Abstract P5-19-16: Effect of palbociclib concentration on heart rate-corrected QT interval in patients with cancer
Authors: Zheng Jenny , Amantea Michael , Wang Diane 
Published: May 2015

Abstract
Background: Palbociclib is a selective cyclin-dependent kinase 4/6 inhibitor that blocks G1/S cell cycle progression. The current population analysis assessed the effect of palbociclib exposure on QT interval and heart rate (via evaluation of RR interval) in cancer patients.
Methods: Plasma palbociclib concentration (C) and electrocardiogram (ECG) data were pooled from 3 studies of once-daily oral palbociclib: (Study 1) phase 1 dose-escalation study in advanced cancer (Schedule 1: 25, 50, 75, 100, 125, and 150 mg on a 3 wk on/1 wk off cycle [3/1]; Schedule 2: 100, 125, 200, and 225 mg [2/1]); (Study 2) phase 2 study in mantle cell lymphoma (125 mg [3/1]); (Study 3) phase 1/2 study in advanced breast cancer (Cycle 1: 125 mg [2/1]; Cycle 2+: 125 mg [3/1] + letrozole 2.5 mg daily). Blood samples were collected predose, after first palbociclib dose, and at steady state, including the anticipated time of maximal palbociclib concentration. Triplicate (∼2 min apart) ECGs were obtained at baseline; 3 h postdose (Study 1); predose on Day (D) 1 and D21 (Study 2); predose on D1 and predose, 2, 4, 8, 24, 48, and 96 h postdose on D14 of Cycle 1, predose and 4 h postdose on D1 and D14 of Cycle 2, and end of treatment (Study 3, phase 1); and predose on D1 of Cycle 1&3, D14 of Cycle 1&2, and end of treatment (Study 3, phase 2). Baseline singlet ECG data (from time closest to first palbociclib dose) were used to estimate a study-specific heart rate correction factor [β], using a linear mixed effect model of log(QT) vs log(RR/1000) with intersubject variability only on intercept. The averaged triplicate ECG data with time-matched palbociclib concentration data were used to explore RR–C and corrected QT interval (QTc)–C relationships. A linear mixed effects model was used to assess RR–C and QTc–C with intersubject variability on both intercept and slope; sex was tested as a covariate on QTc interval intercept.
Results: 184 patients supplied 569 matched pharmacokinetic and ECG assessments. Estimated β values for Studies 1, 2, and 3 were 0.367, 0.369, and 0.363, respectively. Compared with QT correction by Fridericia (QTcF) and Bazett (QTcB) methods, the study-specific correction (QTcS) best minimized the apparent QT–RR correlation and therefore was selected for use in subsequent analyses. Palbociclib had no effect on RR interval in RR–C analysis but increased QTcS in a concentration-dependent manner. The average (90% CI) QTcS increase at the mean and median maximum steady-state concentrations for patients on palbociclib 125 mg (Cmax,ss = 107 and 112 ng/mL, respectively [Study 3]) were 5.60 (2.48–8.72) and 5.88 (2.61–9.16) ms. Sex was not a significant covariate for intercept by analysis of variance. A similar effect of palbociclib on QTcF was observed.
Conclusion: In a pooled population analysis of patients with cancer, palbociclib had no concentration-dependent effect on heart rate. There was a slight positive linear relationship between palbociclib concentration and QTcS; however, the upper bound of the 1-sided 90% CI for the increase in QTcS at Cmax,ss did not exceed the threshold of 10 ms. Therefore, QT prolongation is not a major safety concern for palbociclib at the 125-ng/mL recommended therapeutic dose.
Citation Format: Jenny Zheng, Michael Amantea, Diane Wang. Effect of palbociclib concentration on heart rate-corrected QT interval in patients with cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-16.