Pharmacokinetic/Pharmacodynamic Modeling of Glucose Clamp Effects of Inhaled and Subcutaneous Insulin in Healthy Volunteers and Diabetic Patients

Summary:The pharmacokinetics and pharmacodynamics (PK/PD) of inhaled insulin in humans have not been modeled previously. We rationalized a model for the effects of inhaled insulin on glucose infusion rate during a euglycemic clamp study based on the mechanism of insulin action and compared parameter estimates between subcutaneous and inhaled insulin in healthy and diabetic subjects. Published data from two studies in 11 healthy volunteers and 18 type 1 diabetes patients were digitized. The subjects received four different doses of inhaled insulin and one or three different doses subcutaneously at the start of a 10 h glucose clamp. All data were modeled simultaneously using NONMEM VI. Insulin pharmacokinetics were described by a one-compartment model with one (inhaled) or two (subcutaneous insulin) first-order absorption processes and first-order elimination. Insulin effects on glucose were described by an indirect response model. A biophase direct effect equation for the glucose infusion rate was implemented. Pharmacodynamic parameter estimates were 15.1 mg/min/kg for maximal glucose infusion rate (GIRmax) and 88.0 mIU/L for SC50 for diabetic patients and 62.9 mIU/L for healthy subjects. A PK/PD model based on fundamental principles of insulin action and glucose turnover suggests comparable potencies of inhaled and subcutaneous insulin.