Profil Institute for Clinical Research, Chula Vista, California, USA.
Diabetes Technol Ther. 2011 Oct;13(10):1039-45. doi: 10.1089/dia.2011.0115. Epub 2011 Jun 29.
This study was designed to test the hypothesis that co-administration of recombinant human hyaluronidase (rHuPH20) with regular insulin or insulin lispro will reduce intrasubject variability in pharmacokinetic end points compared with lispro alone.
Healthy adult volunteers (18-55 years old) were enrolled in this phase 1, randomized, double-blind, crossover study. Subjects were administered two injections, each on a separate occasion, of three treatments during six euglycemic clamps. Treatments were 0.15 U/kg insulin lispro, 0.15 U/kg insulin lispro with 5 μg/mL rHuPH20, and 0.15 IU/kg regular insulin with 5 μg/mL rHuPH20. Insulin formulations were administered at a concentration of 40 U/mL. Serum immunoreactive insulin levels, blood glucose concentration, and glucose infusion rate determinations were made at baseline and for approximately 8 h after study drug administration. Intrasubject variability was assessed using a general linear mixed model with a fixed effect for treatment using a compound symmetric covariance matrix.
Co-injection of rHuPH20 with lispro significantly reduced intrasubject root mean square differences in time to peak serum insulin, time to early 50% peak serum insulin (t(50%)), and time to late t(50%) levels compared with lispro alone. Also, the intrasubject coefficient of variation for percentage of total area under the plasma concentration-versus-time curve for early time intervals compared with lispro alone was reduced. Intrasubject variability for regular insulin with rHuPH20 for most pharmacokinetic parameters was similar to the variability of lispro alone, although variability in early exposure was significantly reduced.
Co-administration of rHuPH20 with lispro significantly reduced the variability of insulin pharmacokinetics relative to insulin lispro alone.
本研究旨在检验以下假设，即与单独使用赖脯胰岛素相比，重组人透明质酸酶（rHuPH20）与常规胰岛素或赖脯胰岛素联合使用将降低药代动力学终点的个体内变异性。
这项 1 期、随机、双盲、交叉研究纳入了健康成年志愿者（18-55 岁）。在 6 次血糖正常钳夹中，每位受试者接受了两次单独给药，共 3 种治疗。处理方法为：0.15U/kg 赖脯胰岛素、0.15U/kg 赖脯胰岛素加 5μg/mL rHuPH20、0.15IU/kg 常规胰岛素加 5μg/mL rHuPH20。胰岛素制剂的浓度为 40U/mL。在基线和研究药物给药后约 8 小时，测定血清免疫反应性胰岛素水平、血糖浓度和葡萄糖输注率。采用固定效应为治疗的一般线性混合模型，使用复合对称协方差矩阵评估个体内变异性。
与单独使用赖脯胰岛素相比，rHuPH20 与赖脯胰岛素联合注射显著降低了血清胰岛素达峰时间、早期 50%达峰时间（t(50%)）和晚期 t(50%)的个体内均方根差异。此外，与单独使用赖脯胰岛素相比，早期时间间隔内血浆浓度-时间曲线的总面积百分比的个体内变异系数也降低了。与单独使用赖脯胰岛素相比，rHuPH20 与常规胰岛素联合使用对大多数药代动力学参数的个体内变异性相似，尽管早期暴露的变异性显著降低。
与单独使用赖脯胰岛素相比，rHuPH20 与赖脯胰岛素联合使用可显著降低胰岛素药代动力学的变异性。
