A-B Apical to basal ADME Administration, Distribution, Metabolism and Elimination AUC Area under the plasma concentration-time curve AUC 0-last Area under the plasma concentration-time curve from time zero to last measurable concentration AUC 0-∞ Area under the plasma concentration-time curve from time zero to infinity This article has not been copyedited and formatted. The final version may differ from this version.
Summary
AMPK is an energy sensor modulating metabolism, inflammation, and a target for metabolic disorders. Metabolic dysfunction results in lower AMPK activity. PXL770 is a direct AMPK activator, inhibiting
de novo
lipogenesis (DNL) and producing efficacy in preclinical models. We aimed to assess pharmacokinetics, safety, and pharmacodynamics of PXL770 in humans with metabolic syndrome-associated fatty liver disease. In a randomized, double-blind four-week trial, 12 overweight/obese patients with non-alcoholic fatty liver disease (NAFLD) and insulin resistance received PXL770 500 mg QD; 4 subjects received matching placebo. Endpoints included pharmacokinetics, hepatic fractional DNL, oral glucose tolerance testing, additional pharmacodynamic parameters, and safety. PK parameters show adequate plasma exposure in NAFLD patients for daily oral dosing. PXL770 decreases DNL—both peak and AUC are reduced versus baseline—and improves glycemic parameters and indices of insulin sensitivity versus baseline. Assessment of specific lipids reveals decrease in diacyglycerols/triacylglycerols. Safety/tolerability are similar to placebo. These results unveil initial human translation of AMPK activation and support this therapeutic strategy for metabolic disorders.
Background Imeglimin is a first-in-class novel oral antidiabetic marketed in Japan as TWYMEEG ® to treat type 2 diabetes mellitus. Its mode of action is distinct from all other anti-hyperglycemic classes. Objective To assess the pharmacokinetic and safety profile of imeglimin in Caucasian and Japanese healthy individuals. Methods Two randomized placebo-controlled phase 1 clinical studies were conducted in Caucasian subjects after single (250-8000 mg) and multiple (250-2000 mg twice daily) ascending doses and in Japanese subjects after single (500-6000 mg) and multiple (500-2000 mg twice daily) ascending doses. Imeglimin plasma and urine concentrations were measured. Results All imeglimin doses achieved maximal concentration between 1 and 3.5 h in Caucasians, and 1.5 and 3 h in Japanese subjects. The elimination half-lives (t 1/2 ) were dose-independent and means ranged between 9.03 and 20.2 h for Caucasians, and 4.45 and 12 h for Japanese subjects. Dose-normalized area under the plasma concentration-time curve decreased with dose in the 250-8000 mg and in the 500-6000 mg dose range in Caucasians and Japanese, respectively, suggesting a dose-dependent but less than dose-proportional effect in imeglimin exposure. Plasma accumulation was minimal following repeated dosing, and food did not affect the pharmacokinetics in either population. Exposures were generally similar between Caucasian and Japanese subjects with less than 20% difference, although there was a tendency for exposures in Japanese to be slightly higher. Imeglimin had an acceptable safety and tolerability profile, with dose-dependent mild gastrointestinal adverse events. Conclusion Imeglimin was safe and well tolerated in these two phases 1 studies, with pharmacokinetics comparable between the two populations.
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