The Effect of Hepatic Impairment on the Pharmacokinetics of Dacomitinib

Abstract

Background and objective: Dacomitinib is a kinase inhibitor indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-activating mutations. To evaluate the effect of hepatic impairment on the pharmacokinetics of dacomitinib, two dedicated studies were conducted to inform optimal dosing.

Methods: Study 1 (NCT01571388) evaluated the effect of mild and moderate hepatic impairment on the plasma pharmacokinetics, safety, and tolerability after a single oral dose of dacomitinib 30 mg, and Study 2 (NCT03865446) evaluated the same endpoints in a severe hepatic impairment population. Both studies were phase I, open-label, parallel-group studies. A one-way analysis of variance (ANOVA) with unequal variance assumption and hepatic impairment group as a fixed effect was used to compare the natural log of area under the plasma concentration-time curve extrapolated to infinite time (AUCinf), AUC from time zero to the last quantifiable concentration (AUClast), and maximum plasma concentration (Cmax) for each hepatic impairment group to the respective normal hepatic function group. Since dacomitinib is a cytochrome P450 (CYP) 2D6 substrate, only participants with extensive or intermediate CYP2D6 phenotypes were included in the primary analysis.

Results: The AUCinf for participants with mild, moderate, or severe hepatic impairment decreased by 6%, decreased by 23%, and increased by 4%, respectively, compared with normal hepatic function, while the Cmax for participants with mild, moderate, or severe hepatic impairment increased by 3%, decreased by 20%, and increased by 31%, respectively, compared with normal hepatic function. A single oral dose of dacomitinib 30 mg was well tolerated in all participants.

Conclusion: Based on these pharmacokinetic results, dacomitinib pharmacokinetics of participants with mild, moderate, or severe hepatic impairment were not statistically different relative to participants with normal hepatic function based on the ANOVA analysis. No dacomitinib dose adjustments for patients with hepatic impairment are recommended.

Clinical trial registration: ClinicalTrials.gov NCT01571388, registered 5 April 2012; ClinicalTrials.gov NCT03865446, registered 6 March 2019.

Conflict of interest statement

This research was sponsored by Pfizer Inc. Joseph Chen, Robert R. LaBadie, Joanne Salageanu, Chin-Hee Chung, and Weiwei Tan are employees of Pfizer Inc. and may own Pfizer stock. Joseph Piscitelli (Postdoctoral Fellow) was an unpaid contractor to Pfizer; the fellowship program with the University of California San Diego was supported by an educational grant from Pfizer.

© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Figures

Fig. 1

Median concentrations for dacomitinib and PF-05199265 for Study 1 and Study 2 (linear and semi-log). Concentrations that were below the LLOQ were set as LLOQ/2, 0.05 ng/mL. The vertical dashed error bars represent the 5th and 95th percentiles around the median concentrations. LLOQ lower limit of quantification

Fig. 2

Boxplots for AUCinf and Cmax for Study 1 and Study 2. The red diamond represents the geometric mean value for each respective group; the black line represents the median value; black circles represent the actual parameters; and the upper and lower hinges represent the 25th and 75th percentiles. The lower whisker extends to the smallest value, no less than 1.5 times the interquartile range, and the upper whisker extends to the largest value, no greater than 1.5 times the interquartile range. Black dots outside of the whiskers represent outliers. AUCinf area under the plasma concentration–time curve from time zero extrapolated to infinite time, Cmax maximum plasma concentration