Maraviroc: in vitro assessment of drug-drug interaction potential.
OBJECTIVE
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.


CONCLUSIONS
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.
Hyland
Ruth
R
Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Sandwich, UK. ruth.hyland@pfizer.com
Dickins
Maurice
M
Collins
Claire
C
Jones
Hannah
H
Jones
Barry
B
D019540:Area Under Curve; D000069446:Atazanavir Sulfate; D003510:Cyclohexanes / Q000378:metabolism / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004347:Drug Interactions; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics*; D015497:HIV-1; D006801:Humans; D007654:Ketoconazole / Q000493:pharmacokinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D000077592:Maraviroc; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009842:Oligopeptides / Q000493:pharmacokinetics; D011237:Predictive Value of Tests; D011725:Pyridines / Q000493:pharmacokinetics; D019438:Ritonavir / Q000493:pharmacokinetics; D019258:Saquinavir / Q000493:pharmacokinetics; D014230:Triazoles / Q000378:metabolism / Q000493:pharmacokinetics*
D003510:Cyclohexanes; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D014230:Triazoles; D000069446:Atazanavir Sulfate; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D019258:Saquinavir; D000077592:Maraviroc; D019438:Ritonavir; D007654:Ketoconazole