Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2008 Oct;66(4):498-507.
doi: 10.1111/j.1365-2125.2008.03198.x. Epub 2008 Apr 10.

Maraviroc: in vitro assessment of drug-drug interaction potential

Ruth Hyland  1 , Maurice Dickins, Claire Collins, Hannah Jones, Barry Jones
Affiliations

Maraviroc: in vitro assessment of drug-drug interaction potential

Ruth Hyland et al. Br J Clin Pharmacol. 2008 Oct.

Abstract

Aims: To characterize the cytochrome P450 enzyme(s) responsible for the N-dealkylation of maraviroc in vitro, and predict the extent of clinical drug-drug interactions (DDIs).

Methods: Human liver and recombinant CYP microsomes were used to identify the CYP enzyme responsible for maraviroc N-dealkylation. Studies comprised enzyme kinetics and evaluation of the effects of specific CYP inhibitors. In vitro data were then used as inputs for simulation of DDIs with ketoconazole, ritonavir, saquinavir and atazanvir, using the Simcyptrade mark population-based absorption, distribution, metabolism and elimination (ADME) simulator. Study designs for simulations mirrored those actually used in the clinic.

Results: Maraviroc was metabolized to its N-dealkylated product via a single CYP enzyme characterized by a K(m) of 21 microM and V(max) of 0.45 pmol pmol(-1) min(-1) in human liver microsomes and was inhibited by ketoconazole (CYP3A4 inhibitor). In a panel of recombinant CYP enzymes, CYP3A4 was identified as the major CYP responsible for maraviroc metabolism. Using recombinant CYP3A4, N-dealkylation was characterized by a K(m) of 13 microM and a V(max) of 3 pmol pmol(-1) CYP min(-1). Simulations therefore focused on the effect of CYP3A4 inhibitors on maraviroc pharmacokinetics. The simulated median AUC ratios were in good agreement with observed clinical changes (within twofold in all cases), although, in general, there was a trend for overprediction in the magnitude of the DDI.

Conclusion: Maraviroc is a substrate for CYP3A4, and exposure will therefore be modulated by CYP3A4 inhibitors. Simcyptrade mark has successfully simulated the extent of clinical interactions with CYP3A4 inhibitors, further validating this software as a good predictor of CYP-based DDIs.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Structures of maraviroc and UK-408,027
Figure 2
Figure 2
Michaelis–Menten and Eadie–Hofstee (inset) plots for the conversion of maraviroc to UK-408,027 in human liver microsomes. The values are mean ± SD from seven determinations.
Figure 3
Figure 3
Rate of maraviroc N-dealkylation (left axis, solid bars) and maraviroc intrinsic clearance (right axis, open bars) in a panel of rCYP Supersomes™. Maraviroc concentrations were 50 µM and 1 µM for metabolite formation and substrate depletion, respectively. Each value is mean ± SD, n = 4 (UK-408,027 formation, (▪); Maraviroc Clint, (□))
Figure 4
Figure 4
Michaelis–Menten and Eadie–Hofstee (inset) plots for the conversion of maraviroc to UK-408,027 in rCYP3A4 Supersomes™. The values are mean ± SD from four determinations
See this image and copyright information in PMC

Comment in

References

    1. Dorr P, Westby M, Dobbs S, Griffin P, Irvine B, Macartney M, Mori J, Rickett G, Smith-Burchnell C, Napier C, Webster R, Armour D, Price D, Stammen B, Wood A, Maraviroc Perros M. (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;49:4721–32. - PMC - PubMed
    1. Walker DK, Abel S, Comby P, Muirhead GJ, Nedderman AN, Smith DA. Species differences in the disposition of the CCR5 antagonist, UK-427,857, a new potential treatment for HIV. Drug Metab Dispos. 2005;33:587–95. - PubMed
    1. Fatkenheuer G, Pozniak AL, Johnson MA, Plettenberg A, Staszewski S, Hoepelman AI, Saag MS, Goebel FD, Rockstroh JK, Dezube BJ, Jenkins TM, Medhurst C, Sullivan JF, Ridgway C, Abel S, James IT, Youle M, van der Ryst E. Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Nat Med. 2005;11:1170–2. - PubMed
    1. Yeni PG, Hammer SM, Hirsch MS, Saag MS, Schechter M, Carpenter CC, Fischl MA, Gatell JM, Gazzard BG, Jacobsen DM, Katzenstein DA, Montaner JS, Richman DD, Schooley RT, Thompson MA, Vella S, Volberding PA. Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society-USA Panel. JAMA. 2004;292:251–65. - PubMed
    1. Tseng AL, Foisy MM. Management of drug interactions in patients with HIV. Ann Pharmacother. 1997;31:1040–58. - PubMed

Publication types

MeSH terms