Pharmacokinetics,safety and tolerability of a single oral dose of maraviroc in HIV-negative subjects with mild and moderate hepatic impairment

Abstract

Background

Maraviroc is the first CCR5 antagonist and only oral entry inhibitor approved for the treatment of HIV type-1 infection. Maraviroc is extensively metabolized, primarily by cytochrome P450 3A4 and hence its pharmacokinetics might be affected by impaired hepatic function. The objective of this study was to evaluate the pharmacokinetics of maraviroc in subjects with mild or moderate hepatic impairment compared with subjects with normal hepatic function. Safety and tolerability were also assessed.

Methods

This was an open-label, non-randomized, single- centre, parallel-group study. A total of 24 subjects with mild (n=8) or moderate (n=8) hepatic impairment, or normal hepatic function (n=8) received a single dose of 300 mg maraviroc.

Results

Relative to those with normal hepatic function, the geometric mean ratio (90% confidence interval) for the maximum observed plasma concentration (C_max) of maraviroc was 111% (74.6–166) and 132% (89.6–194) for those with mild and moderate hepatic impairment, respectively; the area under the concentration–time curve from time 0 to the last quantifable concentration (AUC_last) was 125% (84.7–185) and 146% (100–212); oral clearance was 89% (53.2–150) and 83% (49.2–139); and renal clearance was 94% (70.5–126) and 131% (98.6–173), respectively. Maraviroc was well tolerated in all subjects.

Conclusions

Although differences in maraviroc pharmacokinetics were noted in subjects with hepatic impairment compared with those with normal hepatic function, these do not currently support a dose modification. The single 300 mg dose of maraviroc was well tolerated by subjects with normal and impaired hepatic function.

References

Konopnicki

, Mocroft

, De Wit

Hepatitis B and HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort.

AIDS 2005; 19: 593–601.

Mocroft

, Rockstroh

, Soriano

Are specific antiretrovirals associated with an increased risk of discontinuation due to toxicities or patient/physician choice in patients with hepatitis C virus coinfection?

Antivir Ther 2005; 10: 779–790.

Wyles

D.L.

, Gerber

J.G.

Antiretroviral drug pharmacokinetics in hepatitis with hepatic dysfunction.

Clin Infect Dis 2005; 40: 174–181.

Adams

L.A.

, Lymp

J.F.

, St Sauver

The natural history of nonalcoholic fatty liver disease: a population-based cohort study.

Gastroenterology 2005; 129: 113–121.

Angulo

, Keach

J.C.

, Batts

K.P.

, Lindor

K.D.

Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis.

Hepatology 1999; 30: 1356–1362.

Ruhl

C.E.

, Everhart

J.E.

Epidemiology of nonalcoholic fatty liver.

Clin Liver Dis 2004; 8: 501–519.

Fleming

K.M.

, Aithal

G.P.

, Solaymani-Dodaran

, Card

T.R.

, West

Incidence and prevalence of cirrhosis in the United Kingdom, 1992-2001: A general population-based study.

J Hepatol 2008; 49: 732–738.

Sterling

R.K.

, Contos

M.J.

, Smith

P.G.

Steatohepatitis: risk factors and impact on disease severity in human immunodeficiency virus/hepatitis C virus coinfection.

Hepatology 2008; 47: 1118–1127.

Dorr

, Westby

, Dobbs

Maraviroc (UK-427,857): a potent, orally bioavailable and selective small-molecule inhibitor of the chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity.

Antimicrob Agents Chemother 2005; 49: 4721–4732.

10.

Gulick

R.M.

, Lalezari

, Goodrich

Maraviroc for previously treated patients with R5 HIV-1 infection.

N Engl J Med 2008; 359: 1429–1441.

11.

Hardy

W.D.

, Gulick

, Mayer

Efficacy and safety of maraviroc in treatment-experienced patients infected with R5 HIV-1: 96-week combined analysis of the MOTIVATE 1 and 2 studies. Ninth International Congress on Drug Therapy in HIV Infection. 9–13 November 2008, Glasgow, UK. Abstract O425.

12.

Saag

, Ive

, Heera

A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc versus efavirenz, both in combination with combivir (zidovudine/lamivudine), for the treatment of antiretroviral-naive subjects infected with R5 HIV-1: week 48 results of the MERIT study. 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention. 22–25 July 2007, Sydney, Australia. Abstract WESS104.

13.

European Medicines Agency. Celsentri: summary of product characteristics. (Updated August 2009. Accessed 15 September 2009). Available from http://www.emea.europa.eu/humandocs/PDFs/EPAR/celsentri/H-811-PI-en.pdf.

14.

US Food and Drug Administration. Selzentry: prescribing information. (Updated June 2009. Accessed 15 September 2009). Available from http://media.pfizer.com/files/products/uspi_maraviroc.pdf.

15.

Abel

, Russell

, Whitlock

L.A.

, Ridgway

C.E.

, Nedderman

A.N.

, Walker

D.K.

Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjects.

Br J Clin Pharmacol 2008; 65 Suppl 1: 60–67.

16.

Walker

D.K.

, Abel

, Comby

, Muirhead

G.J.

, Nedderman

A.N.

, Smith

D.A.

Species differences in the disposition of the CCR5 antagonist, UK-427,857, a new potential treatment for hiv.

Drug Metab Dispos 2005; 33: 587–595.

17.

Hyland

, Dickins

, Collins

, Jones

Maraviroc: in vitro assessment of drug–drug interaction potential.

Br J Clin Pharmacol 2008; 66: 498–507.

18.

Abel

, Russell

, Whitlock

L.A.

, Ridgway

C.E.

, Muirhead

G.J.

Effect of maraviroc on the pharmacokinetics of midazolam, lamivudine/zidovudine, and ethinyloestradiol/levonorgestrel in healthy volunteers.

Br J Clin Pharmacol 2008; 65 Suppl 1: 19–26.

19.

Abel

, van der Ryst

, Rosario

M.C.

Assessment of the pharmacokinetics, safety and tolerability of maraviroc, a novel CCR5 antagonist, in healthy volunteers.

Br J Clin Pharmacol 2008; 65 Suppl 1: 5–18.

20.

Kolwankar

, Vuppalanchi

, Ethell

Association between nonalcoholic hepatic steatosis and hepatic cytochrome P-450 3A activity.

Clin Gastroenterol Hepatol 2007; 5: 388–393.

21.

Donato

M.T.

, Lahoz

, Jimenez

Potential impact of steatosis on cytochrome P450 enzymes of human hepatocytes isolated from fatty liver grafts.

Drug Metab Dispos 2006; 34: 1556–1562.

22.

Ohnishi

, Murakami

, Akizuki

, Mochizuki

, Echizen

, Takagi

In vivo metabolic activity of CYP2C19 and CYP3A in relation to CYP2C19 genetic polymorphism in chronic liver disease.

J Clin Pharmacol 2005; 45: 1221–1229.

23.

Villeneuve

J.P.

, Pichette

Cytochrome P450 and liver diseases.

Curr Drug Metab 2004; 5: 273–282.

24.

Bastien

M.C.

, Leblond

, Pichette

, Villeneuve

J. P.

. Differential alteration of cytochrome P450 isoenzymes in two experimental models of cirrhosis. Can J Physiol Pharmacol 2000; 78: 912–919.

25.

Peterson

T.C.

, Hodgson

, Fernandez-Salguero

, Neumeister

, Gonzalez

F.J.

Hepatic fibrosis and cytochrome P450: experimental models of fibrosis compared to AHR knockout mice.

Hepatol Res 2000; 17: 112–125.

26.

Pugh

R.N.

, Murray-Lyon

I.M.

, Dawson

J.L.

, Pietroni

M.C.

, Williams

Transection of the oesophagus for bleeding oesophageal varices.

Br J Surg 1973; 60: 646–649.

27.

US Food and Drug Administration Center for Biologics Evaluation and Research. Guidance for industry. Pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and impact on dosing and labeling. (Updated May 2003. Accessed 22 April 2009.) Available from http://www.fda.gov/cber/gdlns/imphep.pdf.

28.

Abel

, Russell

, Taylor-Worth

R.J.

, Ridgway

C.E.

, Muirhead

G.J.

Effects of CYP3A4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers.

Br J Clin Pharmacol 2008; 65 Suppl 1: 27–37.

29.

Abel

, Jenkins

T.M.

, Whitlock

L.A.

, Ridgway

C.E.

, Muirhead

G.J.

Effects of CYP3A4 inducers with and without CYP3A4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers.

Br J Clin Pharmacol 2008; 65 Suppl 1: 38–46.

30.

Verbeeck

R.K.

Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction.

Eur J Clin Pharmacol 2008; 64: 1147–1161.

31.

Abel

, Russell

, Whitlock

L.A.

, Ridgway

C.E.

, Muirhead

G.J.

The effects of cotrimoxazole or tenofovir co-administration on the pharmacokinetics of maraviroc in healthy volunteers.

Br J Clin Pharmacol 2008; 65 Suppl 1: 47–53.

32.

McFadyen

, Jacqmin

, Wade

J.R.

, Weatherley

, Chan

P.L.

Maraviroc (MVC) exposure-efficacy relationship in treatment-experienced HIV-1-infected patients. 11th European AIDS Conference. 24–27 October 2007, Madrid, Spain. Abstract P4.1/06.

33.

Ayoub

, Goodrich

, van der Ryst

, Heera

, Mayer

Adverse event profile of maraviroc in treatment-experienced patients infected with R5 HIV-1. 48th Interscience Conference on Antimicrobial Agents and Chemotherapy/46th Annual Meeting of the Infectious Diseases Society of America. 25–28 October 2008, Washington, DC, USA. Abstract H-1264.