Vol. 286, Issue 2, 959-966, August 1998

Comparative Pharmacokinetic and Pharmacodynamic Studies of Human Insulin and Analogues in Chronic Diabetic Yucatan Minipigs

Senshang Lin, Li-Lan H. Chen and Yie W. Chien

Controlled Drug-Delivery Research Center, College of Pharmacy, Rutgers University, Piscataway, New Jersey

Pharmacokinetics and pharmacodynamics of insulin analogues were compared with human insulin in streptozotocin-induced chronic diabetic Yucatan minipigs. After overnight fasting, insulin or one of the insulin analogues (0.6 nmol/kg) in acid solutions (pH ~3.0) was administered to the minipigs s.c. The plasma insulin concentrations were then measured by radioimmunoassay at predetermined time intervals although blood glucose levels were monitored continuously. The mean (±S.E.) values of C_max (difference between peak and basal plasma insulin levels) were 598 (±21), 528 (±44), 176 (±21), 325 (±60) and 228 (±33) pM, respectively, for analogue Asp^B9Glu^B27, Asp^B9, Glu^B27, Asp^B28 and insulin. The differences in C_max values were statistically significant between Asp^B9Glu^B27 and insulin (P < .02), and between Asp^B9 and insulin (P < .01), but not between Glu^B27 or Asp^B28 and insulin. Moreover, the mean (±S.E.) values of AUC⁰⁶ (integrated area between plasma insulin concentration curve and basal level) were 1877 (±169), 1897 (±70), 485 (±36), 500 (±32) and 677 (±105) pM × hr, respectively, for Asp^B9Glu^B27, Asp^B9, Glu^B27, Asp^B28 and insulin. The differences in AUC⁰⁶ values were statistically significant between Asp^B9Glu^B27 and insulin (P < .05) and between Asp^B9 and insulin (P < .02), but not between Glu^B27 or Asp^B28 and insulin. However, there was no significant difference in the values of nadir (difference between nadir and basal levels) and ABGC⁰¹² (integrated area between blood glucose response curve and basal level) between insulin and various analogues. In conclusion, although the insulin analogues are different from human insulin in pharmacokinetics, they exhibit similar biological activity to human insulin in the streptozotocin-induced chronic diabetic minipigs.