glasdegib and Renal-Insufficiency

Glasdegib is being developed for indications in myeloid malignancies. The effect of renal impairment on the pharmacokinetics (PK) of a single, oral, 100-mg glasdegib dose under fasted conditions was assessed.. Open-label, parallel-group study (NCT03596567). Participants of good general health were selected and categorized, based on their estimated glomerular filtration rate, into normal (≥ 90 mL/min), moderate (≥ 30 to < 60 mL/min), or severe (< 30 mL/min) renal impairment groups. Blood samples were collected up to 120 h post-dose. PK exposure parameters were calculated using non-compartmental analysis.. All 18 participants completed the study. Respectively, ratios of adjusted geometric means (90% confidence interval) for glasdegib area under the curve from time 0 to infinity and peak plasma concentration versus normal participants were 205% (142-295%) and 137% (97-193%) in the moderate group, and 202% (146-281%) and 120% (77-188%) in the severe group. Glasdegib median time to peak plasma concentration was 2.0 h in both impairment groups and 1.5 h in the normal group. Mean oral clearance was decreased by approximately 50% in both renal impairment groups compared with the normal group. The plasma-free fraction of glasdegib was not altered by renal impairment. Five all-causality adverse events were reported in three participants; two were considered treatment-related.. The similar changes in exposure observed for participants with renal impairment, coupled with the known safety data from clinical experience, suggest that a lower starting dose of glasdegib may not be required for moderate or severe renal impairment.. ClinicalTrials.gov: NCT03596567 (started May 17, 2018).

Topics: Administration, Oral; Aged; Antineoplastic Agents; Area Under Curve; Benzimidazoles; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Phenylurea Compounds; Renal Insufficiency; Severity of Illness Index