title: Population pharmacodynamic modeling of exenatide after 2-week treatment in STZ/NA diabetic rats.
abstract: 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 (μg/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.
authors.affiliation: Department of Pharmaceutical Sciences, The State University of New York, University at Buffalo, Buffalo, New York, 14214.
authors.forename: Ting
authors.initials: T
authors.lastname: Chen
authors.forename: Leonid
authors.initials: L
authors.lastname: Kagan
authors.forename: Donald E
authors.initials: DE
authors.lastname: Mager
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000178:diet therapy; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D018450:Disease Progression; D000077270:Exenatide; D005951:Glucose Tolerance Test / Q000379:methods; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D008297:Male; D009536:Niacinamide / Q000494:pharmacology; D010455:Peptides / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin / Q000494:pharmacology; D014688:Venoms / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D009536:Niacinamide; D013311:Streptozocin; D000077270:Exenatide
keywords: Type 2 diabetes; exenatide; mathematical modeling; pharmacodynamics; pharmacokinetics
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