Comparison of the Rabbit, Diabetic Miniature Swine and Non-Human Primate to Evaluate the Clinical Biopotency of Insulin Products

Abstract

The potency of human insulin has classically been evaluated in rabbits following the U.S. Pharmacopeia (USP) guideline. However, since insulin analogues are intentionally different there is a need for a bioassay to assess clinical specific activity (U) in different species. To this extent, we compared the biopotency(U) of different insulin products in rabbits, in type 1 diabetic miniature swine and in normal non-human primates, and used human and pork insulin as reference standards. New Zealand White rabbits were fasted and injected subcutaneously (s.c.) at a dose level of 0.5 U/kg. Yucatan miniature swine (Susscrofa) were made diabetic by intravenous administration of alloxanand insulin products were injected s.c.at dose level of 0.1 U/kg in overnight fasted animals (no feed or insulin for 18 h). Normal insulin suppression tests (nIST) were conducted in fasted male cynomolgusprimates (Macacafascicularis) receiving a bolus intravenous (i.v.) infusion of glucose (ivGTT; 0.25 g/kg) and treated with somatostatin. Insulin products were given at dose level of 0.05 U/kg. Glucose levels were recorded using handheld glucometer devices. The blood glucose kinetic (BGPK) and the blood glucose area under the curve (BGAUC) were used to assess biopotencyin the rabbit and in the diabetic miniature swine. The slope of the blood glucose clearance (kG) was used to assess biopotencyduring the nIST. Our data indicate that the biopotencyof insulin products can be assessed using BGAUC and kG, but that only the type 1 diabetic miniature swine can discriminate between differences in biopotencyfor all aspects of BGPK. In conclusion, the BGPK for short-acting human and pork insulin were similar in the rabbit assay but their respective BGAUCs were different (ratio of 1.2). Accordingly pork insulin was more potent during nISTin the non-human primate (slope of -0.012 vs. -0.010; pork and human, respectively).

Authors

Stricker-Krongrad, A., Bouchard, G.F.

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