The Effect of Hepatic Impairment on the Pharmacokinetics of Dacomitinib.

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.

Pharmacokinetics and Safety of Glasdegib in Participants With Moderate/Severe Hepatic Impairment: A Phase I, Single-Dose, Matched Case-Control Study.

This phase I open-label trial (NCT03627754) assessed glasdegib pharmacokinetics and safety in otherwise healthy participants with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. Participants with hepatic impairment and age/weight-matched controls with normal hepatic function received a single oral 100-mg glasdegib dose under fasted conditions. The primary end points were area under the plasma concentration-time curve from time zero to infinity (AUCinf ) and maximum plasma concentration (Cmax ). Twenty-four participants (8/cohort) were enrolled. Glasdegib plasma exposures in moderate hepatic impairment were similar to controls, with adjusted geometric mean ratios (GMRs) of 110.8% (90% confidence interval [CI], 78.0-157.3) for AUCinf and 94.8% (69.9-128.4) for Cmax versus controls. In severe hepatic impairment, glasdegib plasma exposures were lower than controls (AUCinf GMR, 75.7%; 90%CI, 51.5-111.0; Cmax GMR, 58.0%; 90%CI, 37.8-89.0). Unbound glasdegib exposures were similar to controls for moderate (AUCinf,u GMR, 118.1%; 90%CI, 88.7-157.2; Cmax,u GMR, 101.1%; 90%CI, 78.4-130.3) and severe hepatic impairment (AUCinf,u GMR, 116.3%; 90%CI 81.8-165.5; Cmax,u GMR, 89.2%, 90%CI, 60.2-132.3). No treatment-related adverse events or clinically significant changes in laboratory values, vital signs, or electrocardiograms were observed. Together with previous findings, this suggests glasdegib dose modifications are not required based on hepatic impairment.