Abstract LB-229: A phase 1 open-label fixed-sequence two-period crossover study of the effect of multiple doses of tamoxifen on palbociclib (PD-0332991) pharmacokinetics in healthy male volunteers

Introduction: Tamoxifen and one of its primary active 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 by 37% and 27%, respectively. 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 oral doses alone and in the presence of steady‑state concentrations of tamoxifen and its active metabolites (4‑hydroxy‑tamoxifen, N‑desmethyl‑tamoxifen, and endoxifen (N‑desmethyl‑4-hydroxytamoxifen)) in healthy male subjects in order to inform appropriate palbociclib dosing when administered in combination with tamoxifen in the upcoming Phase 3 PENELOPEB study. Methods: This was an open label, 2‑period fixed‑sequence study of the effect of multiple oral doses of tamoxifen on palbociclib pharmacokinetics in 25 healthy male volunteers. Each subject received a single 125 mg oral dose of palbociclib alone, followed by a single 125 mg dose of palbociclib on Day 22 of a 27-day tamoxifen loading dose regimen (60mg QD for 4 days, followed by 20mg 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 document achievement of steady-state tamoxifen and metabolite concentrations. Plasma concentrations of palbociclib, tamoxifen, 4‑hydroxy‑tamoxifen, N‑desmethyl‑tamoxifen, and endoxifen were each 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, 4‑hydroxy‑tamoxifen, N‑desmethyl‑tamoxifen, and endoxifen 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; 1 subject discontinued due to generalized itchiness which resolved with a single dose of fexofenadine. Citation Format: Justin T. Hoffman, Melissa O9Gorman, Cho-Ming Loi, Anna Plotka, Tanya Boutros, Leonid Kirkovsky, Corrado Gallo Stampino, Diane Wang. A phase 1 open-label fixed-sequence two-period crossover study of the effect of multiple doses of tamoxifen on palbociclib (PD-0332991) pharmacokinetics in healthy male volunteers. [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 LB-229. doi:10.1158/1538-7445.AM2014-LB-229