OBJECTIVEType 2 diabetes pathophysiology is characterized by dysregulated glucagon secretion. LY2409021, a potent, selective small-molecule glucagon receptor antagonist that lowers glucose was evaluated for efficacy and safety in patients with type 2 diabetes. RESEARCH DESIGN AND METHODSThe efficacy (HbA 1c and glucose) and safety (serum aminotransferase) of oncedaily oral administration of LY2409021 was assessed in two double-blind studies. Phase 2a study patients were randomized to 10, 30, or 60 mg of LY2409021 or placebo for 12 weeks. Phase 2b study patients were randomized to 2.5, 10, or 20 mg LY2409021 or placebo for 24 weeks. RESULTSLY2409021 produced reductions in HbA 1c that were significantly different from placebo over both 12 and 24 weeks. After 12 weeks, least squares (LS) mean change from baseline in HbA 1c was -0.83% (10 mg), -0.65% (30 mg), and -0.66% (60 mg) (all P < 0.05) vs. placebo, 0.11%. After 24 weeks, LS mean change from baseline in HbA 1c was -0.45% (2.5 mg), -0.78% (10 mg, P < 0.05), -0.92% (20 mg, P < 0.05), and -0.15% with placebo. Increases in serum aminotransferase, fasting glucagon, and total fasting glucagon-like peptide-1 (GLP-1) were observed; levels returned to baseline after drug washout. Fasting glucose was also lowered with LY2409021 at doses associated with only modest increases in aminotransferases (mean increase in alanine aminotransferase [ALT] £10 units/L). The incidence of hypoglycemia in the LY2409021 groups was not statistically different from placebo. CONCLUSIONSIn patients with type 2 diabetes, glucagon receptor antagonist treatment significantly lowered HbA 1c and glucose levels with good overall tolerability and a low risk for hypoglycemia. Modest, reversible increases in serum aminotransferases were observed.

Blockade of glucagon signalling in patients with type 2 diabetes is well tolerated and results in substantial reduction of fasting and postprandial glucose with minimal hypoglycaemia, but with reversible increases in aminotransferases. Inhibition of glucagon signalling by LY2409021 is a promising potential treatment for patients with type 2 diabetes and should be evaluated in longer clinical trials to better evaluate benefits and risks.

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A sequential pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was used to quantify the effects of a single dose of topiramate (100 or 200 mg) on working memory, attention, and psychomotor speed as measured by the Symbol-Digit Modalities Test (SDMT). Established on data pooled from 3 randomized, crossover studies in healthy subjects (19–55 years of age), using both oral and a novel stable-labeled intravenous (IV) formulation of topiramate, an inhibitory Emax model was found to characterize the topiramate concentration-SDMT score relationship well. At the EC50 of 2.85 μg/mL, this topiramate plasma concentration value was estimated to be associated with a 25.5% reduction of SDMT score relative to baseline. Age was an important determinant of the baseline SDMT score, with an estimated decrease of 1.13% in baseline SDMT score with every year of age. Moreover, this approach enabled the quantification of the practice effect observed with repeated administration of the neuropsychological test over shorter testing intervals than have previously been reported in the literature. The finding of a significant effect following a single dose of topiramate in the range widely used to treat migraine and epilepsy needs to be evaluated in a broader patient population undergoing chronic treatment, as the narrow range of resultant concentrations limits the generalizability of the findings.

Population pharmacokinetics and pharmacodynamics of the leuprolide depot formulation were characterized using an integrated semi-mechanistic model. The developed model adequately describes the leuprolide-testosterone relationship and can potentially be used to facilitate design of clinical studies for new formulations, to aid in the selection of candidate formulations, and for the optimization of doses and dosing schemes.