Pharmacokinetic-pharmacodynamic modelling of the hypoglycaemic effect of pulsatile administration of human insulin in rats.

The relationship between the plasma insulin (INS) concentration-time course and plasma glucose concentration-time course during and after pulsatile INS administration to rats was characterized using a pharmacokinetic-pharmacodynamic (PK-PD) model. A total INS dose of 0.5 IU/kg was intravenously injected in 2 to 20 pulses over a 2-h period. Compared with the single bolus administration, the area under the effect-time curve (AUE) increased depending on the number of pulses, and the AUEs for more than four pulses plateaued at a significantly larger value, which was similar to that after the infusion of a total of 0.5 IU/kg of INS over 2 h. No increase in plasma INS concentration occurred after pulsatile administration. Two indirect response models primarily reflecting the receptor-binding process (IR model) or glucose transporter 4 (GLUT4) translocation (GT model) were applied to describe the PK-PD relationship after single intravenous bolus administration of INS. These models could not explain the observed data after pulsatile administration. However, the IR-GT model, which was a combination of the IR and GT models, successfully explained the effects of pulsatile administration and intravenous infusion. These results indicate that the receptor-binding process and GLUT4 translocation are responsible for the change in AUE after pulsatile administration.