| Object:The study objectives were to evaluate pharmacokinetics(PK) and pharmacodynamics(PD) properties, as well as safety and tolerability of Polyethylene Glycol Loxenatide(PEX-168) after single-dose subcutancous injection in patients with Type2diabetes.Method:This investigation was approved by ethics committee of the First Affiliated Hospital, College of Medicine, Zhejiang University before the study was performed.5patients with type2diabetes were enrolled and randomized to a single subcutaneous injection of PEX-168(100μg or200μg), a follow-up period of about28days was expected to observe safety and treatment-related changes in both PK/PD parameters.1. The primary objective was to determine the safety and tolerability of PEX-168after single-dose subcutancous injection in patients with Type2diabetes.5patients received single subcutaneous injections of PEX-168on Day1, Safety was assessed via monitoring of adverse events from Day1to Day28. All patients recevied physical examinations, clinical laboratory values and electrocardiograms (ECGs) on Day1, Day14, and Day28.2. The secondary objectives were to assess the PK and PD properties of PEX-168. For PK parameters:5patients received single subcutaneous injections of PEX-168(100μg or200μg) on Day1, the blood sample were collected on Day1(after administration), Day2,3,4,6,8,11,14,16,19,22,25and Day28, the serum concentration profiles of PEX-168were determined by EIA. PK parameters were derived from summarized PEX-168serum concentration data by standard non-compartmental methods of analysis using WinNonlin5.2. For PD parameters:5patients recevied OGTT (oral glucose tolerance test) on Day0and Day1, the serum insulin and glucagon levels were measured. The fasting blood glucose and2-h postprandial blood glucose of breakfast were measured on Day1,2,3,4,6,8,11,14,16,19,22,25and Day28, as well as serum insulin and glucagon levels were measured. The HbA1c were measured on Day0and Day28. The body weight was measured on Day0-28. The primary efficacy end point was the change from baseline in HbAlc (percent), assessed Day28, and the absolute changes from baseline in FPG and2-h postprandial. Secondary end points included fasting and postprandial insulin, fasting and postprandial glucagon, body weight parameters.Results1.5subjects completed the study. There were no serious adverse events in either study and no withdrawals related to PEX-168administration, There were no clinically relevant abnormalities in scheduled electrocardiograms, vital signs (including heart rate), or any laboratory parameters after treatment with PEX-168.2. Single doses subcutaneous injection of PEX-168of100μg or200μg, the main pharmacokinetic parameters were as follows:Cmax were (4.98±3.70) ng·mL-1and18.75ng·mL-1, respectively;Tmax were:(109.00±24.69) h and74h, respectively;AUC0-t were:(1502.26±1477.46) ngmL-1·h and5300.32ng mL-1·h, respectively; AUC0-∞were:(2240.75±1219.76) ng·mL-1·h and5304.84ng·mL-1·h respectively; T1/2were (182.94±8.89h and58.6h, respectively; MRT0-∞:(303.75±11.05) h and201.72h respectively;CL/F:(1.02±0.51) mL·h-1and0.652mL·h-1, respectively;Vz-F:(233.60±117.38) mL and54.63mL,respectively; Kel:(0.0037±0.00018) h-1and0.01190h-1, respectively.3. Fasting blood glucose,2-h postprandial blood glucose decreased after a single dose subcutancous injection compared with baseline, especially2-h postprandial blood glucose decreased significantly. HbAlc in100μg and200μg doses were decreased by 0.6%and0.9%, respectively after administration of28days.4patients exhibited weight loss compared with baseline.Conclusions:PEX-168was well tolerated and safety in5subjects. The Cmax, AUC0-t, AUC0-∞, generally indicating dose-dependent increases in exposure respectively, and it demonstrated the long-term characteristics. A single dose of PEX-168improved glycaemic parameters and exhibited weight loss. Based on tolerability and pharmacokinetic/pharmacodynamic parameters,100μg-200lg and once weekly of PEX-168may be considered for further clinical development in patients with type2diabetes. |
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