Hospital Pharmacy Volume 42, Number 11, pp 10461057 2007 Wolters Kluwer Health, Inc.

FORMULARY DRUG REVIEWS

Maraviroc
Dennis J. Cada, PharmD, FASHP, FASCP* (Editor), Terri Levien, PharmD, and Danial E. Baker, PharmD, FASCP, FASHP Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to your Pharmacy and Therapeutics Committee. Subscribers also receive monthly 1-page summary monographs on the agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation (DUE) is also provided each month. With a subscription, the monographs are sent to you in print and CD-ROM forms and are available online. Monographs can be customized to meet the needs of your facility. Subscribers to the The Formulary Monograph Service also receive access to a pharmacy bulletin board, The Formulary Information Exchange (The F.I.X.). All topics pertinent to clinical and hospital pharmacy are discussed on The F.I.X. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. If you would like information about The Formulary Monograph Service or The F.I.X., call The Formulary at 800-322-4349. The November 2007 monograph topics are doripenem, thrombin, topical, zoledronic acid injection in Paget Disease and Osteoporosis, dexrazoxane, and lanreotide. The DUE is on doripenem.

Generic Name: MARAVIROC Proprietary Name: Selzentry (Pfizer) Approval Rating: 1P Therapeutic Class: Antiretroviral Agents; fusion inhibitors Similar Drugs: None Sound- or Look-Alike Names: Cellcept INDICATIONS Maraviroc is indicated for combination antiretroviral treatment of adults infected with only CCR5tropic human immunodeficiency virus 1 (HIV-1) detectable who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.1 Maraviroc use is not recommended in

patients with dual/mixed or CXCR4-tropic HIV-1 because efficacy was not demonstrated in a phase 2 study in this patient population.1 Monogram Biosciences coreceptor tropism assay (Trofile) has been used to determine eligibility for maraviroc therapy. Viral load must be at least 1,000 copies/mL in order to accurately determine viral tropism.2 Subjects most likely to respond to maraviroc therapy are individuals with a viral strain that only enters cells via the CCR5 coreceptor. Subjects unlikely to respond to maraviroc (those with a viral strain that uses the CXCR4 coreceptor to enter cells) were excluded from the trials. In Pfizers screening, 56% of previously treated patients exhibited virus using CCR5.

CLINICAL PHARMACOLOGY Maraviroc (UK-427,857) is an orally-available selective chemokine receptor CCR5 antagonist with potent antiHIV-1 activity. It has exhibited activity against all CCR5-tropic HIV-1 viruses tested, including 43 primary isolates from various diverse sources. Maraviroc was also active against 200 clinically derived HIV-1 enveloperecombinant pseudoviruses, 100 of which were derived from viruses resistant to existing drug classes.3 Maraviroc prevents the binding of the viral envelope, gp120, to CCR5 and, thus, prevents the subsequent membrane fusion events that are necessary for viral entry into the CD4+ cells.3,4 Maraviroc is not active against CCR2-, CXCR4-, and dual-tropic viruses, nor is it cytotoxic.3 Maraviroc binds to the host cells rather than the virus envelope; thus, its mechanism of action differs from enfuvirtide, a fusion inhibitor.5 Additive or synergistic activity has been observed when maraviroc has been assessed in combination with other antiretroviral agents, including abacavir, amprenavir, atazanavir, delavirdine, didanosine, efavirenz, emtricitabine, enfuvirtide, indinavir, lamivudine, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, stavudine, tenofovir, zalcitabine, and zidovudine.3 Resistance to maraviroc has been elicited in HIV-1 isolates

*Executive Editor, The Formulary; Clinical Associate Professor of Pharmacotherapy, Drug Information Center, Washington State University Spokane, WA; Director, Drug Information Center and Professor of Pharmacy Practice; College of Pharmacy, Washington State University Spokane, PO Box 1495, Spokane, WA 99210-1495.

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using maraviroc-bound receptor for entry.6,7 Maraviroc-resistant HIV-1 variants selected by serial passage retain sensitivity to other investigational CCR5 antagonists and enfuvirtide.5,7 CXCR4-using variants have emerged during maraviroc therapy, likely as an outgrowth of a pretreatment CXCR4using reservoir rather than a receptor switch.8,9 In patients expressing both CCR5 and CXCR4, suppression of CCR5 was associated with greater emergence of CXCR4 and more frequent treatment failure.1 PHARMACOKINETICS Following oral administration in the fasted state, peak concentrations are reached within 0.5 to 4 hours.4,10 The rate and extent of absorption is reduced when administered with food. Although administration with food resulted in a 30% to 60% reduction in peak concentration and overall exposure, no impact on virologic response was observed. Food restrictions were not required in phase 3 clinical trials.11 Oral bioavailability is 23% with a 100 mg dose and 33% with a 300 mg dose.4,11-13 The increased oral bioavailability with higher doses is likely the result of saturation of P-glycoprotein metabolism.4,12,13 Maraviroc is approximately 76% bound to plasma proteins, and its volume of distribution is 194 L.1 The terminal half-life is 14 to 18 hours.1,10 Maraviroc is metabolized primarily by the CYP450 system to inactive metabolites.1 About 8% of the dose is recovered in the urine as unchanged drug, and 25% of the dose recovered in the feces as unchanged drug.1 Maraviroc pharmacokinetics have not been evaluated in

patients with renal function impairment; an ongoing study is evaluating maraviroc in patients with mild or moderate hepatic function impairment.11 In the absence of metabolic inhibitors, renal clearance accounts for approximately 25% of the total clearance. Caution is advised in patients with renal or hepatic function impairment.1 COMPARATIVE EFFICACY In an early dose-finding study enrolling 32 patients (baseline viral load, 4.58 log10 copies/mL), viral load declined from baseline to day 11 by 1.42 log10 copies/mL at the maraviroc 100 mg twicedaily dose (range, 1.84 to 1.04) and 1.6 log10 copies/mL at the maraviroc 300 mg twice-daily dose (range, 2.42 to 0.78). In contrast, viral load was essentially unchanged in the placebo group (0.02 log10 copies/mL; range, 0.45 to 0.56), as well as in groups treated with the maraviroc 25 mg once-daily dose (0.43 log10 copies/mL; range, 1.08 to 0.02) or maraviroc 50 mg twice daily (0.66 log10 copies/mL; range, 1.37 to 0.4).4 In a similar study, patients were treated with placebo or maraviroc 100 mg once daily, 150 mg twice daily with or without food, or 300 mg once daily for 10 days. Results from this study are summarized in Table 1.14 The efficacy and safety of maraviroc in conjunction with optimized background therapy were assessed in 2 ongoing, doubleblind, placebo-controlled studies. MOTIVATE 1 enrolled 601 treatment-experienced, HIV-infected patients in the United States and Canada; MOTIVATE 2 enrolled 475 treatment-experienced, HIVinfected patients in Europe, Australia, and North America. Eligible patients were triple-class experi-

enced with HIV-1 RNA of 5,000 copies/mL or greater and only CCR5 virus (as assessed on the Trofile assay). Patients received placebo, maraviroc 300 mg once daily, or maraviroc 300 mg twice daily plus optimized background therapy (3 to 6 antiretroviral agents with or without low-dose ritonavir). If background therapy contained a protease inhibitor other than tipranavir and/or delavirdine, the maraviroc dose was reduced to 150 mg once or twice daily. Approximately 90% of the patients were male and 85% were white; mean age was approximately 46 years (range, 21 to 73 years of age). About two-thirds of the patients were in the United States. Baseline viral load was 4.85 log10 copies/mL in the maraviroc twice-daily group and 4.86 log10 copies/mL in the placebo group; a viral load greater than 100,000 copies/mL was present at baseline in 42% in the maraviroc twicedaily group and 40.2% in the placebo group. Patients in both groups had a median of 10 protease-inhibitor mutations, 1 nonnucleoside reverse transcriptase inhibitor (NNRTI) mutation, and 6 nucleoside reverse transcriptase inhibitor (NRTI) mutations.1,15,16 In MOTIVATE 1, 585 of the 601 randomized patients received at least 1 dose of study medication. Background therapy contained 2 or fewer drugs in 66% to 76% of patients. Viral load declined and CD4 cell count increased in both maraviroc treatment groups by week 24 (see Table 2). Similar proportions of patients discontinued therapy because of adverse reactions (placebo, 5.1%; maraviroc once daily, 4.7%; maraviroc twice daily, 4.3%).16 Additional analysis is planned at 48 weeks, with an option to continue the study for an additional year

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Table 1. Viral Load Changes with 10 Days of Maraviroc Monotherapy in Patients Infected with HIV-114
Dose # of Patients Completing Mean Change in 10-Day Therapy HIV-1 RNA at Day 11 8 8 8 7 8 8 8 8 12 4 0.43 0.66 1.13 1.42 1.45 1.34 1.35 1.6a 0.02 0.09 log10 copies/mL (range) (1.08 to 0.02) (1.37 to 0.4) (1.7 to 0.43) (1.84 to 1.04) (1.71 to 0.9) (1.79 to 0.51) (1.62 to 0.95) (2.42 to 0.78) (0.45 to 0.56) (0.2 to 0.27) # of Patients With 1 log10 Reduction in HIV-1 RNA 1 4 5 7 7 7 7 7 0 0

25 mg once daily 50 mg twice daily 100 mg once daily 100 mg twice daily 150 mg twice daily 150 mg twice daily (fed) 300 mg once daily 300 mg twice daily Placebo Placebo
a

P < 0.01 vs placebo.

Table 2. MOTIVATE 1 Study Results at 24 Weeks16

Parameter Placebo + Background Therapy (n = 118) 4.84 1.03 Maraviroc 300 mg Once Daily + Background Therapy (n = 232) 4.85 1.82 Maraviroc 300 mg Twice Daily + Background Therapy (n = 235) 4.86 1.95

Baseline viral load (log10 copies/mL) Mean change in viral load from baseline (log10 copies/mL) Treatment difference (placebo) % < 400 copies/mL % < 50 copies/mL Mean change in CD4 from baseline
CI = confidence interval.

31.4% 24.6% +52

0.79 (97.5% CI, 1.14 to 0.44) 54.7%, P < 0.0001 42.2%, P = 0.0006 +107 (95% CI, +30 to +79), P < 0.0001

0.92 (97.5% CI, 1.28 to 0.57) 60.4%, P < 0.0001 48.5%, P < 0.0001 +111 (95% CI, +35 to +83), P < 0.0001

based on the 48-week results.17 In MOTIVATE 2, background therapy contained 2 or fewer drugs in 62% to 66% of patients. Of the 475 patients randomized, 464 received at least 1 dose of study medication. Viral load declined and CD4 cell count increased in both maraviroc-treatment groups by week 24 (see Table 3). Similar proportions of patients discontinued therapy because of

adverse reactions (placebo, 2.2%; maraviroc once daily, 4.9%; maraviroc twice daily, 3.7%).1,15 Additional analysis is planned at 48 weeks, with an option to continue the study for an additional year based on the 48-week results.18 Results from a planned, 24week, pooled analysis of these studies were also presented in a meeting abstract and are summarized in Table 4. Higher response

rates were observed in patients receiving maraviroc in conjunction with first-time use of enfuvirtide or lopinavir/ritonavir.19,20 Approximately 50% (106/209 patients) of the patients in the placebo groups in these 2 studies discontinued therapy prior to the 24-week assessment compared with only 29.4% of maraviroctreated patients (172/585 patients; P < 0.0001).11 In a Food and Drug

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Table 3. MOTIVATE 2 Study Results at 24 Weeks15

Parameter Placebo + Background Therapy (n = 91) 4.89 0.93 Maraviroc 300 mg Once Daily + Background Therapy (n = 182) 4.87 1.95 Maraviroc 300 mg Twice Daily + Background Therapy (n = 191) 4.84 1.97

Baseline viral load (log10 copies/mL) Mean change in viral load from baseline (log10 copies/mL) Treatment difference (placebo) % < 400 copies/mL % < 50 copies/mL Mean change in CD4 from baseline
CI = confidence interval

23.1% 20.9% +64

1.02 (97.5% CI, 1.43 to 0.62) 55.5%, P < 0.0001 45.6%, P < 0.0001 +112 (95% CI, +22 to +74), P < 0.001

1.04 (97.5% CI, 1.44 to 0.64) 61.3%, P < 0.0001 40.8%, P = 0.0005 +102 (95% CI, +12 to +64), P < 0.001

Table 4. Pooled Data From the MOTIVATE 1 and MOTIVATE 2 StudiesPercent of Patients Achieving Viral Load Less than 40 and less than 400 Copies/mL19,20
Patient Population Placebo + Background Therapy < 50 copies/mL < 400 copies/mL Overall No active drugs in OBT Baseline CD4 count < 50 cells/mm3 Screening HIV-1 RNA 100,000 copies/mL Enfuvirtide first use/ No mutations 23% (n = 209) 3% (n = 35) 3% (n = 37) 11% (n = 84) 36% (n = 58) 74% (n = 27) 40% 64% (n = 91) 96% 70% (n = 23) 16% 28% (n = 170) 75% 53% (n = 109) 87% 5% 11% (n = 85) 45% 35% (n = 176) 75% 6% 18% (n = 51) 20% 20% (n = 85) 52% 28% Maraviroc 300 mg Once Daily + Background Therapy < 50 copies/mL < 400 copies/mL 44% (n = 414) 26% 29% (n = 56) 31% 55% Maraviroc 300 mg Twice Daily + Background Therapy < 50 copies/mL < 400 copies/mL 45% (n = 426) 41% 61%

Lopinavir/Ritonavir 50% 60% first use/No mutations (n = 10)

OBT = optimized background therapy; based on genotypic/phenotypic test results.

Administration (FDA) review of data from these 2 studies, it was estimated that approximately 67% of patients should achieve a viral load less than 400 RNA copies/mL if treated with the proposed dose. Patients with a trough concentration more than 50 to 75 ng/mL had a greater chance of achieving virologic response. Viro-

logic response may be increased by doubling the dose for patients with a trough concentration less than 75 ng/mL.11 The most common reason for treatment failure in these trials was outgrowth of CXCR4-using viruses not detected at screening.11 Week-48 results were also reported for an additional study

comparing maraviroc with efavirenz, each combined with zidovudine 300 mg and lamivudine 150 mg twice daily, in 1,071 patients naive to antiretroviral therapy. Enrolled patients had CCR5-tropic HIV-1; viral load of 2,000 copies/mL or greater; and no efavirenz, zidovudine, or lamivudine resistance. Patients

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Table 5. Results (Week 48) in Antiretroviral-Naive Patients22

Parameter Maraviroc Twice Daily + Combivir (n = 360) 70.6% Efavirenz + Combivir (n = 361) 73.1% Differencea

Viral load < 400 copies/mL

3 (lower-bound 1-sided 97.5% CI, 9.5%) 4.2 (lower-bound 1-sided 97.5% CI, 10.9%) 26 (95% CI, 7% to 46%)

Viral load < 50 copies/mL Mean change CD4 from baseline

a

65.3% 170 cells/mm3

69.3% 143 cells/mm3

Adjusted for randomization strata; CI = confidence interval.

were randomized to therapy with maraviroc 300 mg once or twice daily or efavirenz 600 mg once daily for 96 weeks. The maraviroc once-daily arm was discontinued early. Results at 48 weeks were reported for 721 patients (29% female) who received at least 1 dose of study medication. Baseline median CD4 cell count was 241 cells/mm3 in the maraviroc arm and 254 cells/mm3 in the efavirenz arm. Baseline mean viral load was 4.9 log10 copies/mL in both the maraviroc and efavirenz arms. Results were summarized in Table 5. More patients in the maraviroc twice-daily group discontinued therapy for lack of efficacy compared with the efavirenz group (11.9% vs 4.2%), while fewer patients in the maraviroc group discontinued therapy because of adverse reactions (4.1% vs 13.6%).21,22 CONTRAINDICATIONS, WARNINGS, AND PRECAUTIONS Contraindications The prescribing information lists no contraindications to the use of maraviroc.1 Warnings and Precautions Hepatotoxicity has been reported with maraviroc use.1 A slight increase in liver-related

adverse reactions was observed with maraviroc compared with placebo. The most common liverrelated adverse reactions were liver enzyme elevation and increased bilirubin.11 Hepatotoxicity may be preceded by evidence of a systemic allergic reaction, including pruritic rash, eosinophilia, or elevated immunoglobulin E (IgE). Patients with signs or symptoms of hepatitis or allergic reaction should be assessed immediately. Discontinuation of therapy should be considered in patients with signs or symptoms of hepatitis, or with increased liver transaminases combined with rash or other systemic symptoms.1 Maraviroc should be used with caution in patients with abnormal hepatic function or hepatitis B or C coinfection.1 Hepatic toxicity requiring liver transplantation occurred in a patient treated with maraviroc, zidovudine, lamivudine, isoniazid, acetaminophen, and co-trimoxazole in a clinical trial. Although a relationship with maraviroc was not confirmed, use of isoniazid subsequently became exclusion criteria for maraviroc use.23 More cardiovascular reactions, including myocardial ischemia and/or infarction, were observed in patients treated with

maraviroc than placebo. Maraviroc should be used with caution in patients at increased risk of cardiovascular reactions.1 Postural hypotension has been identified as a dose-limiting adverse reaction. Caution is advised in patients at risk for developing postural hypotension.1 Maraviroc produced QT-interval prolongation in animal models at plasma levels several times greater than those expected in humans at the therapeutic dose.11 Maraviroc has not been associated with clinically important increases in QTc interval.1,24 Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including maraviroc. During the initial phase of combination therapy, patients with an immune system response to therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as infection with Mycobacterium avium, cytomegalovirus, Pneumocystis jirovecii, Mycobacterium tuberculosis, or reactivation of Herpes simplex and Herpes zoster) and may require further evaluation and treatment.1 Maraviroc antagonizes the CCR5 coreceptor on some

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Table 6. Adverse Reactions Reported in Greater Than 5% of Maraviroc-Treated Patients and at Higher Frequency than Placebo1
Adverse Reaction Maraviroc (n = 426; 267 patient-years of exposure) % Exposure-adjusted rate per 100 patient years 12.7% 12% 9.6% 8.7% 8.2% 8.2% 7.3% 7% 6.8% 6.3% 6.1% 5.9% 5.4% 22.1 20.9 16.5 14.8 14.1 14.1 12.5 11.9 11.4 10.6 10.2 9.7 9.1 Placebo (n = 209; 99 patient-years of exposure) % Exposure-adjusted rate per 100 patient years 4.8% 8.1% 4.8% 7.7% 7.7% 7.7% 6.2% 4.3% 3.8% 3.3% 2.9% 4.3% 2.9% 10.5 18.1 10.7 17 17.1 17.1 13.7 9.4 8.2 7.3 6.2 9.4 6.1

Coughing and associated symptoms Pyrexia Rash Musculoskeletal and connective tissue signs and symptoms Dizziness/Postural hypotension GI and abdominal pain Appetite disorders Disturbances in initiating and maintaining sleep Herpes infection Sinusitis Joint-related signs and symptoms Bronchitis Constipation

immune cells and could increase the risk of developing infections. The overall incidence and severity of infection in phase 3 studies did not differ between treatment groups. A higher rate of some upper respiratory tract infections was reported in maraviroc-treated patients compared with placebo recipients (20% vs 11.5%); however, pneumonia occurred less frequently (2.1% vs 4.8%). A higher incidence of herpes virus infection was also reported in the maraviroc group compared with the placebo group when adjusted for duration of exposure (11.4 per 100 patientyears vs 8.2 per 100 patientyears). Patients should be closely monitored for evidence of infection while receiving maraviroc therapy.1 Maraviroc could also affect immune surveillance and lead to

an increased risk of malignancy. No increase in malignancy has been observed at this time; however, long-term follow-up is necessary to assess this risk.1 Maraviroc has not been studied in patients with renal function impairment; therefore, cautious use is recommended in this population. In the absence of metabolic inhibitors, renal clearance accounts for approximately 25% of the total clearance. Maraviroc concentrations may be increased in patients with renal function impairment, particularly if CYP3A inhibitors are coadministered. Patients with a creatinine clearance less than 50 mL/min who receive maraviroc and a CYP3A inhibitor may be at increased risk of adverse reactions associated with increased maraviroc concentrations such as dizziness and pos-

tural hypotension. Maraviroc should only be administered to such patients if the potential benefit is felt to outweigh the risk. Close monitoring is advised.1 The pharmacokinetics, efficacy, and safety of maraviroc have not been established in children; until data are available, use is not recommended in patients younger than 16 years of age.1 Maraviroc is in Pregnancy Category B.1 Maraviroc was not teratogenic in animal models. Maraviroc should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.1 Maraviroc is extensively secreted into rat milk. It is not known whether it is secreted in human milk. Because of the risk of HIV transmission as well as the potential for serious adverse reac-

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Table 7. Recommended Maraviroc Dosing Regimen1

Concomitant Medications CYP3A Inhibitors (with or without a CYP3A inducer), including: Clarithromycin Delavirdine Itraconazole Ketoconazole Nefazodone Protease inhibitors (except tipranavir/ritonavir) Telithromycin Other concomitant medications, including: Enfuvirtide Nevirapine NRTIs Tipranavir/Ritonavir CYP3A inducers (without a strong CYP3A inhibitor), including: Carbamazepine Efavirenz Phenobarbital Phenytoin Rifampin
Maraviroc can be taken with or without food; NRTIs = nucleoside teverse transcriptase inhibitors.

Maraviroc Dose 150 mg twice daily

300 mg twice daily

600 mg twice daily

tions in breast-feeding infants, breast-feeding is not recommended.1 ADVERSE REACTIONS Adverse reactions occurring at a higher frequency with maraviroc than placebo included cough, pyrexia, upper respiratory tract infection, rash, musculoskeletal symptoms, abdominal pain, and dizziness.1 Table 6 summarizes the most frequently observed adverse reactions in phase 3 studies, with exposure adjusted rates used to correct for the long duration of exposure on maraviroc compared with placebo.1 Adverse reactions reported with short-term maraviroc monotherapy included abnormal vision, asthenia, dizziness, flatulence, gingivitis, headache, nausea, postural hypotension, and rhinitis.10,14,25 DRUG INTERACTIONS Maraviroc is a CYP3A4 sub-

strate and P-glycoprotein substrate. It is not an inhibitor of the major CYP-450 isozymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4).26 Administration with CYP3A inhibitors will result in increased maraviroc concentrations.1 When administered in conjunction with regimens containing lopinavir/ ritonavir, maraviroc exposure was approximately doubled.26 Substantial increases in exposure were also observed when maraviroc was coadministered with ketoconazole, ritonavir, saquinavir/ritonavir, atazanavir, and atazanavir/ ritonavir, as well as combinations containing CYP3A inhibitors plus inducers, such as lopinavir/ritonavir plus efavirenz and saquinavir/ritonavir plus efavirenz.1 Coadministration with the combination of tipranavir/ritonavir did not alter maraviroc exposure.1 Administration with CYP3A

inducers may decrease maraviroc concentrations (eg, efavirenz, rifampin, carbamazepine, phenobarbital, phenytoin).1 When administered in conjunction with regimens containing efavirenz, maraviroc exposure was reduced approximately 50%.26 Substantial reductions were also observed when maraviroc was coadministered with rifampin.1 Concomitant use of maraviroc and St. Johns wort is not recommended. St. Johns wort is expected to substantially reduce maraviroc concentrations and may lead to loss of virologic response and possible maraviroc resistance.1 When administered in conjunction with nevirapine, a small increase in maraviroc peak concentration was observed, but overall exposure was unchanged.26 Maraviroc had no effect on the pharmacokinetics of zidovudine, lamivudine, midazolam, ethinyl estradiol, or levonorgestrel.1

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Maraviroc does not affect the pharmacokinetics of renally-eliminated drugs and is not affected by inhibitors of renal transporters.11 RECOMMENDED MONITORING In addition to assessment of viral load and CD4+ counts, liver function tests should also be monitored. Patients should also be closely monitored for evidence of infection.1 DOSING The maraviroc dose must be individualized and based on coadministered medication (see Table 7). In patients receiving a strong CYP3A inhibitor (with or without CYP3A inducers), including protease inhibitors (except tipranavir/ ritonavir) and delavirdine, the recommended maraviroc dose is 150 mg twice daily. In patients receiving NRTIs, tipranavir/ritonavir, nevirapine, and other drugs that are not strong CYP3A inhibitors or CYP3A inducers, the recommended maraviroc dose is 300 mg twice daily. In patients receiving CYP3A inducers, including efavirenz (without a strong CYP3A inhibitor), the recommended dose is 600 mg twice daily.1 PRODUCT AVAILABILITY AND STORAGE Maraviroc received FDA approval in August 2007; an FDA advisory panel unanimously supported approval in an April 2007 meeting. It is available as 150 and 300 mg tablets packaged in bottles of 60. Maraviroc tablets should be stored at controlled room temperature (25C; 77F), with excursions permitted between 15 and 30C (59 and 86F). The shelf life is 24 months.1 CONCLUSION Maraviroc offers an additional

therapy for HIV infection with a unique mechanism of action. Efficacy (reduction in viral load) has been demonstrated in a heavily pretreated population; at this time, that is the only patient population in which its use is recommended. Prior to use, the patient should have a confirmed case of HIV infection with CCR5-tropic strains and no CXCR4 strains. REFERENCES
1. Selzentry [package insert]. New York, NY: Pfizer Inc; 2007. 2. Trofile Co-Receptor Tropism Assay. Monogram Biosciences Inc Web site. http://www.monogramhiv.com/assays/pat ients/Trofile_pat.aspx. Accessed August 7, 2007. 3. Dorr P, Westby M, Dobbs S, 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. Antimicrob Agents Chemother. 2005; 49(11):4721-4732. 4. Rosario MC, Poland B, Sullivan J, Westby M, van der Ryst E. A pharmacokinetic-pharmacodynamic model to optimize the phase IIa development program of maraviroc. J Acquir Immune Defic Syndr. 2006;42(12):183-191. 5. Westby M, Mori J, Smith-Burchnell C, et al. Maraviroc (UK-427,857)-resistant HIV-1 variants selected by serial passage, are sensitive to CCR5 antagonists and T-20 [abstract]. Antiviral Ther. 2005;10(suppl):S72. 6. Westby M, Smith-Burchnell C, Mori J, et al. Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry. J Virol. 2007;81(5):2359-2371. 7. Mosley M, Smith-Burchnell C, Mori J, et al. Resistance to the CCR5 antagonist maraviroc is characterized by doseresponse curves that display a reduction in maximal inhibition [abstract]. 13th Conference on Retroviruses and Opportunistic Infections; February 58, 2006; Denver, Colorado. Abstract 598. http://www.retroconference.org/2006/a bstracts/27341.htm. Accessed Septem-

ber 4, 2007. 8. Lewis ME, van der Ryst E, Youle M, et al. Phylogenetic analysis and co-receptor tropism of HIV-1 envelope sequences from two patients with emergence of CXCR4 using virus following treatment with the CCR5 antagonist UK-427,857 [abstract]. 44th International Conference on Antimicrobial Agents and Chemotherapy; October 30November 2, 2004; Washington, DC. Abstract H584b. 9. Westby M, Lewis M, Whitcomb J, et al. Emergence of CXCR-4 using human immunodeficiency virus type 1 (HIV-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. J Virol. 2006; 80(10):4909-4920. 10. Abel S, van der Ryst E, Muirhead GJ, Rosario M, Edgington A, Weissgerber G. Pharmacokinetics of single and multiple oral doses of UK-427,857-a novel CCR5 antagonist in healthy volunteers [abstract]. 10th Conference on Retroviruses and Opportunistic Infections; February 1014, 2003; Boston MA. Abstract 547. http://www.retroconference.org/2003/cd/abstract/547.htm. Accessed September 4, 2007. 11. Food and Drug Administration Maraviroc Review Team. Memorandum to FDA Antiviral Products Advisory Committee Members/Guests. FDA Web site. April 24, 2007. http://www.fda. gov/ohrms/dockets/ac/07/briefing/20074283b1-02-01-fda-memo.pdf. Accessed September 4, 2007. 12. Rosario MC, Jacqmin P, Dorr P, van der Ryst E, Hitchcock C. A pharmacokinetic-pharmacodynamic disease model to predict in vivo antiviral activity of maraviroc. Clin Pharmacol Ther. 2005;78(5):508-519. 13. Walker DK, Abel S, Comby P, Muirhead GJ, Nedderman ANR, Smith DA. Species differences in the disposition of the CCR5 antagonist, UK-427,857, a new potential treatment for HIV. Drug Metab Dispos. 2005;33(4):587-595. 14. Fatkenheuer G, Pozniak AL, Johnson MA, et al. Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Nat Med. 2005;11(11): 1170-1172. 15. Nelson M, Fatkenheuer G, Konourina I, et al. Efficacy and safety of maravi-

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roc plus optimized background therapy in viremic, ART-experienced patients infected with CCR5-tropic HIV-1 in Europe, Australia, and North America: 24-week results [abstract]. 14th Conference on Retroviruses and Opportunistic Infections; February 2528, 2007; Los Angeles, CA. Abstract 104aLB. http://www.retroconference.org/2007/a bstracts/30636.htm. Accessed September 4, 2007. 16. Lalezari J, Goodrich J, DeJesus E, et al. Efficacy and safety of maraviroc plus optimized background therapy in viremic ART-experienced patients infected with CCR5-tropic HIV-1: 24-week results of a phase 2b/3 study in the US and Canada [abstract]. 14th Conference on Retroviruses and Opportunistic Infections; February 2528, 2007; Los Angeles, CA. Abstract 104bLB. http:// www.retroconference.org/2007/Abstrac ts/30635.htm. Accessed September 4, 2007. 17. Trial of maraviroc (UK-427,857) in combination with optimized background therapy versus optimized background therapy alone for the treatment of HIV-1 infected subjects. ClinicalTrials.gov Web site. http://clinicaltrials. gov/show/NCT00098306. Accessed September 4, 2007. 18. Trial of maraviroc (UK-427,857) in combination with optimized background therapy versus optimized background therapy alone for the treatment of HIV-1 infected subjects. ClinicalTrials.gov Web site. http://clinicaltrials.gov/ show/NCT00098722. Accessed September 4, 2007.

19. Gulick RM, van der Ryst E, Lampiris H, et al. Efficacy and safety of once-daily (QD) compared with twicedaily (BID) maraviroc plus optimized background therapy (OBT) in treatment-experienced patients infected with CCR5-tropic-HIV-1: 24-week combined analysis of the MOTIVATE 1 and 2 studies [abstract]. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 2225, 2007; Sydney, Australia. Abstract WEPEB116LB. 20. van der Ryst E, Cooper D, Konourina I, et al. Efficacy of maraviroc in combination with at least one other potent new antiretroviral drug: 24-week combined analysis of the MOTIVATE 1 and 2 studies [abstract]. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 2225, 2007; Sydney, Australia. Abstract WEPEB115LB. 21. Trial of maraviroc (UK-427,857) in combination with zidovudine/lamivudine versus efavirenz in combination with zidovudine/lamivudine. ClinicalTrials.gov Web site. http://clinicaltrials. gov/show/NCT00098293. Accessed September 4, 2007. 22. Saag M, Ive P, Heera J, et al. A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc versus efavirenz, both in combination with Combivir (zidovudine [ZDV]/lamivudine [3Tc]), for the treatment of antiretroviral naive subjects infected with R5 HIV-1: week 48 results of the MERIT study [abstract]. 4th International AIDS Society Conference

on HIV Pathogenesis, Treatment and Prevention; July 2225, 2007; Sydney, Australia. Abstract WESS104. 23. Horster S, Goebel FD. Serious doubts on safety and efficacy of CCR5 antagonists: CCR5 antagonists teeter on knife-edge. Infection. 2006;34(2):110113. 24. Davis J, Hilsden F, Sudworth D, Weissgerber G. A single dose study to investigate the effect of the CCR5 antagonist UK-427,857 on the QTc interval in healthy subjects [abstract]. 15th International AIDS Conference; July 1116; 2004; Bangkok, Thailand. Abstract TuPeB4605. http://www.iasociety.org/ print.asp?abstract_id=2170547. Accessed September 4, 2007. 25. McHale M, Abel S, Russell D, Gallagher J, van der Ryst E. Overview of phase 1 and 2a safety and efficacy data of maraviroc (UK-427,857) [abstract]. 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment; July 2427, 2005; Rio de Janeiro, Brazil. Abstract TuOa0204. http://www. iasociety.org/print.asp?abstract_id=217 6681. Accessed September 4, 2007. 26. Muirhead G, Pozniak A, Gazzard B, et al. A novel probe drug interaction study to investigate the effect of selected ARV combinations on the pharmacokinetics of a single oral dose of UK427,857 in HIV + ve subjects [abstract]. 12th Conference on Retroviruses and Opportunistic Infections; February 2225; 2005; Boston, MA. Abstract 663 and poster. http://www.retroconference. org/2005/cd/Abstracts/24409.htm. Accessed September 4, 2007.

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Continuing Education Case Study Quiz

Goal The goal of this program is to educate the reader about the use of maraviroc in the treatment of adults infected with human immunodeficiency virus (HIV). Objectives At the completion of this program, the reader will be able to: 1. Describe the pharmacology and pharmacokinetics of maraviroc. 2. Discuss the risks associated with the use of maraviroc. 3. Discuss the potential benefit of maraviroc for an individual patient. 4. Apply the information on the use of maraviroc to a case study. Key Words new drugs; antiviral agents; human immunodeficiency virus (HIV)

6. Patients enrolled in the MOTIVATE 1 and MOTIVATE 2 studies were all: A. HIV treatment nave. B. Previously treated with HIV triple-class therapy. C. Enfuvirtide treatment experienced. D. Lopinavir/ritonavir treatment experienced. 7. Patients developing signs or symptoms of allergic reactions (rash, eosinophilia, elevated IgE) while on maraviroc therapy, should be promptly evaluated for: A. Cardiovascular toxicity. B. Hepatotoxicity. C. Immune reconstitution syndrome. D. Infection. 8. Which of the following has been identified as a dose-limiting toxicity of maraviroc? A. Cough B. Postural hypotension C. Rash D. Renal toxicity Case History LK is a 46-year-old man coinfected with HIV and hepatitis B viruses. His current regimen consists of lopinavir/ritonavir, abacavir, lamivudine, and enfuvirtide; however, his viral load remains above 10,000 copies/mL. 9. What assessment is necessary prior to initiating maraviroc therapy in LK? A. CD4+ cell count B. Electrocardiogram C. Hemoglobin and hematocrit D. Viral tropism

1. Maraviroc is Food and Drug Administration-approved for use in the treatment of adults infected with: A. Only CCR5-tropic HIV-1 virus detectable. B. Only CCR2-tropic HIV-1 virus detectable. C. Only CXCR4-tropic HIV-1 virus detectable. D. Mixed CCR5- and CXCR4tropic HIV-1 virus detectable. 2. Maraviroc binds to: A. CXCR4. B. Gp120. C. The host cell. D. The viral envelope. 3. In patients expressing both CCR5 and CXCR4, maraviroc therapy was associated with: A. Greater emergence of CCR5 and enhanced treatment response. B. Greater emergence of CCR5 and more frequent treatment failure. C. Greater emergence of CXCR4 and enhanced treatment response. D. Greater emergence of

CXCR4 and more frequent treatment failure. 4. Which of the following statements regarding maraviroc administration with food is true? A. Maraviroc absorption is reduced when administered with food, and dosing should be separated by at least 2 hours. B. Maraviroc absorption is increased when administered with food, and dosing should be separated by at least 2 hours. C. Maraviroc absorption is reduced when administered with food; however, no food restrictions are necessary. D. Maraviroc absorption is increased when administered with food; however, no food restrictions are necessary. 5. The terminal half-life of maraviroc is: A. 2 to 4 hours. B. 8 to 12 hours. C. 14 to 18 hours. D. 24 to 28 hours.

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10. The recommended maraviroc dose for LK is: A. 150 mg twice daily. B. 300 mg twice daily. C. 600 mg twice daily. D. 1,200 mg once daily. 11. Upon initiating maraviroc therapy, LK should also be cautioned regarding the potential for: A. Diarrhea. B. Hypertension. C. Infection. D. Nausea and vomiting. 12. Regular laboratory monitoring associated with LKs mar-

aviroc therapy should include: A. Complete blood counts. B. Liver function tests. C. Pulmonary function tests. D. Renal function tests. 13. If LK was receiving tipranavir/ritonavir instead of lopinavir/ritonavir, his recommended maraviroc dose would be: A. 150 mg twice daily. B. 300 mg twice daily. C. 600 mg twice daily. D. 1,200 mg once daily. 14. In patients receiving an HIV

treatment regimen containing efavirenz, but without a strong CYP3A inhibitor, the recommended maraviroc dose is: A. 150 mg twice daily. B. 300 mg twice daily. C. 600 mg twice daily. D. 1,200 mg once daily. 15. Maraviroc tablets should be stored: A. At room temperature. B. Under refrigeration. C. In the freezer. D. All of the above are acceptable.

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Drug Evaluations: Maraviroc ACPE # 071-999-07-020-H02-P; ACPE # 071-999-07-020-H02-PT 0.15 CEU Program Expires: November 1, 2010 To receive continuing education credit, complete this form and mail with your $7 processing fee (made payable to WSU College of Pharmacy) to: College of Pharmacy, Continuing Education Dept. Washington State University Spokane PO Box 1495 Spokane, WA 992101495
Print clearly or type. Allow 4 weeks for processing. Name__________________________________________ Phamacist Pharmacy Technician pharmacokinetics of maraviroc: completely fairly well

not at all

2. I was able to apply the knowledge from this educational program and other resources to answer questions associated with the case study: completely fairly well not at all 3. The program discussed the risks associated with the use of maraviroc: completely fairly well not at all 4. After this program, I was able to discuss the potential benefit of the maraviroc for an individual patient: completely fairly well not at all 5. The overall quality of the program was: excellent good fair poor

Address: _______________________________________ City:_______________ State: _______ Zip: __________ Note: Your answer sheet will be graded confidentially and you will receive prompt notification of your score. In order to receive continuing education credit for this program, you need a minimum correct response rate of 70%. PROGRAM EVALUATION Please rate our continuing education offering by responding to the following questions. 1. This program described the pharmacology and

6. Was the content of this article relevant to the practice of pharmacy? excellent good fair poor 7. How long did it take you to complete this continuing education program? _______ hours 8. What other continuing education programs or topics would you like to see? ____________________________________________

_________________________________________ _________________________________________

Answer Form
1. A B 2. A B 3. A B 4. A B 5. A B 6. A B 7. A B 8. A B C D C D C D C D C D C D C D C D 9. A B 10. A B 11. A B 12. A B 13. A B 14. A B 15. A B C D C D C D C D C D C D C D
The Washington State University College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmaceutical education.

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