Giri Nagdeep, Lam Lisa H, LaBadie Robert R, Krzyzaniak Joseph F, Jiang Hong, Hee Brian, Liang Yali, Shaik M Naveed
Pfizer Oncology, 10555 Science Center Dr, San Diego, CA, 92121, USA.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
Cancer Chemother Pharmacol. 2017 Dec;80(6):1249-1260. doi: 10.1007/s00280-017-3472-9. Epub 2017 Oct 30.
This phase I open-label study investigated the oral bioavailability of two novel maleate salt-based glasdegib (PF-04449913) tablet formulations (small- and large-particle size) relative to the current clinical formulation (diHCl salt-based). In addition, the effect of a gastric pH-altering agent (rabeprazole) and food on the pharmacokinetics of the large-particle size formulation of glasdegib were evaluated. The pharmacokinetics of glasdegib oral solution was also assessed.
Thirty-four healthy subjects received glasdegib 100 mg as three different formulations in the fasted state (diHCl salt or small- or large-particle size maleate formulation); 13 received the large-particle maleate formulation (fed), and 14 concurrently with rabeprazole (fasted); six subjects received glasdegib 50 mg oral solution (fasted).
For both new tablet formulations of glasdegib, ratios (Test:Reference) of adjusted geometric means (90% confidence interval) of area under the concentration-time curve from 0 to infinity and maximum plasma concentration were within 80-125% compared with the diHCl formulation (fasted). For the large-particle size formulation (fed), these ratios were 86.3% (81.0-92.0%) and 75.7% (65.3-87.7%), respectively, compared with fasted. When the large-particle maleate formulation was administered concurrently with rabeprazole versus alone (fasted), these ratios were 111.9% (102.8-121.9%) and 87.2% (75.9-100.3%), respectively. The pharmacokinetics of oral solution was similar to the tablet.
The maleate salt-based tablet formulations were bioequivalent to the diHCl tablet formulation. The extent of the observed effect of a high-fat, high-calorie meal or concurrent rabeprazole treatment on glasdegib exposure is not considered clinically meaningful.
本I期开放标签研究调查了两种新型马来酸盐基格拉斯吉布（PF - 04449913）片剂制剂（小粒径和大粒径）相对于当前临床制剂（二盐酸盐基）的口服生物利用度。此外，评估了胃pH调节剂（雷贝拉唑）和食物对格拉斯吉布大粒径制剂药代动力学的影响。还评估了格拉斯吉布口服溶液的药代动力学。
34名健康受试者在禁食状态下接受100 mg格拉斯吉布的三种不同制剂（二盐酸盐或小粒径或大粒径马来酸制剂）；13名受试者接受大粒径马来酸制剂（进食），14名受试者同时接受雷贝拉唑（禁食）；6名受试者接受50 mg格拉斯吉布口服溶液（禁食）。
对于格拉斯吉布的两种新片剂制剂，与二盐酸盐制剂（禁食）相比，0至无穷大浓度 - 时间曲线下面积和最大血浆浓度的调整几何均值（90%置信区间）的比值（试验：参比）在80 - 125%范围内。对于大粒径制剂（进食），与禁食相比，这些比值分别为86.3%（81.0 - 92.0%）和75.7%（65.3 - 87.7%）。当大粒径马来酸制剂与雷贝拉唑同时给药与单独给药（禁食）相比时，这些比值分别为111.9%（102.8 - 121.9%）和87.2%（75.9 - 100.3%）。口服溶液的药代动力学与片剂相似。
马来酸盐基片剂制剂与二盐酸盐片剂制剂生物等效。高脂肪、高热量餐食或同时使用雷贝拉唑治疗对格拉斯吉布暴露的观察到的影响程度在临床上不被认为有意义。
