Gu Namyi, Cho Sang-Heon, Kim Jaewoo, Shin Dongseong, Seol Eunyoung, Lee Heeyong, Lim Kyoung Soo, Shin Sang-Goo, Jang In-Jin, Yu Kyung-Sang
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea.
Peptron Inc, Daejeon, Korea.
Clin Ther. 2014 Jan 1;36(1):101-14. doi: 10.1016/j.clinthera.2013.12.002. Epub 2013 Dec 27.
PT302 is a sustained-release exenatide under clinical development for the treatment of type 2 diabetes mellitus.
The aim of this study was to evaluate the pharmacokinetic properties, pharmacodynamic properties, and tolerability of PT302 after a single subcutaneous injection in healthy individuals.
A dose-block randomized, double-blind, placebo-controlled, dose-escalating study (0.5, 1, 2, and 4 mg) was performed in 34 healthy individuals. The plasma concentrations of exenatide in serial blood samples were quantified for 56 days after dosing with an exendin-4 fluorescent immunoassay kit. Noncompartmental analysis was performed to assess the pharmacokinetic characteristics of PT302. Oral glucose tolerance tests were repeated weekly until day 42; the concentrations of serum glucose, serum C-peptide, plasma insulin, and plasma glucagon were measured for 2 hours to evaluate the pharmacodynamic characteristics of PT302. Clinical laboratory tests, vital signs, physical examinations, 12-lead ECGs, and adverse events were monitored to evaluate the safety profile and tolerability.
PT302 exhibits a biphasic pharmacokinetic profile, with the initial peak occurring 2 hours after administration. PT302 was quantifiable in the plasma until days 23, 30, 32, and 55 (median) in the 0.5-mg, 1-mg, 2-mg, and 4-mg dosage groups of PT302, respectively. Systemic exposure increased proportionally to the dose during the entire dose range investigated. The pharmacodynamic effect of PT302 on the postprandial response of insulin and C-peptide was significant on days 21 to 28 at the 4-mg dose and was positively correlated with plasma exenatide concentrations, whereas the correlations with glucose and glucagon were not significant. The fasting levels of these pharmacodynamic biomarkers were not altered by PT302. The most common adverse events were injection site induration and pruritus related to inflammatory foreign body reaction, which were mild and spontaneously resolved within several weeks.
The pharmacokinetic characteristics of PT302 were biphasic and dose proportional. A single 4-mg dose of PT302 significantly increased the insulin and C-peptide response to oral glucose loading and was well tolerated in healthy individuals.
PT302是一种正在进行临床开发用于治疗2型糖尿病的长效艾塞那肽。
本研究旨在评估单次皮下注射PT302在健康个体中的药代动力学特性、药效学特性和耐受性。
在34名健康个体中进行了一项剂量分组随机、双盲、安慰剂对照、剂量递增研究（0.5、1、2和4毫克）。给药后用艾塞那肽-4荧光免疫分析试剂盒对连续血样中艾塞那肽的血浆浓度进行56天的定量分析。采用非房室分析评估PT302的药代动力学特征。每周重复口服葡萄糖耐量试验直至第42天；测量血清葡萄糖、血清C肽、血浆胰岛素和血浆胰高血糖素的浓度2小时，以评估PT302的药效学特征。监测临床实验室检查、生命体征、体格检查、12导联心电图和不良事件，以评估安全性和耐受性。
PT302呈现双相药代动力学特征，给药后2小时出现初始峰值。在PT302的0.5毫克、1毫克、2毫克和4毫克剂量组中，分别在第23天、30天、32天和55天（中位数）血浆中可检测到PT302。在所研究的整个剂量范围内，全身暴露与剂量成比例增加。在第21至28天，4毫克剂量的PT302对胰岛素和C肽餐后反应的药效学作用显著，且与血浆艾塞那肽浓度呈正相关，而与葡萄糖和胰高血糖素的相关性不显著。PT302未改变这些药效学生物标志物的空腹水平。最常见的不良事件是与炎性异物反应相关的注射部位硬结和瘙痒，症状较轻，数周内可自行缓解。
PT302的药代动力学特征为双相且与剂量成比例。单次4毫克剂量的PT302显著增加了口服葡萄糖负荷后胰岛素和C肽的反应，且在健康个体中耐受性良好。
