In Vitro and In Vivo Investigation of Potential for Complex CYP3A Interaction for PF-00251802 (Dagrocorat), a Novel Dissociated Agonist of the Glucocorticoid Receptor

Sharon L Ripp, Arnab Mukherjee, Heather Eng, Thomas Stock, Dona Fleishaker, Tina Checchio, Brinda Tammara, Sharon L Ripp, Arnab Mukherjee, Heather Eng, Thomas Stock, Dona Fleishaker, Tina Checchio, Brinda Tammara

Abstract

The dissociated agonists of the glucocorticoid receptor are a novel class of agents in clinical development for rheumatoid arthritis. PF-04171327 (fosdagrocorat) is a phosphate ester prodrug of PF-00251802 (dagrocorat), a selective high-affinity partial agonist of the glucocorticoid receptor, which is further metabolized to PF-04015475. This study evaluated the cytochrome P450 (CYP)-mediated drug-drug interaction (DDI) potential of PF-00251802 and PF-04015475 in vitro and used model-based prediction approaches to estimate clinical impact. PF-00251802 is a reversible inhibitor of several CYPs, but modeling has suggested no clinically relevant interaction. PF-00251802 and PF-04015475 are time-dependent inhibitors and inducers of CYP3A in vitro; PF-00251802 is also a time-dependent inhibitor of CYP2D6. Model-based prediction suggested the potential for weak inhibition of CYP3A in vivo. A clinical DDI study was conducted with midazolam, a sensitive CYP3A substrate. A phase 1 open-label, multiple-dose study evaluated the effect of PF-04171327 on midazolam pharmacokinetics and safety in 12 healthy volunteers. Administration of midazolam alone or concomitantly with PF-04171327 resulted in equivalent pharmacokinetic profiles (AUCinf , 21.17 vs 20.28 ng·h/mL, respectively), indicating that PF-04171327 had no net effect on CYP3A activity in vivo. These findings support the further development of PF-00251802 and PF-04171327 as potential treatments for patients with rheumatoid arthritis (NCT00987038).

Keywords: CYP3A; PF-00251802; drug-drug interaction; modeling; pharmacokinetics; phase 1.

© 2017, The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Structures of PF‐04171327 (fosdagrocorat), PF‐00251802 (dagrocorat), and PF‐04015475.
Figure 2
Figure 2
Reversible inhibition of CYP3A activity in pooled human liver microsomes by PF‐00251802 (dagrocorat), using midazolam as a probe substrate.
Figure 3
Figure 3
Time‐dependent inhibition of CYP3A activity in pooled human liver microsomes by (A) PF‐00251802 (dagrocorat) and (B) PF‐04015475, using midazolam as a probe substrate.
Figure 4
Figure 4
Mean plasma PF‐00251802 (dagrocorat) trough concentration over time in patients enrolled in the phase 1 study. Arrows indicate midazolam dosing.
Figure 5
Figure 5
Mean plasma concentration–time profile for midazolam ± PF‐04171327 (fosdagrocorat).

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