Abstract
1. This work investigated the drug interaction potential of GSK1292263, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin. 2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by GSK1292263, and a clinical drug interaction study investigated the effect of GSK1292263 (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose). 3. In vitro, GSK1292263 demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (CYP1A2, 2C9, 2C19, 2D6, 3A4), Pgp, OATP1B3, or OCT2. However, GSK1292263 inhibited BCRP and OATP1B1, which are transporters involved in statin disposition. 4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with GSK1292263, which is consistent with an inhibitory effect on intestinal BCRP and CYP3A4. In contrast, GSK1292263 did not inhibit OATP1B1 based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)]. 5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by GSK1292263.
Publication types
-
Clinical Trial
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adolescent
-
Adult
-
Aged
-
Animals
-
Atorvastatin
-
Cytochrome P-450 CYP3A / metabolism
-
Cytochrome P-450 CYP3A Inhibitors
-
Demography
-
Dogs
-
Dose-Response Relationship, Drug
-
Drug Interactions
-
Female
-
Fluorobenzenes / adverse effects
-
Fluorobenzenes / blood
-
Fluorobenzenes / pharmacokinetics
-
Fluorobenzenes / pharmacology
-
Heptanoic Acids / adverse effects
-
Heptanoic Acids / blood
-
Heptanoic Acids / pharmacokinetics
-
Heptanoic Acids / pharmacology
-
Humans
-
Hydroxymethylglutaryl-CoA Reductase Inhibitors / adverse effects
-
Hydroxymethylglutaryl-CoA Reductase Inhibitors / blood
-
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacokinetics*
-
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
-
Madin Darby Canine Kidney Cells
-
Male
-
Mesylates / adverse effects
-
Mesylates / blood
-
Mesylates / pharmacokinetics*
-
Mesylates / pharmacology
-
Middle Aged
-
Oxadiazoles / adverse effects
-
Oxadiazoles / blood
-
Oxadiazoles / pharmacokinetics*
-
Oxadiazoles / pharmacology
-
Piperidines / adverse effects
-
Piperidines / blood
-
Piperidines / pharmacokinetics*
-
Piperidines / pharmacology
-
Pyrimidines / adverse effects
-
Pyrimidines / blood
-
Pyrimidines / pharmacokinetics
-
Pyrimidines / pharmacology
-
Pyrroles / adverse effects
-
Pyrroles / blood
-
Pyrroles / pharmacokinetics
-
Pyrroles / pharmacology
-
Reference Standards
-
Rosuvastatin Calcium
-
Simvastatin / adverse effects
-
Simvastatin / analogs & derivatives
-
Simvastatin / blood
-
Simvastatin / pharmacokinetics
-
Simvastatin / pharmacology
-
Sulfonamides / adverse effects
-
Sulfonamides / blood
-
Sulfonamides / pharmacokinetics
-
Sulfonamides / pharmacology
-
Troleandomycin / adverse effects
-
Troleandomycin / pharmacokinetics
-
Troleandomycin / pharmacology
-
Young Adult
Substances
-
(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methyl methanesulfonate
-
Cytochrome P-450 CYP3A Inhibitors
-
Fluorobenzenes
-
Heptanoic Acids
-
Hydroxymethylglutaryl-CoA Reductase Inhibitors
-
Mesylates
-
Oxadiazoles
-
Piperidines
-
Pyrimidines
-
Pyrroles
-
Sulfonamides
-
Rosuvastatin Calcium
-
simvastatin acid
-
Atorvastatin
-
Simvastatin
-
Troleandomycin
-
Cytochrome P-450 CYP3A
-
CYP3A4 protein, human