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

• AIMS: To investigate the tolerability, pharmacokinetics (PK), and postprandial triglyceride (TG) response of single, escalating oral doses of a selective 5-hydroxytryptamine-2c (5-HT2c) agonist in subjects with overweight/obesity and apply mechanistic population pharmacokinetic-pharmacodynamic modeling to identify a plausible drug mechanism of action.METHODS: This phase 1, single-center, double‑blind, randomized, placebo-controlled, 4 period, 2-alternating cohort, evaluated single escalating oral doses ranging 5-130 mg of LY2140112 (LY) in subjects with overweight/obesity (BMI: 27-39 kg/m2). Postprandial TG response (total TG, chylomicrons, and VLDL-V6) following a high fat meal were assessed for 11-hours post-meal for each dose level. The PK profile was assessed for 96 hours post-dose.  Drug exposure and TG concentrations in chylomicrons and VLDL-V6 were used to characterize the drug mechanism of action using nonlinear mixed-effect modeling.RESULT: Seventeen subjects entered the study and 16 subjects received at least one dose of LY.  LY2140112 was generally well tolerated up to 75mg. The PK of LY were described by a two-compartment model with first-order elimination. The 100 mg and 130 mg dose levels of LY significantly reduced the postprandial TG of VLDL-V6 by ~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 in the postprandial TG of VLDL-V6 following a single dose, when food consumption was controlled. The data indicates that a selective 5-HT2c agonist alters lipid metabolism, beyond the reported reduction in satiety. The application of a lipokinetic model enabled identification of a plausible drug mechanism of action of LY.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)

Nyckelord

Obesity

lipokinetic model

5-HT2c Agonist

Triglycerides

Publikations- och innehållstyp

ref (ämneskategori)

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