Study Reanalysis Using a Mechanism-Based Pharmacokinetic/Pharmacodynamic Model of Pramlintide in Subjects with Type 1 Diabetes

• Published in: The AAPS journal Vol. 15; no. 1; pp. 15 - 29
• Main Authors: Fang, Jing, Landersdorfer, Cornelia B., Cirincione, Brenda, Jusko, William J.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.01.2013
• Subjects: Adult; Biochemistry; Biomedical and Life Sciences; Biomedicine; Biotechnology; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - metabolism; Humans; Hypoglycemic Agents - pharmacokinetics; Islet Amyloid Polypeptide - pharmacokinetics; Islet Amyloid Polypeptide - pharmacology; Male; Models, Biological; Pharmacology/Toxicology; Pharmacy; Research Article; Single-Blind Method; pharmacokinetics; glucose; pramlintide; diabetes; pharmacodynamics
• ISSN: 1550-7416; 1550-7416
• DOI: 10.1208/s12248-012-9409-7

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 (AUC net ) and delayed the time to peak plasma glucose after a meal ( T max ). The delay in glucose T max and reduction of AUC net 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 IC 50 . The parameter estimates are in good agreement with literature values and the IC 50 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.