Evaluation of the impact of renal impairment on the pharmacokinetics of glasdegib in otherwise healthy volunteers

Abstract

Purpose 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. Methods 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. Results 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. Conclusion 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. Trial registration: ClinicalTrials.gov: NCT03596567 (started May 17, 2018).

Selection and management of older patients with acute myeloid leukemia treated with glasdegib plus low-dose cytarabine: expert panel review

“…In a renal impairment study, participants with moderate or severe impairment had similar pharmacokinetic (PK) parameters following a single glasdegib 100-mg dose [77]. Coupled with the known safety profile of glasdegib [40,50], this suggests lower starting doses (<100 mg) may not be required in renal impairment.…”

Impact of COVID‐19 on the Conduct and Design of Clinical Trials: IQ Consortium Perspective

“…controls was explored in the renal impairment study with glasdegib. 6 Data from 83 subjects treated with a single oral dose of 100 mg glasdegib in 4 previously conducted healthy volunteer studies was used. Virtual healthy controls were matched by age (± 20 years) and body weight (±15 kg) to the renal impairment participants from the glasdegib renal impairment study.…”

“…Use of virtual controls, in theory, could facilitate study enrollment and reduce the exposure to healthy participants. The concept of using PK data from healthy participants in other clinical studies as “virtual” matched healthy controls was explored in the renal impairment study with glasdegib 6 . Data from 83 subjects treated with a single oral dose of 100 mg glasdegib in 4 previously conducted healthy volunteer studies was used.…”

Recent Research Progress of Chiral Small Molecular Antitumor-Targeted Drugs Approved by the FDA From 2011 to 2019

“…The therapeutic effect and controllable safety of glasdegib combined with cytarabine have been proved on newly diagnosed AML patients (156). It is preliminarily determined that patients with moderate or severe renal damage may not need to reduce the initial dose of glasdegib (157).…”