Maraviroc is a potent selective CCR5 antagonist and is the first of this new class of oral agents to be approved for the treatment of CCR5-tropic HIV type-1. Maraviroc is extensively metabolized by CYP3A4, with renal clearance accounting for approximately 23% of total clearance. The half-life of maraviroc is approximately 16 h. Maraviroc does not inhibit any of the major CYP450 enzymes at clinically relevant doses and it has not shown any clinically relevant effects on plasma concentrations of other agents; hence, no dose adjustments of coadministered agents are required. Maraviroc exposure is altered by agents that modulate the activity of CYP3A4 and, in some circumstances, maraviroc dose adjustment is necessary. This article aims to review all pharmacokinetic and drug interaction data available for maraviroc, and to provide a comprehensive summary of the dose adjustment recommendations for maraviroc when coadministered with agents from all classes of antiretroviral therapy as well as other commonly coadministered agents.
DorrP., WestbyM., DobbsS.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 Chemother2005; 49: 4721–4732.
3.
LalezariJ., GoodrichJ., DeJesusE.Efficacy and safety of maraviroc (MVC) plus optimized background therapy (OBT) in viremic, antiretroviral treatment experienced patients infected with CCR5-tropic HIV-1: 24-week results of a Phase 2b/3 study in the USA and Canada.14th Conference on Retroviruses and Opportunistic Infections. 25–28 February 2007, Los Angeles, CA, USA. Abstract 104bLB.
4.
NelsonM., FatkenheuerG., KonourinaI.Efficacy and safety of maraviroc (MVC) plus optimized background therapy (OBT) in viremic, antiretroviral treatment experienced patients infected with CCR5-tropic (R5) HIV-1 in Europe, Australia and North America: 24 week results.14th Conference on Retroviruses and Opportunistic Infections. 25–28 February 2007, Los Angeles, CA, USA. Abstract 104aLB.
5.
GulickR.M., LalezariJ., GoodrichJ.Maraviroc for previously treated patients with R5 HIV-1 infection.N Engl J Med2008; 359: 1429–1441.
6.
HardyW.D., GulickR., MayerH.Efficacy and safety of maraviroc in treatment-experienced (TE) patients infected with R5 HIV-1: 96-week combined analysis of the MOTIVATE 1 & 2 studies.9th International Congress on drug therapy in HIV infection. 9–13 November 2008, Glasgow, UK.
7.
SaagM., HeeraJ., GoodrichJ.Reanalysis of the MERIT Study with the Enhanced Trofile™ Assay (MERIT-ES).48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/46th Annual Meeting of the Infectious Diseases Society of America. 25–28 October 2008, Washington, DC, USA. Poster H-1232a.
8.
WalkerD.K., AbelS., CombyP., MuirheadG.J., NeddermanA.N., SmithD.A.Species differences in the disposition of the CCR5 antagonist, UK-427,857, a new potential treatment for HIV.Drug Metab Dispos2005; 33: 587–595.
AbelS., van der RystE., RosarioM.C.Assessment of the pharmacokinetics, safety and tolerability of maraviroc, a novel CCR5 antagonist, in healthy volunteers.Br J Clin Pharmacol2008; 65 Suppl 1: 5–18.
11.
AbelS., RussellD., WhitlockL.A.Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjects.Br J Clin Pharmacol2008; 65 Suppl 1: 60–67.
12.
ChanP.L.S., WeatherleyB., McFadyenL.A population pharmacokinetic meta-analysis of maraviroc in healthy volunteers and asymptomatic HIV-infected subjects.Br J Clin Pharmacol2008; 65 Suppl 1: 76–85.
FätkenheuerG., PozniakA.L., JohnsonM.A.Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1.Nat Med2005; 11: 1170–1172.
15.
WeatherleyB., McFadyenL., ChanP.L.S., MarshallS.Population pharmacokinetic covariate analysis of maraviroc in the MERIT study in treatment naive subjects.9th International Workshop on Clinical Pharmacology of HIV Therapy. 7–9 February 2008, New Orleans, LA, USA. Poster 17B.
16.
DumondJ., PattersonK., PechaA.Maraviroc (MVC) pharmacokinetics (PK) in blood plasma (BP), genital tract (GT) fluid and tissue in healthy female volunteers.15th Conference on Retroviruses and Opportunistic Infections. 3–6 February 2008, Boston, MA, USA. Abstract 135LB.
17.
HylandR., DickinsM., CollinsC., JonesH., JonesB.Maraviroc: in vitro assessment of drug-drug interaction potential.Br J Clin Pharmacol2008; 66: 498–507.
18.
WeatherleyB., McFadyenL., ChanP.L.S., MarshallS.Population pharmacokinetic covariate analysis of maraviroc in Phase 2b/3 studies in treatment experienced (TE) HIV-1 infected subjects on optimized background therapy (OBT). 9th International Workshop on Clinical Pharmacology of HIV Therapy. 7–9 February 2008, New Orleans, LA, USA. Poster 17A.
19.
RussellD., RidgwayC., Taylor-WorthR., WeissgerberG., TanY., MuirheadG.Comparison of the pharmacokinetics of maraviroc (UK-427,857) in healthy Asian and Caucasian subjects.6th International Workshop on Clinical Pharmacology of HIV Therapy. 28–30 April 2005, Quebec City, QC, Canada. Poster 3.7.
20.
AbelS., RidgwayC., HamlinJ., DavisJ.An open, parallel group study to compare the pharmacokinetics, safety and toleration of a single oral dose of maraviroc in subjects with mild and moderate hepatic impairment with subjects with normal hepatic function.8th International Workshop on Clinical Pharmacology of HIV Therapy. 16–18 April 2007, Budapest, Hungary. Poster 8.
21.
Panel on Antiretroviral Guidelines for Adults and Adolescents.Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 29, 2008; 1–128. (Accessed 27 October 2008.) Available from http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.
22.
AbelS., RussellD., WhitlockL.A., RidgwayC.E., MuirheadG.J.Effect of maraviroc on the pharmacokinetics of midazolam, lamivudine/zidovudine, and ethinyloestradiol/levonorgestrel in healthy volunteers.Br J Clin Pharmacol2008; 65 Suppl 1: 19–26.
23.
DavisJ., Scholler-GyureM., KakudaT.N.An open, randomized, two-period, crossover study in two cohorts to investigate the effect of steady-state TMC125 (etravirine) and the combination of TMC125/darunavir/ritonavir on the steady-state pharmacokinetics of oral maraviroc in healthy subjects.11th European AIDS Conference (EACS). 24–27 October 2007, Madrid, Spain. Poster P4.3/02.
24.
RamanathanS., WestS., AbelS., EnejosaJ., KearneyB.P.Pharmacokinetics of coadministered ritonavir-boosted elvitegravir plus maraviroc.47th Interscience Conference on Antimicrobial Agents and Chemotherapy. 17–20 September 2007, Chicago, IL, USA. Poster H-1425.
25.
AbelS., RidgwayC., HamlinJ., DavisJ., MackR., SekarV.An open, randomized, 2-way crossover study to investigate the effect of darunavir/ritonavir on the pharmacokinetics of maraviroc in healthy subjects.8th International Workshop on Clinical Pharmacology of HIV Therapy. 16–18 April 2008, Budapest, Hungary. Abstract 55.
26.
AbelS., RussellD., Taylor-WorthR.J., RidgwayC.E., MuirheadG.J.Effects of CYP3A4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers.Br J Clin Pharmacol2008; 65 Suppl 1: 27–37.
BarryM., MulcahyF., MerryC., GibbonsS., BackD.Pharmacokinetics and potential interactions amongst antiretroviral agents used to treat patients with HIV infection.Clin Pharmacokinet1999; 36: 289–304.
29.
AndrewsE., GlueP., LaBadieR., CrownoverP., TresslerR., DamleB.A pharmacokinetic (PK) study to evaluate an interaction between maraviroc (MVC) and raltegravir (RAL) in healthy adults.48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/46th Annual Meeting of the Infectious Diseases Society of America. 25–28 October 2008, Washington, DC, USA. Poster H-4005.
30.
US Food and Drug Administration.Antiviral Drugs Advisory Committee Meeting. ISENTRESS™ (raltegravir) 400 mg for treatment of HIV (NDA 22-145). September 5, 2007, Briefing document (background package). (Accessed 4 November 2008.) Available from http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4314b1-01-Merck.pdf.
31.
DahlM.L., JohanssonI., BertilssonL., Ingelman-SundbergM., SjöqvistF.Ultrarapid hydroxylation of debrisoquine in a Swedish Population. Analysis of the molecular genetic basis.J Pharmacol Exp Ther1995; 274: 516–520.
32.
MasimirembwaC., HaslerJ., BertilssonsL., JohanssonI., EkbergO., Ingelman-SundbergM.Phenotype and genotype analysis of debrisoquine hydroxylase (CYP2D6) in a Black Zimbabwean population. Reduced enzyme activity and evaluation of metabolic correlation of CYP2D6 probe drugs.Eur J Clin Pharmacol1996; 51: 117–122.
33.
PozniakA.L., BoffitoM., RussellD., RidgwayC.E., MuirheadG.J.A novel probe drug interaction study to investigate the effect of selected antiretroviral combinations on the pharmacokinetics of a single oral dose of maraviroc in HIV-positive subjects.Br J Clin Pharmacol2008; 65 Suppl 1: 54–59.
34.
McFadyenL., JacqminP., WadeJ.R., WeatherleyB., ChanP.Maraviroc (MVC) exposure-efficacy relationship in treatment-experienced HIV-1-infected patients.11th European AIDS Conference (EACS). 24–27 October 2007, Madrid, Spain. Abstract P4.1/06.
35.
US Department of Health and Human Services, US Food and Drug Administration.Draft guidance for industry. Drug interaction studies – study design, data analysis and implications for dosing and labelling. September 2006; pp. 1–55. (Accessed 27 October 2007.) Available from http://www.fda.gov/cder/guicance/6695dft.pdf.
36.
AbelS., JenkinsT.M., WhitlockL.A., RidgwayC.E., MuirheadG.J.Effects of CYP3A4 inducers with and without CYP3A4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers.Br J Clin Pharmacol2008; 65 Suppl 1: 38–46.
37.
VourvahisM., DumondJ., PattersonK.Effects of tipranavir/ritonavir on the activity of hepatic and intestinal cytochrome P450 3A4/5 and P-glycoprotein: implications for drug interactions.14th Conference on Retroviruses and Opportunistic Infections. 25–28 February 2007, Los Angeles, CA, USA. Abstract 563.
AlticeF.L., FriedlandG.H., CooneyE.L.Nevirapine induced opiate withdrawal among injection drug users with HIV infection receiving methadone.AIDS1999; 13: 957–962.
42.
LamsonM., MacGregorT., RiskaP.Nevirapine induces both CYP3A4 and CYP2B6 metabolic pathways.Clin Pharmacol Ther1999; 65: 137.
43.
MoulyS., Rizzo-PadoinN., SimoneauG.Effect of widely used combinations of antiretroviral therapy on liver CYP3A4 activity in HIV-infected patients.Br J Clin Pharmacol2006; 62: 200–209.
44.
AbelS., RussellD., WhitlockL.A., RidgwayC.E., MuirheadG.J.The effects of cotrimoxazole or tenofovir co-administration on the pharmacokinetics of maraviroc in healthy volunteers.Br J Clin Pharmacol2008; 65 Suppl 1: 47–53.
45.
ChengC-L.M.S., SmithD.E., CarverP.L.Steady state pharmacokinetics of delavirdine in HIV-positive patients: effect on erythromycin breath test.Clin Pharmacol Ther1997; 61: 531–543.
46.
RayA.S., CihlarT., RobinsonK.L.Mechanism of active renal tubular efflux of tenofovir.Antimicrob Agents Chemother2006; 50: 3297–3304.
47.
MaussS., BergerF., SchmutzG.Antiretroviral therapy with tenofovir is associated with mild renal dysfunction.AIDS2005; 19: 93–99.
48.
WinstonA., AminJ., MallonP.W.G.Minor changes in calculated creatinine clearance and anion-gap are associated with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy.HIV Med2006; 7: 105–111.
49.
PeruccaE.Clinically relevant drug interactions with antiepileptic drugs.Br J Clin Pharmacol2006; 61: 246–255.
50.
PeruccaE., HedgesA., MakkiK.A., RuprahM., WilsonJ.F., RichensA.A comparative study of the relative enzyme inducing properties of anticonvulsant drugs in epileptic patients.Br J Clin Pharmacol1984; 18: 401–410.
51.
PeruccaE., GrimaldiR., FrigoG.M., SardiA., MönigH., OhnhausE.E.Comparative effects of rifabutin and rifampicin on hepatic microsomal enzyme activity in normal subjects.Eur J Clin Pharmacol1988; 34: 595–599.
52.
ChattonJ.Y., MunafoA., ChaveJ.P.Trimethoprim, alone or in combination with sulphamethoxazole, decreases the renal excretion of zidovudine and its glucuronide.Br J Clin Pharmacol1992; 34: 551–554.
53.
MooreK.H., YienG.J., RaaschR.H.Pharmacokinetics of lamivudine administered alone and with trimethoprim-sulfamethoxazole.Clin Pharmacol Ther1996; 59: 550–558.
54.
WenX., WangJ-S, BackmanJ.T., LaitilaJ., NeuvonenP.J.Trimethoprim and sulfamethoxazole are selective inhibitors of CYP2C8 and CYP2C9 respectively.Drug Metab Dispos2002; 30: 631–635.
