Leveraging a Clinical Phase Ib Proof-of-Concept Study for the GPR40 Agonist MK-8666 in Patients With Type 2 Diabetes for Model-Informed Phase II Dose Selection.

GPR40 mediates free fatty acid-induced insulin secretion in beta cells. We investigated the safety, pharmacokinetics, and glucose response of MK-8666, a partial GPR40 agonist, after once-daily multiple dosing in type 2 diabetes patients. This double-blind, multisite, parallel-group study randomized 63 patients (placebo, n = 18; 50 mg, n = 9; 150 mg, n = 18; 500 mg, n = 18) for 14-day treatment. The results showed no serious adverse effects or treatment-related hypoglycemia. One patient (150-mg group) showed mild-to-moderate transaminitis at the end of dosing. Median MK-8666 Tmax was 2.0-2.5 h and mean apparent terminal half-life was 22-32 h. On Day 15, MK-8666 reduced fasting plasma glucose by 54.1 mg/dL (500 mg), 36.0 mg/dL (150 mg), and 30.8 mg/dL (50 mg) more than placebo, consistent with translational pharmacokinetic/pharmacodynamic model predictions. Maximal efficacy for longer-term assessment is projected at 500 mg based on exposure-response analysis. In conclusion, MK-8666 was generally well tolerated with robust glucose-lowering efficacy.

A randomized, placebo-controlled study of the effects of telcagepant on exercise time in patients with stable angina.

Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being evaluated for acute migraine treatment. CGRP is a potent vasodilator that is elevated after myocardial infarction, and it delays ischemia during treadmill exercise. We tested the hypothesis that CGRP receptor antagonism does not reduce treadmill exercise time (TET). The effects of supratherapeutic doses of telcagepant on TET were assessed in a double-blind, randomized, placebo-controlled, two-period, crossover study in patients with stable angina and reproducible exercise-induced angina. Patients received telcagepant (600 mg, n = 46; and 900 mg, n = 14) or placebo and performed treadmill exercise at T(max) (2.5 h after the dose). The hypothesis that telcagepant does not reduce TET was supported if the lower bound of the two-sided 90% confidence interval (CI) for the mean treatment difference (telcagepant-placebo) in TET was more than -60 s. There were no significant between-treatment differences in TET (mean treatment difference: -6.90 (90% CI: -17.66, 3.86) seconds), maximum exercise heart rate, or time to 1-mm ST-segment depression using pooled data or with stratification for dose.

Cholecalciferol 25-hydroxylation is similar in liver microsomes from male and female rats when cholecalciferol concentration is low.

We compared cholecalciferol 25-hydroxylation in liver microsomes of male and female rats. The rate of production of 25-hydroxycholecalciferol was similar in liver microsomes from female rats and those from male rats when cholecalciferol concentration ranged from 50 to 200 nmol/L. The liver cytosolic fraction stimulated the 25-hydroxylase activity of the microsomes up to 100% in both male and female rats at 44 nmol/L cholecalciferol. Cytosol metabolized cholecalciferol to a currently unidentified metabolite. At 300 nmol/L cholecalciferol, synthesis of the cytosolic metabolite was 100% greater than at 100 nmol/L and coincided with 32% lower synthesis of 25-hydroxycholecalciferol. These results suggest similar 25-hydroxy-lase activity in liver microsomes from male and female rats and similar ability of liver cytosol from these rats to stimulate 25-hydroxylation at low nanomolar concentrations of cholecalciferol, whereas inhibitory effects of cytosol at higher concentrations of cholecalciferol were shown.

Identification of 8 alpha,25-dihydroxy-9,10-seco-4,6,10(19)-cholestatrien-3-one as a product of metabolism of 25-hydroxycholecalciferol by liver microsomes.

The ability of liver microsomes, sites of synthesis of 25-hydroxycholecalciferol, to further metabolize 25-hydroxycholecalciferol has been assessed. When liver microsomes were incubated with 25-hydroxycholecalciferol in the presence of cytosol, a metabolite was isolated that comigrated with 8 alpha,25-dihydroxy-9,10-seco-4,6,10(19)-cholestatrien-3- one in three different chromatographic systems. The ultraviolet spectrum (220-350 nm) and mass spectrum of the purified metabolite were identical to that of synthetic 8 alpha,25-dihydroxy-9,10-seco-4,6,10(19)-cholestatrien-3-one. This study indicates that liver microsomes convert 25-hydroxycholecalciferol to 8 alpha,25-dihydroxy-9,10-seco-4,6,10(19)-cholestatrien-3-one. The significance of this metabolite, which has been shown previously by others to be produced by alveolar macrophages, has yet to be determined.