Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 102, Issue 10, Pages 3844-3851Publisher
ELSEVIER SCIENCE INC
DOI: 10.1002/jps.23682
Keywords
Type 2 diabetes; exenatide; pharmacokinetics; pharmacodynamics; mathematical modeling
Funding
- NIH [GM57980]
- Center for Protein Therapeutics, University at Buffalo, SUNY
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The purpose of this study is to investigate the effect of exenatide on glycemic control following two administration routes in a streptozotocin/nicotinamide (STZ/NA)-induced diabetic rat model, and to develop a pharmacodynamic model to better understand the disease progression and the action of exenatide in this experimental system. Two groups of STZ/NA-induced diabetic rats were treated for 2 weeks with 20 (g/kg/day) of exenatide, either by continuous subcutaneous (SC) infusion or two SC injections daily. Disease progression was associated with slower glucose utilization. Fasting blood glucose was significantly reduced by 30 mg/dL in both treatment groups at the end of 2 weeks. A subsequent intravenous glucose tolerance test (IVGTT) confirmed an improved glucose tolerance in both treatment groups; however, overall glycemic control was similar between groups, likely due to the relatively low and short-term drug exposure. A population indirect response model was successfully developed to simultaneously describe the STZ/NA-induced disease progression, responses to an IVGTT, and exenatide effects on these systemic challenges. The unified model includes a single set of parameters, and the cumulative area under the drug-receptor concentration curve was used as a unique driving force to account for systemic effects long after drug elimination. (c) 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3844-3851, 2013
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