title: Evaluation of drug interactions of GSK1292263 (a GPR119 agonist) with statins: from in vitro data to clinical study design.
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.
authors.affiliation: Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Inc., Research Triangle Park, NC 27709-3398, USA. joseph.w.polli@gsk.com
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Polli
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hussey
authors.forename: Mark
authors.initials: M
authors.lastname: Bush
authors.forename: Grant
authors.initials: G
authors.lastname: Generaux
authors.forename: Glenn
authors.initials: G
authors.lastname: Smith
authors.forename: David
authors.initials: D
authors.lastname: Collins
authors.forename: Susan
authors.initials: S
authors.lastname: McMullen
authors.forename: Nancy
authors.initials: N
authors.lastname: Turner
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Nunez
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000069059:Atorvastatin; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D003710:Demography; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005464:Fluorobenzenes / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D006538:Heptanoic Acids / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008698:Mesylates / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D008875:Middle Aged; D010069:Oxadiazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D010880:Piperidines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011743:Pyrimidines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D011758:Pyrroles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D012015:Reference Standards; D000068718:Rosuvastatin Calcium; D019821:Simvastatin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D013449:Sulfonamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D014217:Troleandomycin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: C587902:(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methyl methanesulfonate; D065692:Cytochrome P-450 CYP3A Inhibitors; D005464:Fluorobenzenes; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008698:Mesylates; D010069:Oxadiazoles; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; C063287:simvastatin acid; D000069059:Atorvastatin; D019821:Simvastatin; D014217:Troleandomycin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human