Abstract CT419: A phase 1 randomized, open-label, 2-sequence, 2-period crossover study of the effect of multiple doses of palbociclib (PD-0332991) on midazolam pharmacokinetics in healthy women of non-childbearing potential

Introduction: Palbociclib (PD‑0332991) is an oral cyclin‑dependent kinase (CDK) 4/6 inhibitor currently in Phase 2 and Phase 3 clinical trials in multiple oncology indications. In vitro, palbociclib and its active lactam metabolite (PF‑05089326) caused time‑dependent inhibition of CYP3A-mediated midazolam 1’‑hydroxylase and testosterone 6β‑hydroxylase activities. The primary objective of this study is to investigate the effect of multiple doses of palbociclib on the pharmacokinetics of a single oral dose of the sensitive CYP3A4/5 probe substrate midazolam in healthy women of non-childbearing potential. Methods: This was an open label, randomized, 2‑period 2‑sequence study of the effect of multiple oral doses of palbociclib on midazolam pharmacokinetics in 26 healthy female volunteers of non-childbearing potential. Simulations were performed with SimCYP, using the in vitro CYP inhibition data and human pharmacokinetic data for palbociclib from Study A5481001 as inputs, to optimize the duration of dosing and washout periods. Each subject received two treatments (Treatment A = 2 mg oral dose of midazolam alone, Treatment B = 2 mg oral dose of midazolam on Day 7 of an 8-day 125 mg QD palbociclib dose regimen) in a crossover scheme. Subjects were randomized to one of two sequences (Sequence 1 = A→B, Sequence 2 = B→A). In Sequence 2 there was a washout period of no less than 14 days after the last administered dose of palbociclib to ensure that there was no carryover effect of CYP3A inhibition into Period 2. Serial blood sampling for midazolam pharmacokinetics was performed up to 36 hours post-midazolam dose in both periods. Palbociclib pre-dose blood sampling was performed on specified visits to document achievement of steady-state concentrations. Plasma concentrations of midazolam and palbociclib were each measured using validated LC/MS/MS (liquid chromatography- tandem mass spectrometry) methods. Midazolam plasma pharmacokinetic (PK) parameters were estimated using standard non-compartmental methods. Discussion:In general, palbociclib reached steady-state levels prior to co-administration of midazolam, allowing for a worst case assessment of the potential palbociclib-mediated time-dependent CYP3A inhibition. Midazolam geometric mean Cmax and AUCinf values increased 37% and 61%, respectively, when midazolam was co-administered with multiple doses of palbociclib as compared to its administration alone. These results indicate that palbociclib is a weak CYP3A inhibitor following daily 125 mg dosing at steady-state according to the FDA classification. In general, the combination of palbociclib and midazolam were well tolerated with no reported serious adverse events or treatment discontinuations. Reversible neutropenia was reported in 15 out of the 26 subjects. Citation Format: Justin T. Hoffman, Anna Plotka, Melissa O9Gorman, Cho-Ming Loi, Leonid Kirkovsky, Corrado Gallo-Stampino, Diane Wang. A phase 1 randomized, open-label, 2-sequence, 2-period crossover study of the effect of multiple doses of palbociclib (PD-0332991) on midazolam pharmacokinetics in healthy women of non-childbearing potential. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT419. doi:10.1158/1538-7445.AM2014-CT419