Abstract LB-198: A phase I open-label fixed-sequence two-period crossover study of the effect of multiple doses of modafinil on palbociclib (PD–0332991) pharmacokinetics in healthy volunteers
Authors: Hoffman Justin T. , Loi Cho-Ming , Plotka Anna , O’Gorman Melissa , Shi Haihong , Mori Ave , Wang Diane D. 
Published: July 2016

Introduction: In vitro, the oxidative metabolism of palbociclib (PD–0332991) is primarily mediated by CYP3A. The concurrent administration of the strong CYP3A inducer rifampin with palbociclib resulted in an 85% and 70% decrease in palbociclib AUCinf and Cmax, respectively. These results lead to the recommendation that strong CYP3A inducers should be avoided when taking palbociclib. However, the effect of a moderate CYP3A inducer on the pharmacokinetics (PK) of palbociclib is not known. Modafinil is known to induce CYP3A in vitro. In vivo, modafinil decreased the mean Cmax and AUCinf of triazolam by 42% and 59%, respectively, meeting classification as a moderate CYP3A inducer. The primary objective of this study is to determine the effect of multiple doses of modafinil on the single dose PK of palbociclib in healthy subjects.

Methods: This was an open label, 2–period, fixed–sequence study in 14 healthy subjects. Each subject received a single 125 mg oral dose of palbociclib alone, followed by a single 125 mg dose of palbociclib on Day 28 of a 32-day modafinil dose titration regimen (200 mg QD for 7 days, followed by 400 mg QD for 25 days). Serial blood sampling for palbociclib pharmacokinetics was performed up to 120 hours post-palbociclib dose in both periods. Modafinil and modafinil sulfone pre-dose blood sampling was performed on specified visits to document compliance with the outpatient dosing regimen. Plasma concentrations of palbociclib, modafinil, and modafinil sulfone were each measured using validated liquid chromatography-tandem mass spectrometry methods. Palbociclib plasma PK parameters were estimated using standard non-compartmental methods.

Results and Discussion: Co-administration of palbociclib in the presence of steady-state levels of the moderate CYP3A inducer modafinil modestly decreased palbociclib exposure compared to palbociclib given alone. The AUCinf and Cmax were decreased by approximately 32% and 11%, respectively. Plasma concentrations of modafinil and modafinil sulfone generally reached steady-state prior to co-administration of palbociclib. In general, palbociclib and the combination of palbociclib and modafinil were well tolerated with no reported treatment-related serious adverse events; 1 subject discontinued due to moderate vomiting which was considered related to modafinil treatment by the Investigator. Moderate CYP3A inducers can be given concurrently with palbociclib when it cannot be avoided. No palbociclib dose adjustment is necessary. Pfizer Sponsored Study.

Citation Format: Justin T. Hoffman, Cho-Ming Loi, Anna Plotka, Melissa O’Gorman, Haihong Shi, Ave Mori, Diane D. Wang. A phase I open-label fixed-sequence two-period crossover study of the effect of multiple doses of modafinil on palbociclib (PD–0332991) pharmacokinetics in healthy volunteers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-198.