Dong Jennifer Q, Rossulek Michelle, Somayaji Veena R, Baltrukonis Daniel, Liang Yali, Hudson Krischan, Hernandez-Illas Martha, Calle Roberto A
Pfizer, Inc., Cambridge, MA, USA.
Pfizer, Inc., Groton, CT, USA.
Br J Clin Pharmacol. 2015 Nov;80(5):1051-63. doi: 10.1111/bcp.12676. Epub 2015 Jul 29.
The aim of the present study was to evaluate the pharmacokinetics/pharmacodynamics (PK/PD), safety and tolerability of single intravenous (IV) doses of PF-05231023, a long acting fibroblast growth factor 21 (FGF21) analogue being developed for the treatment of type 2 diabetes mellitus (T2DM).
T2DM subjects (glycosylated haemoglobin: 7.0-10.5%; on stable metformin therapy and/or diet and exercise) were randomized to receive a single dose of placebo or PF-05231023 (0.5-200 mg). Safety evaluations were performed up to 14 days after dosing. PK and PD endpoints were measured and a PK/PD model was developed for triglyceride - an early marker of drug activity.
No antidrug antibody or serious adverse events (AEs) were observed. The most frequent AEs were gastrointestinal but were generally mild. Plasma PF-05231023 levels peaked immediately post-IV dosing, with mean terminal half-lives of 6.5-7.7 h and 66.5- 96.6 h for intact C- and N-termini, respectively. Intact C-terminus exposures increased proportionally with increasing dose, whereas N-terminus exposures appeared to trend higher than dose-proportionally. Although no apparent effect on plasma glucose was seen, dose-dependent decreases in triglyceride were observed, with a maximum reduction of 48.5 ± 10.0% (mean ± standard deviation) for the 200 mg dose compared with a reduction of 19.1 ± 26.4% for placebo, demonstrating proof of pharmacology. Moreover, a reduction in total cholesterol and low-density lipoprotein cholesterol and an increase in high-density lipoprotein cholesterol were observed in the high-dose groups.
Single IV doses of PF-05231023 up to 200 mg were generally safe and well tolerated by subjects with T2DM. The observed early sign of pharmacology supports further clinical testing of PF-05231023 upon repeated administration.
本研究旨在评估单次静脉注射PF - 05231023（一种正在研发用于治疗2型糖尿病（T2DM）的长效成纤维细胞生长因子21（FGF21）类似物）的药代动力学/药效学（PK/PD）、安全性和耐受性。
将T2DM受试者（糖化血红蛋白：7.0 - 10.5%；接受稳定的二甲双胍治疗和/或饮食及运动）随机分组，接受单次剂量的安慰剂或PF - 05231023（0.5 - 200毫克）。给药后长达14天进行安全性评估。测量PK和PD终点，并针对甘油三酯（药物活性的早期标志物）建立PK/PD模型。
未观察到抗药抗体或严重不良事件（AE）。最常见的AE为胃肠道反应，但一般较轻微。静脉注射给药后血浆PF - 05231023水平立即达到峰值，完整C末端和N末端的平均终末半衰期分别为6.5 - 7.7小时和66.5 - 96.6小时。完整C末端的暴露量随剂量增加成比例增加，而N末端的暴露量似乎高于剂量成比例增加的趋势。虽然未观察到对血糖有明显影响，但观察到甘油三酯呈剂量依赖性降低，200毫克剂量组的最大降幅为48.5±10.0%（平均值±标准差），而安慰剂组的降幅为19.1±26.4%，证明了药理学作用。此外，高剂量组观察到总胆固醇和低密度脂蛋白胆固醇降低，高密度脂蛋白胆固醇升高。
高达200毫克的单次静脉注射PF - 05231023对T2DM受试者总体安全且耐受性良好。观察到的早期药理学迹象支持对PF - 05231023进行重复给药后的进一步临床试验。
