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).

Keywords: Glasdegib; Pharmacokinetics; Renal impairment; Safety.

Conflict of interest statement

Drs N. Shaik, R. LaBadie, B. Hee, and G. Chan were employees of Pfizer during this study.

Figures

Fig. 1

a Linear and b semi-logarithmic scales of median plasma glasdegib concentration–time profiles following a single 100-mg oral dose. The lower limit of quantification was 3 ng/mL

Fig. 2

Regression plots of plasma glasdegib CL/F versus a eGFR and b CrCl following a single 100-mg oral dose. The solid line is the predicted line of the response variable. The shadow area is 90% confidence region for the response variable. Treatment group indicates the degree of renal impairment. a Day –1 eGFR calculated from MDRD equation is used in this presentation. Cl = 3.06 + 0.08 × eGFR; R = 0.5524835197; slope p value = 0.0006. b Day –1 CrCl calculated from C-G formula is used in this presentation. Cl = 3.09 + 0.07 × CrCl; R = 0.4550467229; slope p value = 0.0030. BSA body surface area, C-G Cockcroft–Gault, Cl clearance, CL/F apparent clearance of total drug from plasma, CrCl creatinine clearance, eGFR estimated glomerular filtration rate, MDRD modification of diet in renal disease

Fig. 3

Overall survival by renal impairment and normal renal function in patients with AML or high-risk MDS in BRIGHT MDS & AML 1003. AML acute myeloid leukemia, CI confidence interval, MDS myelodysplastic syndrome, OS overall survival