Exenatide pharmacokinetics in healthy Chinese subjects.

OBJECTIVES: Exenatide is an adjunctive treatment for Type 2 diabetes. This was the first study to evaluate the pharmacokinetics, safety and tolerability of therapeutic doses (5 microg and 10 microg) of exenatide after single and multiple subcutaneous injections in healthy adult Chinese subjects. METHODS: 24 healthy volunteers were randomized to receive either 5 microg or 10 microg of exenatide by subcutaneous injection. Subjects received a single injection of exenatide on Day 1, twice daily on Days 2 and 3, and once on Day 4. Serial blood samples were drawn for pharmacokinetic assessment at pre-dose and up to 12 h post dose on Day 1 and Day 4. Adverse events, vital signs, 12-lead ECG, body weight and clinical laboratory evaluations were assessed. RESULTS: Exenatide, 5 microg and 10 microg, was rapidly absorbed with a median tmax of 1 h after single and multiple doses. Exenatide Cmax and AUCtau,ss were (geometric mean (90% CI)) 145 (119 - 176) pg/ml and 370 (297 - 460) pg x h/ml, respectively, after multiple dosing with 5 microg. The Cmax and AUCtau,ss were 311 (271 - 357) pg/ml and 878 (785 - 983) pg x h/ml, respectively, for 10 microg. Mean half-life (t1/2, range 0.99 - 1.25 h), apparent volume of distribution (Vz/F, 19.2 - 22.3 l), and apparent clearance (CL/F, range 11.4 - 13.5 l/h) remained consistent between single and multiple doses and across the two dose levels. Both the accumulation ratios and linearity index approached 1.0. The most common adverse events were gastrointestinal in nature and mild in severity. The frequency of adverse events increased with dose, such that 8% of subjects who received 5 microg and 42% of subjects who received 10 microg experienced adverse events. CONCLUSIONS: Exenatide was rapidly absorbed, with similar pharmacokinetic properties following single and multiple doses. Exenatide exposure after multiple doses approximately doubled from 5 microg to 10 microg.

Lean, nondiabetic Asian Indians have decreased insulin sensitivity and insulin clearance, and raised leptin compared to Caucasians and Chinese subjects.

OBJECTIVE: To study and compare the insulin sensitivity of healthy, nondiabetic Asian Indians with that of two other ethnic groups (Caucasian and Chinese) living in Singapore. DESIGN: Study of insulin sensitivity using euglycaemic hyperinsulinaemic glucose clamp. SUBJECTS: A total of 10 healthy, lean, young male subjects of each ethnic group, matched for age, body mass index (BMI) and physical activity. They all had normal glucose tolerance and had no family history of diabetes. MEASUREMENTS: Anthropometric parameters (BMI, waist-hip ratio (WHR) and percentage body fat (PBF)), fasting lipid profile and leptin concentration, insulin sensitivity index, and insulin clearance. RESULTS: Healthy lean (BMI 22.1+/-1.5 kg/m(2) (mean+/-s.d.)) Indians had significantly higher fasting serum leptin (5.1+/-2.5 vs Chinese 1.0+/-0.9 vs Caucasian 2.3+/-1.2 ng/ml; P<0.001), lower insulin sensitivity index (9.9+/-3.3 vs Chinese 14.1+/-3.5 vs Caucasian 18.8+/-9.2 mg/min kg fat-free mass/microU/ml; P<0.002), and lower insulin clearance (461.4+/-54.8 vs Chinese 621.0+/-99.3 vs Caucasian 646.9+/-49.2 ml/min m(2); P<0.001). Indians also had a higher PBF (26.5+/-5.2 vs Chinese 19.5+/-2.2 vs Caucasians 22.9+/-1.4%; P<0.001), diastolic blood pressure (P=0.036), fasting insulin (P<0.006) and fasting triglyceride (P=0.022). Stepwise regression analysis showed that ethnicity was the only significant independent determinant variable for the differences in insulin sensitivity index (P=0.008). CONCLUSION: Healthy lean nondiabetic Indians were more insulin resistant compared to other ethnic groups despite the similarity in living environment. These findings may warrant preventive health-care strategies for type II diabetes and coronary artery disease to target Indians at an earlier stage compared to other ethnic groups.