Study Reanalysis Using a Mechanism-Based Pharmacokinetic/Pharmacodynamic Model of Pramlintide in Subjects with Type 1 Diabetes
- 638 Downloads
This report describes a pharmacokinetic/pharmacodynamic model for pramlintide, an amylinomimetic, in type 1 diabetes mellitus (T1DM). Plasma glucose and drug concentrations were obtained following bolus and 2-h intravenous infusions of pramlintide at three dose levels or placebo in 25 T1DM subjects during the postprandial period in a crossover study. The original clinical data were reanalyzed by mechanism-based population modeling. Pramlintide pharmacokinetics followed a two-compartment model with zero-order infusion and first-order elimination. Pramlintide lowered overall postprandial plasma glucose AUC (AUCnet) and delayed the time to peak plasma glucose after a meal (T max). The delay in glucose T max and reduction of AUCnet indicate that overall plasma glucose concentrations might be affected by differing mechanisms of action of pramlintide. The observed increase in glucose T max following pramlintide treatment was independent of dose within the studied dose range and was adequately described by a dose-independent, maximum pramlintide effect on gastric emptying of glucose in the model. The inhibition of endogenous glucose production by pramlintide was described using a sigmoidal function with capacity and sensitivity parameter estimates of 0.995 for I max and 23.8 pmol/L for IC50. The parameter estimates are in good agreement with literature values and the IC50 is well within the range of postprandial plasma amylin concentrations in healthy humans, indicating physiological relevance of the pramlintide effect on glucagon secretion in the postprandial state. This model may prove to be useful in future clinical studies of other amylinomimetics or antidiabetic drugs with similar mechanisms of action.
KEY WORDSdiabetes glucose pharmacodynamics pharmacokinetics pramlintide
This work was supported in part by Amylin Pharmaceutical Inc., the UB-Pfizer Strategic Alliance, and NIH Grant GM 57980. We appreciate the seminal PKPD contributions of the late University of Buffalo alumnus, Dr. Wayne Colburn, who initiated modeling of pramlintide PKPD.
Ms. Cirincione is an employee of Amylin Pharmaceuticals, Inc.
- 5.Evers F, Jeworrek C, Tiemeyer S, Weise K, Sellin D, Paulus M, et al. Elucidating the mechanism of lipid membrane-induced IAPP fibrillogenesis and its inhibition by the red wine compound resveratrol: a synchrotron X-ray reflectivity study. J Am Chem Soc. 2009;131(27):9516–21.PubMedCrossRefGoogle Scholar
- 24.Bea SB, Broeckmann AJ, Sheiner LB, Group NP. NONMEM users guides. San Francisco, CA: University of California; 2007.Google Scholar
- 43.Porksen S, Nielsen LB, Kaas A, Kocova M, Chiarelli F, Orskov C, et al. Meal-stimulated glucagon release is associated with postprandial blood glucose level and does not interfere with glycemic control in children and adolescents with new-onset type 1 diabetes. J Clin Endocrinol Metab. 2007;92(8):2910–6.PubMedCrossRefGoogle Scholar