In this study in patients with type 2 diabetes, near maximal glucose-lowering efficacy of sitagliptin after single oral doses was associated with inhibition of plasma DPP-4 activity of 80% or greater, corresponding to a plasma sitagliptin concentration of 100 nm or greater, and an augmentation of active GLP-1 and GIP levels of 2-fold or higher after an OGTT.

Cannabinoid 1 receptor (CB1R) inverse agonists are emerging as a potential obesity therapy. However, the physiological mechanisms by which these agents modulate human energy balance are incompletely elucidated. Here, we describe a comprehensive clinical research study of taranabant, a structurally novel acyclic CB1R inverse agonist. Positron emission tomography imaging using the selective CB1R tracer [(18)F]MK-9470 confirmed central nervous system receptor occupancy levels ( approximately 10%-40%) associated with energy balance/weight-loss effects in animals. In a 12-week weight-loss study, taranabant induced statistically significant weight loss compared to placebo in obese subjects over the entire range of evaluated doses (0.5, 2, 4, and 6 mg once per day) (p < 0.001). Taranabant treatment was associated with dose-related increased incidence of clinical adverse events, including mild to moderate gastrointestinal and psychiatric effects. Mechanism-of-action studies suggest that engagement of the CB1R by taranabant leads to weight loss by reducing food intake and increasing energy expenditure and fat oxidation.

Doravirine is generally well tolerated in single doses up to 1,200 mg and multiple doses up to 750 mg once daily for up to 10 days, with a pharmacokinetic profile supportive of once-daily dosing. Doravirine at steady state slightly reduced the exposure of coadministered midazolam, to a clinically unimportant extent.

AIMSTo evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of odanacatib (ODN), a cathepsin K inhibitor, in humans. METHODSTwo double-blind, randomized, placebo-controlled, single oral dose studies were performed with ODN (2-600 mg) in 44 healthy volunteers (36 men and eight postmenopausal women). RESULTSAdverse experiences (AEs) with single doses of ODN were transient and mild to moderate, with the exception of one severe AE of gastroenteritis. Headache was the most frequent AE. After absorption of ODN (initial peak concentrations 4-6 h postdose), plasma concentrations exhibited a monophasic decline, with an apparent terminal half-life of 40-80 h. The area under the curve0-24 hours (AUC0-24 h), concentration at 24 hours (C24 h) and maximum concentration (Cmax,overal) increased in a less than dose-proportional manner from 2 to 600 mg. Administration of ODN with a high-fat meal led to~100% increases in AUC0-24 h, Cmax,day1, Cmax,overall and C24 h relative to the fasted state, while administration with a low-fat meal led to a~30% increase in those parameters. Reduction of biomarkers of bone resorption, the C-and N-telopeptides of cross-links of type I collagen, (CTx and NTx, respectively), was noted at 24 h for doses Ն5 mg and at 168 h postdose for Ն10 mg. In postmenopausal women administered 50 mg ODN, reductions in serum CTx of -66% and urine NTx/creatinine (uNTx/Cr) of -51% relative to placebo were observed at 24 h. At 168 h, reductions in serum CTx (-70%) and uNTx/Cr (-78%) were observed relative to baseline. Pharmacokinetic/pharmacodynamic modeling characterized the ODN concentration/ uNTx/Cr relation, with a modeled EC50 value of 43.8 nM and~80% maximal reduction. CONCLUSIONSOdanacatib was well tolerated and has a pharmacokinetic and pharmacodynamic profile suitable for once weekly dosing.

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