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

Content Provider	Springer Nature Link
Author	Fang, Jing Landersdorfer, Cornelia B. Cirincione, Brenda Jusko, William J.
Copyright Year	2012
Abstract	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.
Starting Page	15
Ending Page	29
Page Count	15
File Format	PDF
ISSN	12341234
Journal	The AAPS Journal
Volume Number	15
Issue Number	1
e-ISSN	15507416
Language	English
Publisher	Springer US
Publisher Date	2012-10-02
Publisher Institution	American Association of Pharmaceutical Scientists
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Pharmacology/Toxicology Biochemistry Biotechnology Pharmacy
Content Type	Text
Resource Type	Article

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