Maraviroc

(USAN, rINN)
Maraviroc Chemical formula
Synonyms: Maravirocum; UK-427857. 4,4-DifluoroN-((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.
Cyrillic synonym: Маравирок.

💊 Chemical information

Chemical formula: C29H41F2N5O = 513.7.
CAS — 376348-65-1.
ATC — J05AX09.
ATC Vet — QJ05AX09.

💊 Adverse Effects and Precautions

On the basis of limited data, maraviroc appears to be well tolerated; non-specific adverse effects associated with maraviroc-based regimens include asthenia, cough and upper respiratory-tract infections, dizziness, abdominal pain and distension, constipation, diarrhoea, dyspepsia, nausea, vomiting, fever, headache, insomnia, somnolence, muscle spasms and back pain, pruritus, and rash. Less frequently reported adverse effects include osteonecrosis and cardiovascular effects such as myocardial ischaemia and myocardial infarction; cardiac adverse effects were reported mainly for patients with pre-existing cardiac disease or risk factors. Hepatotoxicity has occurred; raised liver enzyme values and bilirubin have also been reported and caution is advised in patients with pre-existing liver dysfunction or co-infection with hepatitis B or C. Although renal clearance normally accounts for only a small proportion of the dose, maraviroc should be used with caution in patients with renal impairment (creatinine clearance less than 80 mL/minute) who are also taking potent inhibitors of the cytochrome P450 isoenzyme CYP3A4 as concentrations of maraviroc may be significantly increased.

💊 Interactions

Maraviroc is a substrate for the cytochrome P450 isoenzyme CYP3A4 and for P-glycoprotein, and may therefore have a number of clinically significant interactions. Inhibitors of CYP3A4, such as HIV-protease inhibitors (other than tipranavir), increase the serum concentration of maraviroc. Inducers of CYP3A4 such as efavirenz may decrease serum maraviroc concentrations. No clinically significant interaction is expected between maraviroc and NRTIs, nevirapine, or boosted fosamprenavir or tipranavir. Non-antiretroviral medications that significantly alter maraviroc metabolism include the CYP3A4 inhibitors ketoconazole, itraconazole, clarithromycin, and nefazodone and the CYP3A4 inducers rifampicin and St John’s wort. Maraviroc does not appear to cause clinically significant changes in concentrations of other medications.

💊 Antiviral Action

Maraviroc is an antagonist of the CCR5 chemokine receptor. During infection, HIV binds to the CD4 receptor on the surface of host cells, and then interacts with one of two co-receptors, CCR5 or CXCR4, to allow cell membrane fusion and entry to the cell. By binding to CCR5, maraviroc inhibits this process and prevents strains of HIV-1 that use CCR5 (CCR5-tropic viruses), which appear to be more common in early infection, from entering the cell. It is not active against CXCR4tropic strains or those with dual or mixed tropism.

💊 Pharmacokinetics

Maraviroc is absorbed after oral doses, and peak concentrations occur in 0.5 to 4 hours. There is considerable interindividual variation in the pharmacokinetics. It is 76% bound to plasma proteins. Maraviroc is metabolised by the cytochrome P450 system (specifically the isoenzyme CYP3A4) to inactive metabolites. It is excreted in both urine (20%) and faeces (76%) as unchanged drug and metabolites.

💊 Uses and Administration

Maraviroc is an antagonist of the CCR5 chemokine receptor (see Antiviral Action, above). It is used, with other antiretrovirals, for the treatment of HIV infection and AIDS in treatment-experienced adult patients with exclusively CCR5-tropic HIV-1 infection. Co-receptor tropism should be determined by specific testing before maraviroc is used. Maraviroc is given orally in a dose of 300 mg twice daily, although dose adjustments may be needed depending on interactions with other medicines.
For patients also taking CYP3A4 inhibitors such as HIV-protease inhibitors (other than fosamprenavir or tipranavir), delavirdine, ketoconazole, itraconazole, clarithromycin, nefazodone, and telithromycin, the recommended dose is 150 mg twice daily.
In those whose therapy includes CYP3A4 inducers (without a CYP3A4 inhibitor) such as efavirenz, rifampicin, carbamazepine, phenobarbital, and phenytoin, the recommended dose is 600 mg twice daily.
Patients taking other antiretrovirals (including fosamprenavir or tipranavir), or other drugs, may be given the standard dose of 300 mg twice daily.
1. Carter NJ, Keating GM. Maraviroc. Drugs 2007; 67: 2277–88
2. Vandekerckhove L, et al. Maraviroc: integration of a new antiretroviral drug class into clinical practice. J Antimicrob Chemother 2008; 61: 1187–90.

Administration in renal impairment.

UK licensed product information recommends that the oral dose of maraviroc be adjusted in patients with renal impairment who are also taking potent inhibitors of cytochrome P450 isoenzyme CYP3A4. The dosing interval should be modified according to the creatinine clearance (CC) of the patient:
For patients also taking CYP3A4 inhibitors such as ritonavirboosted HIV-protease inhibitors (other than fosamprenavir, tipranavir, or saquinavir), ketoconazole, itraconazole, clarithromycin, and telithromycin and who have a CC less than 80 mL/minute: 150 mg every 24 hours
For patients also taking ritonavir-boosted saquinavir:
CC 50 to 80 mL/minute: 150 mg every 24 hours
CC 30 to 49 mL/minute: 150 mg every 48 hours
CC 29 mL/minute or less: 150 mg every 72 hours
No adjustment is necessary when maraviroc is given without potent CYP3A4 inhibitors or with fosamprenavir or tipranavir

💊 Preparations

Proprietary Preparations

Canad.: Celsentri; Cz.: Celsentri; Fr.: Celsentri; UK: Celsentri; USA: Selzentry.
Published December 05, 2018.