A Phase I Open-Label, Fixed-Sequence, Two-Period Crossover Study Of The Effect Of Multiple Doses Of Itraconazole On Palbociclib (Pd-0332991) Pharmacokinetics In Healthy Volunteers

Abstract Introduction: Itraconazole is recognized by the FDA and the EMA as a strong inhibitor of CYP3A and is included in both agencies published drug-drug interaction (DDI) guidances on the list of preferred interacting drugs for use in CYP3A inhibition studies. The oxidative metabolism of palbociclib (PD–0332991) is primarily mediated by CYP3A4, thus coadministration of strong CYP3A inhibitors and palbociclib could result in increased exposure of palbociclib. The primary objective of this study is to determine the effect of multiple doses of itraconazole on the single dose pharmacokinetics (PK) of palbociclib in healthy subjects in order to inform appropriate palbociclib dosing when administered in combination with strong CYP3A inhibitors. Methods: This was an open label, 2–period, fixed–sequence study in 12 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 5 of an 11-day itraconazole dose regimen (200 mg QD for 11 days). Serial blood sampling for palbociclib pharmacokinetics was performed up to 120 hours post palbociclib dose when administered alone and up to 168 hours post-palbociclib dose when administered with itraconazole. Plasma concentrations of palbociclib were measured using a validated liquid chromatography-tandem mass spectrometry method. Palbociclib plasma PK parameters were estimated using standard non-compartmental methods. Results and Discussion: Coadministration of a single 125–mg palbociclib dose and multiple 200-mg doses of itraconazole increased palbociclib total exposure (AUCinf) and peak exposure (Cmax) by approximately 87% and 34%, respectively, relative to a single 125 mg palbociclib dose given alone. Mean estimates of the t½ for palbociclib increased from 22.1 hours to 33.9 hours following co-administration with itraconazole. In general, palbociclib and the combination of palbociclib and itraconazole were well tolerated with no reported serious adverse events; 1 subject was discontinued from the study due to an adverse event of mild reversible rash during multiple-dose itraconazole treatment, described by the investigator as likely due to allergic reaction to itraconazole. Concurrent administration of palbociclib with strong CYP3A inhibitors should be avoided. If coadministration cannot be avoided, dose of palbociclib should be reduced to 75 mg. Pfizer Sponsored Study. Citation Format: Justin T. Hoffman, Cho-Ming Loi, Melissa O’Gorman, Anna Plotka, Maha Kosa, Anna Jakubowska, Diane D. Wang. A phase I open-label, fixed-sequence, two-period crossover study of the effect of multiple doses of Itraconazole 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-196.