Maraviroc

Maraviroc, sold under the brand names Selzentry (US) and Celsentri (EU), is an antiretroviral medication used to treat HIV infection.^[2][3] It is taken by mouth.^[2][3] It is in the CCR5 receptor antagonist class.^[2][3]

Maraviroc

Clinical data
Pronunciation	/məˈrævɪrɒk/ mə-RAV-i-rok Selzentry: /sɛlˈzɛntri/
Trade names	Selzentry, Celsentri
Other names	UK-427857, 4,4-Difluoro-N-[(1S)-3-{(1R,3s,5S)-3-[3-methyl-5-(propan-2-yl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]octan-8-yl}-1-phenylpropyl] cyclohexanecarboxamide
AHFS/Drugs.com	Monograph
MedlinePlus	a607076
License data	EU EMA: by INN US FDA: Maraviroc
Pregnancy category	AU: B1
Routes of administration	By mouth
ATC code	J05AX09 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: WARNING[1]Rx-only[2] EU: Rx-only[3]
Pharmacokinetic data
Bioavailability	23%[4]
Protein binding	~76%[2]
Metabolism	Liver (CYP, predominantly CYP3A)[2]
Metabolites	Secondary amine formed by N-dealkylation (major)
Elimination half-life	14–18 hours[2] (mean 16 hours)[5]
Excretion	Feces (76%), urine (20%)[2]
Identifiers
IUPAC name 4,4-Difluoro-N-{(1S)-3-[3-(3-isopropyl- 5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}cyclohexanecarboxamide
CAS Number	376348-65-1 Y
PubChem CID	3002977
IUPHAR/BPS	806
DrugBank	DB04835 Y
ChemSpider	20078004 N
UNII	MD6P741W8A
ChEBI	CHEBI:63608 N
ChEMBL	ChEMBL1201187 N
NIAID ChemDB	104834
CompTox Dashboard (EPA)	DTXSID8048949
ECHA InfoCard	100.124.927
Chemical and physical data
Formula	C29H41F2N5O
Molar mass	513.678 g·mol−1
3D model (JSmol)	Interactive image
SMILES Cc5nnc(n5[C@@H]1C[C@H]4CC[C@@H](C1)N4CC[C@H](NC(=O)C2CCC(F)(F)CC2)c3ccccc3)C(C)C
InChI InChI=1S/C29H41F2N5O/c1-19(2)27-34-33-20(3)36(27)25-17-23-9-10-24(18-25)35(23)16-13-26(21-7-5-4-6-8-21)32-28(37)22-11-14-29(30,31)15-12-22/h4-8,19,22-26H,9-18H2,1-3H3,(H,32,37)/t23-,24+,25-,26-/m0/s1 N Key:GSNHKUDZZFZSJB-QYOOZWMWSA-N N
NY (what is this?)  (verify)

It was approved for medical use in the United States in August 2007,^[2] and in the European Union in September 2007.^[3]

Medical uses

Maraviroc is indicated, in combination with other antiretroviral medications, for the treatment of only CCR5-tropic HIV-1 infection.^[2][3]

Side effects

Maraviroc can cause serious, life-threatening side effects. These include liver problems, skin reactions, and allergic reactions. An allergic reaction may happen before liver problems occur.^[6] Official labeling of Selzentry has black box warning for hepatotoxicity.^[2] The MOTIVATE trials showed no clinically relevant differences in safety between the maraviroc and placebo groups.^[7]

Mechanism of action

Maraviroc is an entry inhibitor. Specifically, maraviroc is a negative allosteric modulator of the CCR5 receptor, which is found on the surface of certain human cells. The chemokine receptor CCR5 is an essential co-receptor for most HIV strains and necessary for the entry process of the virus into the host cell. The drug binds to CCR5, thereby blocking the HIV protein gp120 from associating with the receptor. HIV is then unable to enter human macrophages and T cells.^[8] Because HIV can also use other coreceptors, such as CXCR4, an HIV tropism test such as a trofile assay must be performed to determine if the drug will be effective.^[9]

History

Maraviroc, originally designated UK-427857, was developed by the drug company Pfizer in its UK labs located in Sandwich. On 24 April 2007 the U.S. Food and Drug Administration advisory panel reviewing maraviroc's New Drug Application unanimously recommended approval for the new drug,^[10] and the drug received full FDA approval on 6 August 2007 for use in treatment experienced patients.^[11]

Two randomized, placebo-controlled clinical trials, compared 209 people receiving optimized therapy plus a placebo to 426 people receiving optimized therapy plus 150 mg maraviroc once daily and 414 patients receiving optimized therapy plus 150 mg maraviroc twice daily. At 48 weeks, 55% of participants receiving maraviroc once daily and 60% of participants receiving the drug twice daily achieved a viral load of less than 400 copies/mL compared with 26% of those taking placebo; about 44% of the once-daily and 45% of the twice-daily maraviroc group had a viral load of less than 50 copies/mL compared with about 23% of those who received placebo. In addition, those who received the entry inhibitor had a mean increase in CD4⁺ cells of 110 cells/μL in the once-daily group, 106 cells/μL in the twice-daily group, and 56 cells/μL in the placebo group.^[7][12][13] Maraviroc was approved for medical use in the European Union in September 2007.^[3]

Names

Maraviroc is the International nonproprietary name (INN).^[14]

Research

Maraviroc appears to reduce graft-versus-host disease in people treated with allogeneic bone marrow transplantation for leukemia, in a Phase I/II study.^[15][16]

References

1. "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
2. "Selzentry- maraviroc tablet, film coated Selzentry- maraviroc solution". DailyMed. 18 July 2018. Retrieved 31 July 2020.
3. "Celsentri EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 31 July 2020.
4. Abel S, Russell D, Whitlock LA, Ridgway CE, Nedderman AN, Walker DK (April 2008). "Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjects". British Journal of Clinical Pharmacology. 65 (Suppl 1): 60–7. doi:10.1111/j.1365-2125.2008.03137.x. PMC 2311408. PMID 18333867.
5. Abel S, Back DJ, Vourvahis M (2009). "Maraviroc: pharmacokinetics and drug interactions". Antiviral Therapy. 14 (5): 607–18. doi:10.1177/135965350901400514. PMID 19704163. S2CID 29064286.
6. "Maraviroc (HIV treatment) Dosage, Side Effects". AIDSinfo.
7. Stephenson J (April 2007). "Researchers buoyed by novel HIV drugs: will expand drug arsenal against resistant virus". JAMA. 297 (14): 1535–6. doi:10.1001/jama.297.14.1535. PMID 17426263.
8. Levy JA (January 2009). "HIV pathogenesis: 25 years of progress and persistent challenges". AIDS. 23 (2): 147–60. doi:10.1097/QAD.0b013e3283217f9f. PMID 19098484. S2CID 10571856.
9. Biswas P, Tambussi G, Lazzarin A (May 2007). "Access denied? The status of co-receptor inhibition to counter HIV entry". Expert Opinion on Pharmacotherapy. 8 (7): 923–33. doi:10.1517/14656566.8.7.923. PMID 17472538. S2CID 32675897.
10. Gay News From 365Gay.com
11. Krauskopf, Lewis (6 August 2007). "Pfizer wins U.S. approval for new HIV drug". Reuters. Retrieved 6 August 2007.
12. Emmelkamp JM, Rockstroh JK (October 2007). "CCR5 antagonists: comparison of efficacy, side effects, pharmacokinetics and interactions--review of the literature". European Journal of Medical Research. 12 (9): 409–17. PMID 17933722.
13. "Maraviroc reduces viral load in naive patients at 48 weeks". AIDS Patient Care and STDs. 21 (9): 703–4. September 2007. PMID 17941136.
14. World Health Organization (2005). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 53". WHO Drug Information. 19 (1): 84–5. hdl:10665/73323. License: CC BY-NC-SA 3.0 IGO.
15. Reshef R, Luger SM, Hexner EO, Loren AW, Frey NV, Nasta SD, et al. (July 2012). "Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease". N. Engl. J. Med. 367 (2): 135–45. doi:10.1056/NEJMoa1201248. PMC 3568501. PMID 22784116.
16. "HIV Drug Reduces Graft-versus-Host Disease in Bone Marrow Transplant Patients, Penn Study Shows". Penn Medicine (Press release).

Further reading

• Dean L (2015). "Maraviroc Therapy and CCR5 Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520358. Bookshelf ID: NBK279895.

External links

• "Maraviroc". Drug Information Portal. U.S. National Library of Medicine.
• Maraviroc at the U.S. National Library of Medicine Medical Subject Headings (MeSH)