Evaluation of drug interactions of GSK1292263 (a GPR119 agonist) with statins: from in vitro data to clinical study design. (June 2013)

• Record Type: Journal Article
• Authors: Polli, Joseph W.; Hussey, Elizabeth; Bush, Mark; Generaux, Grant; Smith, Glenn; Collins, David; McMullen, Susan; Turner, Nancy; Nunez, Derek J.
• Is Part Of: Xenobiotica. Volume 43:Number 6(2013:Jun.)
• Page Start: 498
• Page End: 508
• Publication Date: 2013-06
• Subjects: Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.3109/00498254.2012.739719
• Languages: English
• ISSNs: 0049-8254

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <p>1. This work investigated the drug interaction potential of GSK1292263, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin.</p> <p>2.<italic> In vitro</italic> 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).</p> <p>3. <italic>In vitro</italic>, GSK1292263 demonstrated little/weak inhibition (IC<sub>50</sub> 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.</p> <p>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)].</p> <p>5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the <italic>in vivo</italic> inhibition of transporters and enzymes by GSK1292263.</p> </abstract>