Naveed Shaik1, Robert R LaBadie2, Brian Hee3, Geoffrey Chan4. 1. Clinical Pharmacology, Pfizer Inc, La Jolla, CA, USA. Naveed.Shaik@pfizer.com. 2. Clinical Statistics, Pfizer Inc, Groton, CT, USA. 3. Clinical Pharmacology, Pfizer Inc, La Jolla, CA, USA. 4. Clinical Development Oncology, Pfizer Inc, Collegeville, PA, USA.
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).
RCT Entities:
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).
Authors: Michael J Munchhof; Qifang Li; Andrei Shavnya; Gary V Borzillo; Tracey L Boyden; Christopher S Jones; Susan D LaGreca; Luis Martinez-Alsina; Nandini Patel; Kathleen Pelletier; Larry A Reiter; Michael D Robbins; George T Tkalcevic Journal: ACS Med Chem Lett Date: 2011-12-21 Impact factor: 4.345
Authors: Jorge E Cortes; Florian H Heidel; Andrzej Hellmann; Walter Fiedler; B Douglas Smith; Tadeusz Robak; Pau Montesinos; Daniel A Pollyea; Pierre DesJardins; Oliver Ottmann; Weidong Wendy Ma; M Naveed Shaik; A Douglas Laird; Mirjana Zeremski; Ashleigh O'Connell; Geoffrey Chan; Michael Heuser Journal: Leukemia Date: 2018-12-16 Impact factor: 11.528
Authors: Jorge E Cortes; B Douglas Smith; Eunice S Wang; Akil Merchant; Vivian G Oehler; Martha Arellano; Daniel J DeAngelo; Daniel A Pollyea; Mikkael A Sekeres; Tadeusz Robak; Weidong Wendy Ma; Mirjana Zeremski; M Naveed Shaik; A Douglas Laird; Ashleigh O'Connell; Geoffrey Chan; Mark A Schroeder Journal: Am J Hematol Date: 2018-09-09 Impact factor: 10.047