76P - A phase 1 open-label fixed-sequence two-period crossover study of the effect of multiple doses of tamoxifen on palbociclib (PD-0332991) pharmacokine...

Date 08 May 2014
Event IMPAKT 2014
Session Welcome reception and Poster Walk
Topics Drug Development
Pharmacology
Breast Cancer
Presenter Justin Hoffman
Citation Annals of Oncology (2014) 25 (suppl_1): i25-i27. 10.1093/annonc/mdu071
Authors J.T. Hoffman1, M. O'Gorman2, C. Loi3, A. Plotka4, L. Kirkovsky5, T. Boutros5, C. Gallo Stampino6, D. Wang7
  • 1Clinical Pharmacology, Oncology Business Unit, Pfizer, 92121 - San Diego/US
  • 2Global Pharmacometrics, Pfizer, Groton/US
  • 3Pdm, Pfizer, La Jolla/US
  • 4Biostatistics, Pfizer, Collegeville/US
  • 5Clinical Assay Group, Pfizer, La Jolla/US
  • 6Clin Dev Oncology, Pfizer, Milan/IT
  • 7Clinical Pharmacology, Pfizer, La Jolla/US

Abstract

Introduction:

Tamoxifen and one of its primary metabolites, 4-hydroxy-tamoxifen, are known to induce CYP3A4 in vitro, and in vivo coadministration of tamoxifen with letrozole and anastrozole (both CYP3A4 substrates) has resulted in decreased exposures (AUC) of each. The primary route of oxidative metabolism of palbociclib (PD-0332991) is through CYP3A4, thus coadministration of tamoxifen and palbociclib could result in decreased exposure of palbociclib. The primary objective of this study is to estimate the relative exposure of single 125 mg palbociclib doses with and without steady-state concentrations of tamoxifen and its active metabolites (4-hydroxy-tamoxifen, N-desmethyl-tamoxifen, and endoxifen) in healthy male subjects.

Methods:

This was an open label, 2-period fixed-sequence study of the effect of multiple doses of tamoxifen on palbociclib pharmacokinetics in 25 healthy male volunteers. Each subject received a single 125 mg dose of palbociclib alone, followed by a single 125 mg dose of palbociclib on Day 22 of a 27-day tamoxifen loading dose regimen (60 mg QD for 4 days, followed by 20 mg QD for 23 days). Serial blood sampling for palbociclib pharmacokinetics was performed up to 144 hours post-palbociclib dose in both periods. Tamoxifen pre-dose blood sampling was performed on specified visits to assess tamoxifen and metabolite concentrations. Plasma concentrations of each analyte were measured using validated LC/MS/MS (liquid chromatography coupled with mass spectrometry) methods. Palbociclib plasma pharmacokinetic (PK) parameters were estimated using standard non-compartmental methods.

Discussion:

There were no significant changes in the palbociclib plasma PK parameters AUCinf (area under the curve from time zero to infinity) and Cmax (maximal plasma concentration) in the presence of steady-state tamoxifen when compared to palbociclib alone. Tamoxifen and the 3 metabolites all achieved steady-state prior to administration of palbociclib in period 2. In general, palbociclib and the combination of palbociclib and tamoxifen were well tolerated with no reported serious adverse events.

Disclosure:

All authors have declared: Author is a full-time employee of Pfizer, which owns the rights to the drug (palbociclib) used in the study described within this abstract.