ESTABLISHMENT OF TIME-ACTION PROFILES FOR REGULAR AND NPH INSULIN USING PHARMACODYNAMIC MODELING

OBJECTIVE - To provide distinct definitions and quantify the establish ment of onset, peak, and duration of action for insulins. RESEARCH DES IGN AND METHODS - We administered single subcutaneous doses of 10 U re gular insulin to 10 volunteer subjects and 25 U NPH insulin to 6 healt hy male volunteer subj ects on separate occasions. Each dose was given after an overnight fast during a glucose clamp to maintain an euglyce mic state. We measured serum insulin concentrations and glucose infusi on rates (GIR) from frequent blood sampling after each treatment. Seru m insulin concentrations were related to GIR values at each collection time and a counter-clockwise hysteresis resulted. An effect compartme nt model was used to simultaneously describe the pharmacokinetics and pharmacodynamics of each insulin and to resolve the hysteresis. RESULT S - From the resulting relationship, GIR could then be predicted, with onset and duration of action reflecting the time when effect compartm ent concentrations initially exceeded then declined below a 10% maximu m possible effect (E(max)) level. Ninety-five percent confidence inter vals were constructed allowing a predictive range of values. For regul ar insulin, a mean onset of 0.75 h, peak of 2 h, and duration of 6 h w as estimated. Mean values were also produced with NPH, with an onset o f 3 h, peak of 6-7 h, and a duration of 13 h estimated. CONCLUSIONS - This method estimates the onset, peak, and duration of insulin action. Although these estimates were from single doses, we believe they can provide good estimations of insulin activity.