Introduction:

Vicriviroc is an investigational antiviral drug that is used to inhibit the deadly Human Immunodeficiency
Virus-1(HIV-1) to cause infection in the host cell. This pyrimidine based drug was developed by
Schering-Plough Corp which is still under clinical trial phase. It is an antagonist of coreceptor CCR5 i.e.
it blocks the CCR5 coreceptor so that the HIV-1 virus can not bind to it to cause infection.

Formerly Vicriviroc was known as SCH-D or SCH 417690 and is much more potent and improved than
previously CCR5 antagonist SCH-C.

Chemistry:[4]

Molecular formula: C28H38F3N5O2

Molecular weight: 533.6g/mol

Density: 1.2g/cm3

Boiling point: 608.1 at 760mmHg

Water solubility: 0.0362mg/mL

Structure:

API purity:

The purity of vicriviroc in vicriviroc maleate is 99.41%

Routes of administration:

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This drug is taken orally for managing inhibition of HIV-1.[5]

Dosage forms:

Vicriviroc is still under clinical trial i.e. it is not an approved drug and yet not marketed but in clinical
trial they are given in tablet formation.[5]

Disintegration and dissolution

The vicriviroc drug is taken orally. So after administration the drugs are broken in the gastrointestinal
tract and are readily disintegrated as well as dissolution also occurs at a fast rate. Sufficient information
on the disintegration and dissolution is not given.[2]

Absorption

The absorption of vicriviroc is very fast( tmax is 1-1.5h). In a clinical trial the absorption rate, Ka is
0.31/h is seen after taking the drugs for a week.[2]

Vicriviroc when tested in monkeys and rats excellent bioavailability was seen administrating both by
orally and through IV[1]. Problems in the gastrointestinal tract can affect the bioavailability of the drug
when taken orally.[2]

This antiretroviral drug is a highly water soluble drug having pKa of 8.85[4]. The weight of the free base
of the drug is 533[1]. The stereochemistry of the drug is absolute. And there is a salt of the drug called
vicriviroc maleate.[4]

Distribution

As we all know that after absorption the drugs are distributed. It was seen in clinical trials that the central
volume of distribution of the drug was 42.3L and the peripheral volume of distribution was 662L after
first taking the drugs for a week.[3]

Protein bound: 84%[2]

ClogP: 3.29[4]

Vd: centrally 42.3L and peripherally 662L[3]

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Metabolism

The drug is metabolized through the liver. They are metabolized by N-oxidation, N,N-dealkylation,
oxidation to a carboxylic group metabolite. These metabolism were catalyzed by the CYP3A4 where
CYP3A5 and CYP2C9 also played role in but to some extent.[1]

In clinical trials it is seen that the drug doesn’t inhibit the activities of the CYP2A6, 1A2, 2D6. The
metabolism was affected only on those who had liver abnormalities and had gastrointestinal effects in a
patient from beforehand.[1]

Elimination

In clinical trial when vicriviroc was given in animals, it was mostly eliminated through the feces but whe
radioactive labeled vicriviroc is given in human then elimination of the drug was 47% through and 45%
through feces.[6]

In one study it is seen that the elimination rate constant, Ke of vicriviroc is 0.08[3]. The factors that might
affect the elimination of the drugs are[3]:

 Any renal diseases will cause disturbance in renal function which will affect the elimination of
the drug.
 If vicriviroc is taken with any other antiretroviral drugs the potency might increase but the after a
certain point the elimination will be affected which will increase the toxicity inside the body.
 The usual dosing of the drug in clinical trial is seen once daily but it is tested by giving two doses
daily which increases the amount of the drug inside the body which gives the evidence of the fact
that the elimination is not occurring at its certain rate.

Pharmacology and Mechanism of action

CCR5 is a chemokine receptor that is present in the surface of the cells like in the surface of CD4+
macrophages, T-cells. These receptors do not take part in human functions predominantly but they are
very essential for the HIV-1 infection to enter the cells. We are aware of the fact that viruses have
envelop and the envelop glycoprotein complex comprising three subunits of gp120 of HIV-1 interacts
with the CCR5 receptors to enter the host cells and cause infection.[1]

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Vicriviroc is a CCR5 antagonist that inhibits the connection between the gp120 of the virus and the
coreceptor for which the virus can not enter the host cells and replicate which ultimately reduce the virus
load.[6]

In the clinical trial it is seen that when 50mg vicriviroc was given two times a day the plasma half life was
about 28h.

Pregnancy class

As mentioned earlier that vicroviroc is an investigational drug and until now clinical trial has been
conducted in healthy human, HIV-1 infected patients but no test has been done among the pregnant or
breastfeeding women for which there is no data of the effectiveness of the drug among the among the
pregnant women. [6]

Toxicity

As vicriviroc is still a drug under clinical trial very less information about its toxicity is known.
Moreover, it is seen that this is the antiretroviral drug with minimal toxicity and maximum therapeutic
effectiveness. [1]

At first ancriviroc was developed but it showed interval prolongation of QTc in humans due to the
inhibition of the hERG potassium ion channel in the heart tissue. For this reason later on vicriviroc was
developed whose which was screened for hERG activity and it was 5 fold less active than the ancriviroc
and in monkeys upto 40mg/kg use of this drug didn’t show any toxicity in the heart. But chornic toxicity
is seen in gastrointestinal tract.[1]

Side effects and adverse effects

Every drugs have some side effects for which many of the drugs are banned or withdrawn as their side
effects are more than their therapeutic effects. Like all other drugs in clinical trials different adverse
effects as well as side effects are seen

In phase I it was seen that there was no dose related adverse effects but some effects were seen. About
69% of patients had different adverse effects like headache, nausea and abdominal pain.[1]

In phase II trial some more adverse affects are seen like drowsiness, fatigue, vomiting, nausea,
nasopharyngitis, abdominal pain in the upper section, headache.[1]

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In phase III adverse effects like the phase I and II were seen but in addition malignancies have been seen
among the patients. Moreover liver abnormalities were reported in some patients who were having the
drug for a longer period of time.[1]

Indication and contra indication

Vicrovirac is a next generation antiretroviral drug that is still under clinical trial. It is mainly developed
for treating HIV-1 infected patients.

Dose, frequency, regular vs sustain release

The dose of the drug is 30mg of tablet once daily for having a longer half life.[5]

There is no sufficient data of sustain release of this drug. Till now the clinical trial that have been
conducted were done by giving regular dose especially orally and in some animals through intravenously.

Re-purposing of the drug

The drug is an investigational drug for which this is still not marketed and there is no re-purposing of the
drug.

Conclusion

Vicroviroc has shown better potency and higher tolerability in the clinical trial phase than any other
antiretroviral CCR5 antagonist. But it couldn’t show its superiority over placebo for which the phase III
trial of the drug was stopped afterwards for which it was not used in treating the infected patient
population and still remained as a investigational drug.[2]

Reference:

1. Klibanov, O. (2014). Vicriviroc, a CCR5 receptor antagonist for the potential treatment of HIV
infection.
2. Lenz, J., & Rockstroh, J. (2010). Vicriviroc, a new CC-chemokine receptor 5 inhibitor for
treatment of HIV: properties, promises and challenges. Expert Opinion On Drug Metabolism &
Toxicology, 6(9), 1139-1150. doi: 10.1517/17425255.2010.510833
3. Crawford, K., Li, C., Keung, A., Su, Z., Hughes, M., & Greaves, W. et al. (2010).
Pharmacokinetic/Pharmacodynamic Modeling of the Antiretroviral Activity of the CCR5
Antagonist Vicriviroc in Treatment Experienced HIV-Infected Subjects (ACTG Protocol

5
 5211). JAIDS Journal Of Acquired Immune Deficiency Syndromes, 53(5), 598-605. doi:
10.1097/qai.0b013e3181c9caac
4. Vicriviroc - DrugBank. (2020). Retrieved 6 June 2020, from
https://www.drugbank.ca/drugs/DB06652
5. NCATS Inxight: Drugs — VICRIVIROC. (2020). Retrieved 6 June 2020, from
https://drugs.ncats.io/drug/TL515DW4QS
6. Vicriviroc Clinical Trials, Side Effects. (2020). Retrieved 4 June 2020, from
https://aidsinfo.nih.gov/drugs/519/vicriviroc/0/patient