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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. [ABSTRACT FROM AUTHOR]

The pharmacokinetics (PK) and pharmacodynamics (PD) of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, were compared following a single 150‐mg subcutaneous dose administered to healthy subjects (n = 156–158/arm) via: (1) a prefilled syringe (PFS) using drug substance (DS) manufactured by Pfizer, (2) a PFS using DS manufactured by Boehringer Ingelheim Pharma, (3) a prefilled pen using DS manufactured by Pfizer (NCT02458209). Blood samples were collected for 12 weeks postdose. Safety was monitored throughout. Mean maximum plasma concentration (Cmax) ranged between 11.0 and 11.3 μg/mL, and area under the plasma concentration‐time curve (AUCinf) ranged between 177.6 and 185.0 μg·day/mL across treatments. The 90% confidence intervals for the ratios of adjusted geometric means for Cmax and AUCinf fell within the 80%–125% range for both DS and delivery device comparisons. Comparable low‐density lipoprotein cholesterol profiles were observed, with nadir values of 54.3–56.1 mg/dL across treatments. Similar PCSK9 responses were also observed. Safety profiles were similar across treatments, and the majority of adverse events (AEs) were mild. Three subjects reported serious AEs. The most frequently reported AEs were headache, injection‐site reaction, and upper respiratory tract infection, with no clear differences across treatments. Comparable PK, PD, and safety were observed following a single bococizumab 150‐mg subcutaneous injection regardless of site of DS manufacture or delivery device used. [ABSTRACT FROM AUTHOR]