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Research ArticleENDOCRINE AND REPRODUCTIVE

Exendin-4 Pharmacodynamics: Insights from the Hyperglycemic Clamp Technique

Donald E. Mager, Darrell R. Abernethy, Josephine M. Egan and Dariush Elahi
Journal of Pharmacology and Experimental Therapeutics November 2004, 311 (2) 830-835; DOI: https://doi.org/10.1124/jpet.104.069765
Donald E. Mager
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Darrell R. Abernethy
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Josephine M. Egan
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Dariush Elahi
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Abstract

The purpose of this study is to ascertain the pharmacodynamic properties of exendin-4, a glucose-dependent insulinotropic agent, from plasma glucose and insulin concentration-time profiles following a 60-min intravenous infusion in healthy and type 2 diabetic subjects. Plasma glucose and insulin concentrations were obtained from a previous clinical study, whereby a hyperglycemic clamp was established and maintained in healthy (n = 7) and type 2 diabetic (n = 7) volunteers (plasma glucose raised 5.4 mM above fasting level). Exendin-4 was infused (0.15 pmol/kg/min) during the 2nd hour of a 5-h clamp. A physiological pharmacodynamic model was developed and fitted to individual glucose and insulin responses simultaneously. Because drug concentrations were unavailable, hypothetical pharmacokinetic driving functions were approximated during the modeling process and used to enhance a proportionality constant relating elevated glucose and the rate of second-phase insulin release. Exendin-4 infusions produced substantial insulin release in both subject populations that required higher glucose infusion rates to maintain stable hyperglycemia. Observed plasma glucose-insulin profiles were well characterized by the final pharmacodynamic model. Apparent exendin-4 elimination rate constants for healthy and diabetic subjects were similar (0.0386 ± 0.0192 and 0.0460 ± 0.0145 min-1). Capacity and sensitivity parameters of drug effect were 2-fold lower in diabetic subjects, but mean differences were not statistically significant. Simulations confirm that diabetic subjects exhibit a reduced capacity to enhance second-phase insulin release in response to exendin-4 compared with healthy subjects. Type 2 diabetic subjects demonstrate a significant response to exendin-4, but to a lesser extent than nondiabetic subjects, despite comparable measures of apparent drug exposure and efficacy.

Footnotes

  • This study was funded in part by the Intramural Research Program of the National Institute on Aging and by Grant NIA-00599 (to D.E.) from the National Institutes of Health.

  • doi:10.1124/jpet.104.069765.

  • ABBREVIATIONS: GLP-1, glucagon-like peptide-1; PD, pharmacodynamics; PK, pharmacokinetics; AUC, area under the curve; MAP, maximum a posteriori.

    • Received April 8, 2004.
    • Accepted June 15, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 311 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 311, Issue 2
1 Nov 2004
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Research ArticleENDOCRINE AND REPRODUCTIVE

Exendin-4 Pharmacodynamics: Insights from the Hyperglycemic Clamp Technique

Donald E. Mager, Darrell R. Abernethy, Josephine M. Egan and Dariush Elahi
Journal of Pharmacology and Experimental Therapeutics November 1, 2004, 311 (2) 830-835; DOI: https://doi.org/10.1124/jpet.104.069765

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Research ArticleENDOCRINE AND REPRODUCTIVE

Exendin-4 Pharmacodynamics: Insights from the Hyperglycemic Clamp Technique

Donald E. Mager, Darrell R. Abernethy, Josephine M. Egan and Dariush Elahi
Journal of Pharmacology and Experimental Therapeutics November 1, 2004, 311 (2) 830-835; DOI: https://doi.org/10.1124/jpet.104.069765
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