Postprandial triglyceride reduction following acute treatment of a selective 5-hydroxytryptamine-2c agonist and characterization using a semi-physiological model

Abstract

Aim: To investigate the tolerability, pharmacokinetics (PK) and postprandial triglyceride (TG) response of single, escalating oral doses of a selective 5-hydroxytryptamine-2c (5-HT_2c ) agonist in subjects with overweight/obesity and apply mechanistic population pharmacokinetic-pharmacodynamic modelling to identify a plausible drug mechanism of action.

Materials and methods: This phase 1, single-centre, double-blind, randomized, placebo-controlled, four-period, two-alternating cohorts study evaluated single escalating oral doses ranging from 5 to 130 mg of LY2140112 (LY) in subjects with overweight/obesity (body mass index: 27-39 kg/m² ). Postprandial TG response (total TG, chylomicrons and very low-density lipoprotein particles [VLDL]-V6) following a high-fat meal were assessed for 11 h postmeal for each dose level. The PK profile was assessed for 96 h postdose. Drug exposure and TG concentrations in chylomicrons and VLDL-V6 were used to characterize the drug mechanism of action using non-linear mixed-effect modelling.

Results: Seventeen subjects entered the study and 16 subjects received at least one dose of LY. LY2140112 was generally well tolerated up to 75 mg. The PK of LY were described by a two-compartment model with first-order elimination. The 100 and 130 mg dose levels of LY significantly reduced the postprandial TG of VLDL-V6 by approximately 50%, while total TG and chylomicrons were not significantly different from placebo. The application of a published lipokinetic model successfully described the postprandial TG response in this study and indicated that LY reduced the conversion of TGs from chylomicron to VLDL-V6.

Conclusions: LY significantly reduced the postprandial TG of VLDL-V6 following a single dose, when food consumption was controlled. The data indicate that a selective 5-HT_2c agonist alters lipid metabolism, beyond the reported reduction in satiety. The application of a semi-physiological lipokinetic model enabled identification of a plausible drug mechanism of action of LY.

Keywords: antiobesity drug; dose-response relationship; drug development; drug mechanism; phase I-II study.