. 2012 Oct;55(2):134-9. doi: 10.1016/j.jcv.2012.06.021. Epub 2012 Jul
Detection of HIV-1 CXCR4 tropism and resistance in treatment experienced subjects
receiving CCR5 antagonist-Vicriviroc.
McNicholas P(1), Vilchez RA, Greaves W, Kumar S, Onyebuchi C, Black T, Strizki
(1)Merck Research Laboratories, Kenilworth, NJ, USA.
BACKGROUND: Vicriviroc (VCV), a small-molecule antagonist of the C-C chemokine
receptor 5 (CCR5), blocks HIV's entry into CD4+ cells. Small studies have
suggested that resistance to CCR5 antagonists is slow to develop.
OBJECTIVES: To examine resistance to VCV in isolates from treatment experienced
patients who experienced virologic failure in two phase 3 trials.
STUDY DESIGN: Genotypic and phenotypic susceptibility to VCV, and other
antiretroviral drugs were evaluated at baseline and at defined intervals during
the study. In a post hoc analysis, viral tropism at baseline was evaluated using
the Trofile-ES assay. Only subjects with R5-tropic virus were included in the
analysis. Viral envelope sequencing was performed on samples from subjects with
emergent VCV resistance defined using a relative MPI cutoff.
RESULTS: 71/486 subjects treated with VCV for 48 weeks met the protocol-defined
virologic failure criteria. 7/71 (10%) had DM/X4 virus at the time of virologic
failure; VCV resistance was identified in 4/486 treated subjects (1%). No control
subject had detectable DM/X4 virus or VCV resistance at virologic failure. Clonal
analysis of envelope sequences from VCV-resistant virus identified 2-5 amino acid
substitutions at or near the crown of the V3 loop; however, no signature V3
mutations were identified. Changes outside the V3 loop were also observed in
resistant clones; no consistent variant pattern was observed.
CONCLUSIONS: In these trials, use of a sensitive tropism assay and potent
antiretroviral drug combinations contributed to the infrequent detection of
X4-tropic virus and VCV resistance. Substitutions in the V3 loop were associated
with VCV resistance, however, no specific pattern of amino acid changes were
sufficient to reliably predict VCV susceptibility.
2. Virology. 2012 Jun 5;427(2):158-65. doi: 10.1016/j.virol.2012.02.006. Epub 2012
V3 determinants of HIV-1 escape from the CCR5 inhibitors Maraviroc and
Berro R(1), Klasse PJ, Jakobsen MR, Gorry PR, Moore JP, Sanders RW.
(1)Department of Microbiology and Immunology, Weill Medical College of Cornell
University, New York, NY 10065, USA.
Virology. 2012 Jun 20;428(1):76. Jakobsen, Martin R [added]; Gorry, Paul R
HIV-1 develops resistance to CCR5 antagonists such as Maraviroc (MVC) and
Vicriviroc (VVC) both in vitro and in vivo, with most changes arising in the
gp120 V3 region. Both compounds bind to the same hydrophobic cavity in CCR5 in
subtly different ways. Here, we investigated which V3 sequence changes are most
associated with MVC and VVC resistance and how they affect the interaction
between gp120 and the CCR5 NT. We found that VVC- and MVC-selected amino acid
changes map to different V3 locations and involve residues that interact with the
CCR5 NT in different ways. Changes in VVC-selected, but not MVC-selected,
variants often involve charged residues. Although the overall V3 charge tends not
to change, the introduction or removal of charged residues at specific positions
affects the local electrostatic potential and could have structural and
functional implications. In summary, VVC and MVC trigger the evolution of
distinct HIV-1 resistance patterns in V3.
3. Clin Ther. 2011 Oct;33(10):1503-14. doi: 10.1016/j.clinthera.2011.08.012. Epub
2011 Oct 19.
Effect of vicriviroc with or without ritonavir on oral contraceptive
pharmacokinetics: a randomized, open-label, parallel-group, fixed-sequence
crossover trial in healthy women.
Kasserra C(1), Li J, March B, O'Mara E.
(1)Schering-Plough, Merck & Co., Inc., Kenilworth, New Jersey, USA.
BACKGROUND: Because women of childbearing potential represent 20% to 25% of the
HIV population, it is important to determine any potential drug interactions
between vicriviroc, an antiretroviral agent, and an oral contraceptive (OC) to
provide guidance on any potential dose adjustments.
OBJECTIVE: The primary study objective was to determine the effect of vicriviroc,
a C-C chemokine receptor type 5 inhibitor, alone or in the presence of ritonavir,
on the pharmacokinetics (AUC and C(max)) of the study OC (ethinyl estradiol [EE]
0.035 mg + norethindrone [NET] 1 mg). A secondary objective was to monitor the
safety and tolerability of vicriviroc plus an OC with and without ritonavir.
METHODS: This was a randomized, open-label, parallel-group, single-center study
with a fixed-sequence crossover design. Female subjects were randomized into 2
groups and treated for 2 menstrual cycles. In cycle 1, all received the OC alone,
per standard 28-day pack instructions. On the first 10 days of cycle 2, group 1
received OC + vicriviroc and group 2 received OC + ritonavir; on the following 11
days, both groups received OC + vicriviroc + ritonavir. Blood samples were
collected up to 24 hours after dosing on prespecified days. Pharmacokinetic
parameters, including AUC(0-24), C(max), and C(min), were calculated using
noncompartmental methods, and drug interactions were evaluated using an ANOVA
model by treatment group. Adverse events were collected using physical
examination, vital sign measurements, clinical laboratory analysis,
electrocardiography, and questioning at predefined time points throughout the
study to assess the safety profile.
RESULTS: Twenty-seven subjects were enrolled (26 white, 1 black). The median age
and body mass index were 21 years (range, 18-36 years) and 24.5 kg/m(2) (range,
19.1-31.3 kg/m(2)), respectively. Twenty-one subjects completed the study and
were included in the pharmacokinetic analysis; 4 discontinued for reasons
unrelated to study drug and 2 discontinued because of adverse events. Vicriviroc
had little effect on the pharmacokinetics of the OC. EE mean ratio estimates for
C(max) and AUC(0-24) compared with OC administered alone were 91% and 97%,
respectively, and for NET were 106% and 93%. Subjects receiving ritonavir, alone
or with vicriviroc, experienced decreases in exposure of EE (C(max) mean ratio
estimates, 89% and 76%; AUC(0-24) mean ratio estimates, 71% each, for ritonavir
alone and ritonavir with vicriviroc, respectively) and, to a lesser extent,
decreases in NET (C(max) mean ratio estimates 89% each; AUC(0-24) mean ratio
estimates: 93% and 83%, for ritonavir alone and ritonavir with vicriviroc,
respectively). Twenty-two of 27 (81%) subjects reported ≥1 treatment-emergent
adverse event (TEAE). During cycle 1, TEAEs were reported for 18 of 27 (67%)
subjects while receiving OC alone and for 3 of 24 (13%) subjects while receiving
placebo OC. During cycle 2, TEAEs were reported for 8 of 12 (67%) subjects while
receiving vicriviroc with OC, 4 of 12 (33%) subjects while receiving ritonavir
with OC, 7 of 22 (32%) subjects while receiving vicriviroc + ritonavir with OC,
and 2 of 22 (9%) subjects while receiving placebo OC. The most commonly reported
TEAE was headache (vicriviroc + OC, n = 1; ritonavir + OC, n = 3; vicriviroc +
ritonavir + OC, n = 2; OC alone, n = 12; placebo OC, n = 2). No TEAEs were
CONCLUSIONS: In this population of healthy female subjects, vicriviroc had little
effect on the pharmacokinetics of EE or NET, whereas ritonavir, alone or with
vicriviroc, was associated with consistent decrease in exposure of EE and a
lesser decrease in NET.
4. Expert Opin Drug Metab Toxicol. 2010 Sep;6(9):1139-50. doi:
Vicriviroc, a new CC-chemokine receptor 5 inhibitor for treatment of HIV:
properties, promises and challenges.
Lenz JC(1), Rockstroh JK.
(1)University of Bonn, Medicine I, Sigmund-Freudstr. 25, Bonn 53105, Germany.
IMPORTANCE OF THE FIELD: Although HIV has become a treatable disease with near to
normal life expectancy, the quest for the development of better tolerated drugs
with simple dosing schedules and a high barrier to the emergence of drug
resistance remains. Vicriviroc is a small-molecule chemokine receptor antagonist
that inhibits the binding of R5-tropic HIV-1 to host cells at the CC-chemokine
receptor 5 (CCR5) co-receptor, thus, preventing viral entry. CCR5 inhibitors are
believed to possibly decrease inflammation from the immune system and thereby
offer additional properties further to their antiretroviral efficacy.
AREAS COVERED IN THIS REVIEW: This review is based on a PubMed search covering
the years 2005 - 2010 for pharmacokinetic, pharmacological and clinical data of
WHAT THE READER WILL GAIN: In this review, the pharmacokinetic, pharmacological
and clinical data of vicriviroc are presented. Moreover, the potential role of
vicriviroc in the growing HIV armamentarium is discussed.
TAKE HOME MESSAGE: Vicriviroc is being developed to be administered in
combination with a ritonavir-boosted protease inhibitor for patients with
R5-tropic virus. Early clinical trials have established the safety of vicriviroc
in both treatment-naive and -experienced R5-tropic HIV-1 infected individuals.
Recently, two Phase III clinical trials in treatment-experienced patients failed
to prove its superiority over available HIV medications. Phase III trials for
treatment-naive patients are still under planning. Clearly, more favorable study
results are needed to move vicriviroc into drug registration and approval.