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 disease progression and the action of exenatide in this experimental system. Two groups of STZ/NA-induced diabetic rats were treated for two weeks with 20 µg/kg/day of exenatide, either by continuous SC infusion or twice daily SC injections. 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 two weeks. A subsequent IV 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 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.

In vivo dual-delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 (DPP4) inhibitor through composites prepared by microfluidics for diabetes therapy

“… 27 This model was described as being the most suitable to study the biochemical and pharmacological antidiabetic drug effects, and was previously used to test GLP-1 analogs. 16 , 33 , 34 It is based on the protective effects of nicotinamide against the β-cytotoxic effects caused by STZ, a widely used drug to induce diabetes mellitus in rodents. 35 This model presents a number of features similar to T2DM, as described in detail elsewhere.…”

Exendin-4, a glucagon-like peptide-1 analogue, accelerates diabetic wound healing

“…18,19 However, blood glucose could better be controlled by parenteral injection of higher doses of Ex4 (up to 20 mg/kg/d) over a 2wk treatment period in diabetic rats. 48 Therefore, we believe that the hypoglycemic effect of Ex4 is treatment dose and duration dependent in experimental animals. In this study, we showed that low dose Ex4 mediated anti-inflammatory and proangiogenic effects, in turn improving excisional wound healing, which were consistent with the characteristic responses reported by other study groups.…”

Target-mediated pharmacokinetic/pharmacodynamic model based meta-analysis and dosing regimen optimization of a long-acting release formulation of exenatide in patients with type 2 diabetes mellitus

“…Type 2 diabetes disease progression is associated with worsening glycemic control in the clinic (35) and quantitative modeling of disease progression can improve the understanding of disease and drug efficacy (32). The information on average HbA1c change is available to further evaluate the patient status of type 2 diabetes, and an increase of 0.2% HbA1c per year has reflected the rate of disease progression of patients (36).…”