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

Joanna C Masters, Robert R LaBadie, Joanne Salageanu, Jerry Li, Naveed Shaik, Joanna C Masters, Robert R LaBadie, Joanne Salageanu, Jerry Li, Naveed Shaik

Abstract

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.

Keywords: acute myeloid leukemia; glasdegib; hepatic; oncology; pharmacokinetics.

Conflict of interest statement

All authors are employees of Pfizer. Joanna C. Masters, Robert R. LaBadie, Joanne Salageanu, and Naveed Shaik hold Pfizer stock.

© 2020 Pfizer Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Plasma concentration–time profiles for total glasdegib. Concentration values below the lower limit of quantification (3 ng/mL) were set to zero.
Figure 2
Figure 2
Individual and summary of glasdegib total and unbound AUCinf and Cmax. Circles represent individual participant values and stars represent geometric mean. Box plot provides median and 25%/75% quartiles with whiskers to the last data point within 1.5 × the interquartile range. Mean (SD) displayed numerically under box plot. AUCinf, AUC from time zero to infinity; Cmax, maximum plasma concentration; mean, arithmetic mean; SD, standard deviation; u, unbound.
Figure 3
Figure 3
Plasma concentration–time profiles for unbound glasdegib. Concentration values below the lower limit of quantification (3 ng/mL) were set to zero.

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