Charles Meyers

Pharmacokinetics, pharmacodynamics, safety, and tolerability of pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor in overweight or obese, but otherwise healthy human subjects

Pradigastat is a potent and selective inhibitor of diacylglycerol acyltransferase 1, an enzyme highly expressed in the small intestine that plays a key role in postprandial triglyceride synthesis. This first‐in‐human study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of pradigastat administered at single and multiple doses in overweight or obese healthy subjects. In single‐dose cohorts (n = 72), subjects were randomized sequentially to receive single doses of pradigastat (1, 3, 10, 30, 100, or 300 mg) or placebo under fasted condition and prior to breakfast. In multiple‐dose cohorts (n = 106), subjects were randomized to receive pradigastat (1, 5, 10, or 25 mg) or placebo prior to breakfast for 14 days. Following a single oral dosing, pradigastat was absorbed slowly, with a median tmax of ∼10 hours and eliminated slowly with a long half‐life. With multiple oral doses, a 10‐ to17‐fold higher systemic exposure was observed. Pradigastat treatment (single and multiple doses) led to dose‐dependent suppression of postprandial triglyceride excursions over 9 hours following a high‐fat meal test. In addition, pradigastat suppressed postprandial glucose and insulin and increased plasma glucagon‐like peptide‐1 levels. Overall, pradigastat was safe and tolerated at single and multiple doses in healthy subjects.

Medical resource use and costs associated with chylomicronemia.

Abstract Background: The prevalence of severe hypertriglyceridemia (TG > 1000 mg/dl) is estimated at 150–400 per 100,000 individuals in North America. Severe hypertriglyceridemia in the fasting state is associated with increased acute pancreatitis risk and is a sign of chylomicronemia which reflects the accumulation in the bloodstream of chylomicrons, the large lipoprotein particles produced in the gut after a meal. Objective: To assess medical resource use and costs associated with chylomicronemia. Methods: Patients with chylomicronemia of different causes (≥2 diagnoses with ICD-9 code 272.3) were identified from a large US claims database (years 2000 to 2009) and matched 1:1 to controls free of chylomicronemia based on age, gender, demographics, comorbidities, and use of lipid lowering drugs. During a 1-year study period, medical resource use and costs associated with chylomicronemia or acute pancreatitis were compared between matched cases and controls. Results: Among 6472 matched pairs, annual per-patient medical costs, calculated independently of the occurrence of acute pancreatitis, were significantly greater by

Bimagrumab improves body composition and insulin sensitivity in insulin‐resistant individuals

808 for chylomicronemia cases vs controls (

Discovery of an Orally Bioavailable Benzimidazole Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor That Suppresses Body Weight Gain in Diet-Induced Obese Dogs and Postprandial Triglycerides in Humans

8029 vs

Type Of Preexisting Lipid Therapy Predicts LDL-C Response to Ezetimibe

7220, p < 0.01), half of which was attributable to chylomicronemia-related services (p < 0.01). Chylomicronemia cases with a history of acute pancreatitis (n = 46) had greater rates of inpatient visits (p < 0.05) and greater average costs for subsequent acute pancreatitis or abdominal pain (p < 0.01) as well as greater total medical costs (

Pradigastat disposition in humans: in vivo and in vitro investigations

33,587 vs

Effect of Pradigastat, a Diacylglycerol Acyltransferase 1 Inhibitor, on the QTcF Interval in Humans

4402, p < 0.01) vs matched controls. The average episode of acute pancreatitis (n = 104 episodes) generated medical costs of

Effect of pradigastat a diacylglycerol acyltransferase 1 inhibitor on the pharmacokinetics of a combination oral contraceptive in healthy female subjects.

31,820, almost entirely due to inpatient stays. Limitations: Triglyceride levels were not available to characterize disease severity. Conclusions: Patients with chylomicronemia, and especially those with a history of acute pancreatitis, incurred significantly greater total medical costs compared with individuals without chylomicronemia but with an otherwise comparable health profile.

Evaluation of food effect on the oral bioavailability of pradigastat, a diacylglycerol acyltransferase 1 inhibitor

To test the hypothesis that an improving body composition in insulin‐resistant individuals could enhance insulin sensitivity.

Anticipating the evolution of clinical cholesterol guidelines: implications of recent statin intervention trials.

Modification of a gut restricted class of benzimidazole DGAT1 inhibitor 1 led to 9 with good oral bioavailability. The key structural changes to 1 include bioisosteric replacement of the amide with oxadiazole and α,α-dimethylation of the carboxylic acid, improving DGAT1 potency and gut permeability. Since DGAT1 is expressed in the small intestine, both 1 and 9 can suppress postprandial triglycerides during acute oral lipid challenges in rats and dogs. Interestingly, only 9 was found to be effective in suppressing body weight gain relative to control in a diet-induced obese dog model, suggesting the importance of systemic inhibition of DGAT1 for body weight control. 9 has advanced to clinical investigation and successfully suppressed postprandial triglycerides during an acute meal challenge in humans.