Maraviroc: in vitro assessment of drug-drug interaction potential

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 Simcyp? 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 µM 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 µM 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. Simcyp? has successfully simulated the extent of clinical interactions with CYP3A4 inhibitors, further validating this software as a good predictor of CYP-based DDIs.

WHAT IS ALREADY KNOWN ABOUT THE SUBJECT

• Maraviroc is known to undergo oxidative metabolism in vivo and is a substrate for cytochrome P450 (CYP).
• Simcyp? has recently become more widely used for the prediction of CYP-mediated drug–drug interactions (DDIs) using in vitro metabolism data.

WHAT THIS STUDY ADDS

• Maraviroc has been identified as a CYP3A4 substrate and the kinetic constants characterized.
• The predicted DDIs associated with maraviroc as a CYP3A4 substrate using Simcyp? have been compared against the clinical data.
• This study demonstrates the value of a reliable Simcyp? model for prediction of DDIs.