Adverse events in healthy subjects exposed to single and multiple doses of LY2140023 monohydrate: pooled results from 10 phase 1 studies.

Ten phase 1 studies of LY2140023 monohydrate (LY2140023), an mGlu2/3 receptor agonist, in healthy male and female subjects were pooled to evaluate the adverse event profile. These studies included both single-dose (5-200 mg) and multiple-dose (20-160 mg 2 times a day) treatment groups. The percentage of subjects reporting treatment-emergent adverse events (TEAEs) were assessed in placebo and LY2140023 dose groups: 5 to 20, 40, 60 to 80, and more than 80 mg (120-200 mg). The severity and duration of TEAEs were also determined. Electroencephalograms were performed in 1 study to detect if there were any prodromal signs of convulsions or seizures. Subjects who received either placebo or LY2140023 and participated in the single-dose (n = 159) and multiple-dose (n = 102) treatment groups were included in these analyses. No clear trends for increased TEAE incidence occurred with higher doses of LY2140023 in both the single-dose and multiple-dose treatment groups. The TEAEs with the highest incidence were gastrointestinal and nervous system events. No serious adverse events occurred in any of the 10 studies, and most TEAEs were mild in severity and transient in nature. There were no clinically significant changes in electroencephalograms in subjects receiving LY2140023 (n = 26). LY2140023 was generally well tolerated in healthy subjects.

Pharmacokinetics and pharmacodynamics of insulin lispro protamine suspension compared with insulin glargine and insulin detemir in type 2 diabetes.

OBJECTIVE: The primary aim was to evaluate duration of action of a single 0.8 U/kg dose of insulin lispro protamine suspension (ILPS) in type 2 diabetes (T2DM) patients; secondarily to compare onset and duration of action of ILPS, glargine (G), and detemir (D) (0.8 U/kg) and evaluate pharmacokinetic (PK) and pharmacodynamic (PD) dose responses of ILPS. RESEARCH DESIGN AND METHODS: In a single-center, double-blind, five-arm crossover study, 34 patients were randomized to a treatment sequence which included a single subcutaneous 0.8 U/kg dose of G and D and three doses of ILPS (0.4 U/kg, 0.8 U/kg, and 1.2 U/kg) and were studied using 24-hour euglycemic glucose clamps. PRIMARY OUTCOME MEASURE: Duration of action was determined as the time to the last measurable glucose infusion rate (tR(last)) during glucose clamps. RESULTS: The duration of insulin action (tR(last)) for ILPS at 0.8 U/kg was >23 hours and was similar to G (p = 0.114) and D (p = 0.570). Post-hoc analysis demonstrated the probability of achieving 24 hours of glucose-lowering activity after a 0.8 U/kg dose: 48% (ILPS), 43% (G), and 26% (D). G(tot) and R(max) were significantly greater for ILPS versus G or D. The median ILPS time-dependent values demonstrated a significantly earlier maximum PD response (tR(max) and early 50% tR(max)) versus either G or D. ILPS demonstrated dose-dependent increases in PK and PD measures across the dose range. CONCLUSIONS: Following a single 0.8 U/kg dose in T2DM patients, ILPS, G, and D demonstrated similar durations of glucose-lowering activity and ILPS demonstrated significantly greater glucose-lowering activity (R(max) and G(tot)) and earlier maximum PD response. These results potentially support once-daily dosing of ILPS in T2DM. LIMITATIONS: The observed number of 24-hour censored observations was higher than expected and the wash-out period for basal insulin treated patients may have been too short to definitively rule out a carry-over effect; however, such an effect, if present, would potentially only affect onset of action and not the primary outcome measure.