Brand Name:                         Selzentry®

Generic Name:                       Maraviroc (mah RAV er rock)

Manufacturer:                       Pfizer Laboratories

Drug Class:                            Antiviral; small-molecule CCR5 antagonist; HIV fusion inhibitor^1,2

Uses:                                       Treatment of CCR5-tropic HIV infection^1,2

Mechanism of Action:           Maraviroc is an orally active antiviral agent that blocks the entry of human immunodeficiency virus into human cells via the CCR5 co-receptor.  Maraviroc interferes with the entry of HIV-1 into host cells by inhibiting the fusion of the virus and cell membranes. In order for HIV-1 to enter and infect a human cell, the viral surface glycoprotein known as gp120 binds to the host CD4+ cell receptor, along with a chemokine co-receptor CCR5 or CXCR4 (both expressed on lymphocytes and monocytes). Then, the viral transmembrane glycoprotein gp41 changes conformation and facilitates the fusion of cellular and viral membranes. Maraviroc blocks the CCR5 receptor and prevents the functional viral envelope protein-co-receptor interaction required for membrane fusion and subsequent viral entry into target cells. ³

Pharmacokinetics:

Metabolism:                           Maraviroc undergoes hepatic metabolism via the cytochrome P450 system to inactive metabolites. Studies have pointed to CYP3A as the major enzyme responsible for metabolism. ³

Elimination:                           Major route—fecal 76%^1,2

                                               Minor route—urinary 20%^1,2

Efficacy:

Citation:  Fätkenhauser G, Pozniak AL, Johnson MA, Plettenberg A, Staszewski S, Hoepelman AIM, et al.  Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1.  Nature Medicine2005.Oct 11;(11):1170-1173.

Study Design:              Two combined, placebo-controlled, phase 2A studies

Study Description:  The authors noted that they combined their two studies because of similarities in study design and patient populations.  82 patients with HIV-1 infection were randomized to receive placebo or maraviroc 25 mg, 100 mg, or 300 mg once daily or maraviroc 50 mg, 100 mg, 150 mg or 300 mg twice daily.  The primary objective in this study was to determine the efficacy of short-term (ten-day) treatment with maraviroc in patients with CCR5 positive HIV.  Following treatment, researchers compared viral load (mean change in log₁₀ plasma viral load) to baseline and found that all maraviroc-treated groups had a greater mean reduction in viral load compared to placebo.  The secondary outcome in this study was the occupancy of CCR5 cellular receptors by the virus measured with an experimental assay.  They found that all those treated with maraviroc (except for the 25 mg group) had increased occupancy of the receptors (>80%) by days 5 and 10, and by day 15(>60%), post therapy.  AUC_0-24 was also measured, and the authors found a great deal of variability between patients.   Similar viral load reductions were seen at doses of 100 mg twice a day and above (including the 300 mg once daily). In addition, the researchers monitored dosing with relation to food intake and their findings implied that the drug could be taken with or without food.

Limitations:  The written report of this study possesses numerous limitations.  Pfizer provided funding for the study, introducing possible bias, particularly if the results are favorable.  Additionally, statistical tests are lacking regarding the results and tolerability, and there is no mention of the potential of type-I or type-II error.  The authors refer the reader to the journal’s website for more in-depth supplementary notes, but these are not available without purchase or a subscription to the journal.  Without further statistical evaluation, it is difficult to determine the significance of the results.

Conclusion:  From the results presented by the authors in this study, it appears that maraviroc does reduce viral load and significantly occupies CCR5 receptors to prevent viral entry into cells.  However, as mentioned before, the limitations prevent liberal use of these results in clinical recommendations.

Citation:  Westby M, Lewis M, Whitcomb J, Youle M, Pozniak AL, James IT, et al.  Emergence of CXCR4-using human immunodeficiency virus (HIV) type 1 variants in a minority of HIV-1-infected patients following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir. Journal of Virology. 2006 May;80(10): 4909-4020.

Study Design:            Analysis of patients involved in two phase-II randomized, double-blind placebo-controlled trials

Study Description:  This study was conducted with the results of the above-mentioned study by first phenotypically determining coreceptor tropism and then by performing phylogenetic analysis.  The researchers wanted to determine if CXCR4-using HIV levels increased as a viral compensatory mechanism in patients being treated by a CCR5 antagonist.  In addition, researchers wanted to determine the predominant tropism that recurred after maraviroc discontinuation at a variety of time points ranging from day 1 to day 433 post-treatment.  Sixty-four patients were studied and followed up in this trial.   As above, patients received maraviroc 25 mg, 100 mg, or 300 mg once daily or with maraviroc 50 mg, 100 mg, 150 mg or 300 mg twice daily.  Phenotypic analysis (with PhenoSense HIV Entry assay) was used to determine CCR5 tropism in 62 patients.  Phylogenetic analysis was carried using nucleotide sequence alignments of near-full-length gp160.  The researchers claim to have found that CXCR4-using virus was not selected in-vivo in the majority of patients following treatment with maraviroc, and that for the majority of patients, CCR5-tropic virus reemerged as the dominant species after maraviroc discontinuation.  Additionally, they deduced that the two variants were genetically distinct, and they asserted that this would make mutation from one tropic form to the other unlikely.   

Limitations:  The researchers excluded patients with dual-tropism disease, and this seems like an ethical concern, as the number of medications used to treat HIV/AIDS is finite, and dual-tropic patients may have benefited from therapy.  While interesting, a disproportionate amount of time was centered on select patients who did not respond as the majority of patients did, and this deterred from the results and their applicability.  Statistical testing was not mentioned, which further limits applicability of results.  The manufacturer funded the prior studies, and this is a potential conflict of interest when examining the results.

Conclusion:  While the authors make some hopeful claims about the control of the virus from their observations, the clinical implications for their findings is limited to single CCR5-tropic patients, excluding CXCR-4 patients, and patients with dual-tropic disease.  Statistical significance of the findings is lacking and this further limits the value of the findings.  However, the authors’ observations can be used to imply that maraviroc has a distinct role for a particular kind of patient, and more research and post-marketing surveillance can further establish its place in treatment of HIV.

Citation:  Dorr P, Westby M, Dobbs S, Griffin P, Irvine B, Macartney M, et al.  Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-Human Immunodeficiency Virus type 1 activity.  Antimicrobial Agents and Chemotherapy.  2005 November; (49)11: 4721-4732.

Study Design:  In-vitro and in-vivo animal trial to establish the efficacy of maraviroc

Study Description:  Through a series of laboratory assays, the researchers in this study wanted to determine the following:  Maraviroc’s activity against HIV-1 envelope binding to CCR5 and cellular fusion, maraviroc’s activity against both lab-adapted strains and primary HIV-1 isolates, maraviroc’s activity against clinically derived HIV-1 envelopes antiretroviral-resistant patients, and maraviroc’s antiviral activity in combination with other antiretroviral agents.  A pharmacokinetic profile was also established in animal models (rats and dogs).  Assays included:  Flow cytometry to determine maraviroc’s effects on CCR5 internalization, measure of radioactive anti-HIV-1 glycoprotein to determine inhibition of CCR5-mediated cell-cell fusion, and measures of intercellular chemokine-dependent calcium redistribution in cells exposed to maraviroc.  From their findings, the researchers predicted that maraviroc would by useful in patients with CCR5-tropic disease, and that obtaining an optimal balance between pharmacological efficacy and pharmacokinetics would be a concern for later in-vivo studies.  In-vitro action of maraviroc is not antagonistic of other antiretrovirals, thus offering a novel venue of viral control for a specific group of patients.  They also assess in-vitro hERG channel activity, as this can often predict a medication’s potential for causing QT_c Interval prolongation in susceptible patients, and the found that the drug possesses a wide therapeutic index in that regard.

Limitations:  Though extensive and highly detailed in their research, this study dealt primarily with in-vitro measures and animal models, neither of which can necessarily predict safety and efficacy in the human model.

Conclusion:  Through a number of assays and in-vitro studies, the authors establish the efficacy of maraviroc in the laboratory setting, and they establish the drug’s activity in relation to other HIV antivirals.  While their findings are promising, they cannot necessarily be translated to clinical practice.  They do, however, provide an excellent framework for further, in-vivo research.  

Contraindications^1,2:                         Hypersensitivity to maraviroc or any component of the formulation

Precautions^1,2,3:

Hepatotoxicity:

Boxed Warning:  

• Hepatotoxicity may occur, and it is often preceded by allergic type reactions (eg, pruritic rash, eosinophilia or increased IgE) and/or hepatic adverse events (transaminase increases or signs/symptoms of hepatitis).
• Consider discontinuation in any patient with possible hepatitis or with elevated transaminases combined with systemic allergic events.

Immune reconstitution syndrome:

• Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection; further evaluation and treatment may be required.

Infections:

• Monitor closely for signs/symptoms of developing infections.
• Maraviroc has been associated with a small increase of certain upper respiratory tract infections and herpes virus infections during clinical trials and post-marketing.

Postural hypotension:

• Use caution in patients at risk for postural hypotension due to concomitant medication or history of condition, as symptomatic postural hypotension has been known to occur.

Cardiovascular disease:

• A small increase in cardiovascular events (myocardial ischemia and/or infarction) may occur in patients with preexisting cardiovascular disease, although a contributory relationship relative to therapy is unknown.

Adverse Events^1,2,3: (Items in bold print occur in 10% or more of patients)

• Common
• Central nervous system: Fever (12%), Dizziness (8%), Insomnia (7%)
• Respiratory: Upper respiratory tract infection (20%), Cough (13%), Bronchitis (6%), Sinusitis (6%).

• Dermatologic: Rash (10%), Pruritus (4%), Folliculitis (3%), Skin neoplasms (benign; 3%), Dermatitis (3%)
• Gastrointestinal: Abdominal pain (8.2%), Appetite disorders (7%), Constipation (5.4%)
• Musculoskeletal: Musculoskeletal symptoms (8.7%), Arthropathy (6.1%)
• Endocrine & metabolic: Lipodystrophy (3%) Sweat gland disturbances (5%)

• Serious

• Hematologic: Neutropenia (4%)
• Cardiovascular: Vascular hypertensive disorder (3%)
• Dermatologic:  Rash (10%)*, Pruritis (3.8%)*
• Hepatic:  Liver Failure (<2%)

• Renal:  Acute renal failure (<1%)

*Note:  Dermatologic side effects, though typically not severe, may precede the development of hepatotoxicity; therefore, patients with signs of an allergic reaction (rash, eosinophilia, elevated IgE) should be evaluated for evidence of liver toxicity.

Drug and Food Interactions^1,2,3:

• Food
• Maraviroc can be administered with or without food.
• Decreased Cmax by 33% to 60%, and AUC by 33% to 50% when administered with food
• Grapefruit juice inhibits maraviroc’s metabolism.  A dosage reduction to 150 mg twice daily may be warranted
• Drug
• This medication interacts extensively with a number of other drugs via the cytochrome P-450 CYP 3A4 isozyme, in addition to P-glycoprotein (Pgp).

Dosage/Administration:        Normal dosing for patients with CCR5-tropic HIV infection

• 300 mg twice daily

Strong CYP 3A4 Inducer present (See “Drug Interactions”)

• 600 mg twice daily

Strong CYP 3A4 Inhibitor present (See “Drug Interactions”)

• 150 mg twice daily

Geriatric dose:                       Maraviroc should be used with caution in the elderly due to decreased hepatic, cardiac, and renal function.^1,2

Pediatric dose:                       Safety and efficacy have not been established for children under 16 years of age.^1,2,3,4

Renal impairment:                No guidelines are yet in existence for renal impairment.  Patients who have a creatinine clearance < 50 ml/min and are receiving a CYP3A inhibitor may be at an increased risk of increased maraviroc concentrations.  Monitor closely and use only if benefits outweigh risks.^1,2,3

Hepatic impairment:             Specific guidelines for dosage adjustments in hepatic impairment are not available.^1,2,3,4  However, maraviroc is metabolized by the liver.  Hepatic impairment may result in increased plasma concentrations of maraviroc.^1,2,3,4

Special Circumstances:

Fertility:                                 Deferasirox was found to have no adverse effects on fertility and reproductive performance of male and female rats at oral doses up to 75 mg/kg.⁶

Pregnancy:                             Risk Factor Category B.^1,2  Adverse fetal effects were not observed in animal studies. There are no adequate and well-controlled studies in pregnant women and available data is insufficient to recommend use in pregnancy.^1,2,3  To date, there are no well-controlled studies in pregnant women; therefore, maraviroc should be used during pregnancy only if benefits clearly outweigh risks.^1,2,3,4

Lactation:                               Excretion in breast milk is unknown.^1,2,3,4 Mothers with HIV are discouraged from breast-feeding to prevent spread of the virus.^1,2

Additional Pertinent Information:

May be taken with or without food^1,2,3,4

Do not break or chew tablets^1,2,3,4

A comprehensive list of the patient’s other medications is required for appropriate dosing of maraviroc^1,2,3,4

Conclusion:                            Human Immunodeficiency Virus has been responsible for millions of deaths worldwide for more than a quarter-century.  While great strides have been made in controlling the disease, it still kills millions of people each year.  A limited number of drugs are in existence for treating HIV, and any new classes are a welcome addition to the arsenal for combating this devastating virus.  Maraviroc is one such medication.  By preventing viral fusion to CD4 cells via the CCR5 channel, maraviroc is the first orally available fusion inhibitor.  Its use should be limited to patients with CCR5-tropic disease who are treatment-experienced, and have shown resistance to other antiretroviral agents.  This medication has numerous drug-drug interactions via the cytochrome p450 isoenzyme system, and many of these require dosing adjustments for maraviroc.  Studies have shown the medications efficacy both in-vitro and in-vivo, in the aforementioned patient population, but as with many new medications, adverse reactions may occur when the medication is administered to a wider patient population.  Indeed, maraviroc has a boxed warning issued by the FDA for rare hepatotoxicity.  Additional surveillance and reporting of adverse reactions, in addition to post-marketing studies examining the long-term use of maraviroc and its effect on morbidity and mortality are required before this medication can be recommended as first line therapy for patients with HIV. 

References:

1. Maraviroc. Lexi-Drugs [database online]. Lexi-Comp, Inc; February 14, 2008.
2. Maraviroc. In DRUGDEX® Drug Point System [Internet database]. Greenwood Village, Colo:   Thomson Micromedex. Updated periodically. Accessed February 14, 2008.
3. Maraviroc. Clinical Pharmacology [database online].  Gold Standard, Inc; February 19, 2008.
4. Selsentry [package insert]. NY, NY: Pfizer Pharmaceuticals Corp; 2007.
5. Fätkenhauser G, Pozniak AL, Johnson MA, Plettenberg A, Staszewski S, Hoepelman AIM, et al.  Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1.  Nature Medicine.  2005 5 Oct: 11 (11):  1170-1173.
6. Westby M, Lewis M, Whitcomb J, Youle M, Pozniak AL, James IT, et al.  Emergence of CXCR4-using human immunodeficiency virus (HIV) type 1 variants in a minority of HIV-1-infected patients following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir. Journal of Virology. 2006 May;80(10): 4909-4020.
7. Rosario MC, Jacqmin P, Dorr P, van der Ryst E, and Hitchcock C. A pharmacokinetic-      pharmacodynamic disease model to predict in vivo antiviral activity of maraviroc. Clin Pharmacol Ther. 2005 Nov;78(5):508-1.

Prepared by:  Jeremy R. Armentrout, Doctor of Pharmacy Candidate, February 2008

Revised:  3/6/08