Shaik Naveed, LaBadie Robert R, Hee Brian, Chan Geoffrey
Clinical Pharmacology, Pfizer Inc, La Jolla, CA, USA.
Clinical Statistics, Pfizer Inc, Groton, CT, USA.
Cancer Chemother Pharmacol. 2021 Feb;87(2):241-250. doi: 10.1007/s00280-020-04207-9. Epub 2021 Jan 3.
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).
glasdegib正在针对髓系恶性肿瘤适应症进行研发。评估了肾功能损害对空腹条件下单次口服100mg glasdegib剂量的药代动力学（PK）的影响。
开放标签、平行组研究（NCT03596567）。选择总体健康状况良好的参与者，并根据其估计的肾小球滤过率分为正常（≥90 mL/分钟）、中度（≥30至<60 mL/分钟）或重度（<30 mL/分钟）肾功能损害组。给药后长达120小时采集血样。使用非房室分析计算PK暴露参数。
所有18名参与者均完成了研究。在中度组中,glasdegib从时间0至无穷大的曲线下面积和血浆峰浓度与正常参与者相比，调整几何均值（90%置信区间）的比值分别为205%（142-295%）和137%（97-193%），在重度组中分别为202%（146-281%）和120%（77-188%）。两个损害组中glasdegib血浆峰浓度的中位时间均为2.0小时，正常组为1.5小时。与正常组相比，两个肾功能损害组的平均口服清除率均降低了约50%。肾功能损害未改变glasdegib的血浆游离分数。三名参与者报告了5起全因性不良事件；两起被认为与治疗相关。
肾功能损害参与者观察到的暴露量有相似变化，再加上临床经验中的已知安全数据，表明中度或重度肾功能损害可能不需要降低glasdegib的起始剂量。
ClinicalTrials.gov：NCT03596567（2018年5月17日开始）
