[Effect of peripheral hyperinsulinemia on assessment of pharmacokinetics and pharmacodynamics of insulin preparations in euglycemic clamp].

Objective: To evaluate the effect of peripheral hyperinsulinemia on assessment of pharmacokinetics (PK) and pharmacodynamics (PD) of insulin preparations in euglycemic clamp. Method: A total of 40 healthy male volunteers aged 18-45 years old in West China Hospital between 2015 and 2017 were divided into euglycemic-hyperinsulinaemic clamp (A) group and euglycemic clamp (B) group. Humulin R (0.2 U/kg) was given subcutaneously at steady state of clamp after infusion of short-acting insulin in A group while in B group Humulin R was given subcutaneously without establishment of artificial hyperinsulinemia. The blood glucose was maintained within target range during the whole clamp. Result: Maximum insulin concentration [(667±141) pmol/L vs (267±68) pmol/L, P<0.01] and area under curve (AUC) of insulin concentration [(152±32) nmol·L(-1)·min vs (57±7) nmol·L(-1)·min, P<0.01] in A group were higher while maximum glucose infusion rate (GIR) [(3.70±0.70) mg·kg(-1)·min(-1) vs (7.66±2.11) mg·kg(-1)·min(-1), P<0.01] and AUC of GIR [(931±272) mg/kg vs (1 920±452) mg/kg, P<0.01] were lower compared to B group. The serum C-peptide levels were lower in both groups after administration of insulin compared with baseline. Conclusion: It is not necessary applying euglycemic-hyperinsulinaemic clamp to evaluate the PK/PD of insulin preparations, which may overestimate the PKparameters and underestimate the PD parameters of insulin preparations.目的： 探讨在采用正葡萄糖钳夹试验评价胰岛素制剂药代动力学（PK）/药效动力学（PD）参数时，给药前建立或不建立高胰岛素血症平台对受试胰岛素制剂的PK/PD参数的影响。 方法： 2015至2017年40例来源于四川大学华西医院，年龄18~45岁的健康男性受试者按照入组先后顺序分入高胰岛素正葡萄糖钳夹试验组（A组）与正葡萄糖钳夹试验组（B组）。A组首先建立高胰岛素血症平台（以1.0 mU·kg(-1)·min(-1)的速率静脉输入短效人胰岛素），钳夹试验达平台后皮下注射受试胰岛素制剂重组人胰岛素（0.2 U/kg），并持续维持血糖于靶值范围内。B组给药前不建立高胰岛素血症平台，在给予受试胰岛素制剂重组人胰岛素（0.2 U/kg）后采用正葡萄糖钳夹试验将血糖维持在靶值范围内。收集两组受试者皮下注射重组人胰岛素后的PK/PD参数。 结果： A组的胰岛素峰值[（667±141）pmol/L比（267±68）pmol/L，P<0.01]及胰岛素药时曲线下面积[（152±32）nmol·L(-1)·min比（57±7）nmol·L(-1)·min，P<0.01]高于B组，而A组的葡萄糖输注率峰值[（3.70±0.70）mg·kg(-1)·min(-1)比（7.66±2.11）mg·kg(-1)·min(-1)，P<0.01]及曲线下面积[（931±272）mg/kg比（1 920±452）mg/kg，P<0.01]低于B组。两组受试者给予受试胰岛素制剂后血清C肽水平较给药前均有不同程度降低（A组下降30.9%±16.4%，B组下降49.2%±10.8%，P<0.01）。 结论： 采用高胰岛素正葡萄糖钳夹试验评价受试胰岛素制剂的PK/PD特征时有可能高估受试胰岛素制剂的PK参数而低估PD参数，不建立外源性高胰岛素血症的正葡萄糖钳夹试验可较准确获得受试胰岛素制剂的PK/PD参数，且试验流程更简便。.