Elucidation of the biochemical basis for a clinical drug–drug interaction between atorvastatin and 5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid (CP-778 875), a subtype selective agonist of the peroxisome proliferator-activated receptor alpha

Author： Kalgutkar Amit S. Chen Danny Varma Manthena V. Feng Bo Terra Steven G. Scialis Renato J. Rotter Charles J. Frederick Kosea S. West Mark A. Goosen Theunis C. Gosset James R. Walsky Robert L. Francone Omar L.

Publisher： Informa Healthcare

ISSN： 1366-5928

Source： Xenobiotica, Vol.43, Iss.11, 2013-11, pp. : 963-972

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Abstract

Abstract1. 5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid (CP-778 875), an agonist of the peroxisome proliferator-activated receptor alpha, has been evaluated in the clinic to treat dyslipidemia and type 2 diabetes mellitus. Herein, we investigate the effect of CP-778 875 on the pharmacokinetics of atorvastatin acid and its metabolites in humans.2. The study incorporated a fixed-sequence design conducted in two groups. Group A was designed to estimate the effects of multiple doses of CP-778 875 on the single dose pharmacokinetics of atorvastatin. Subjects in group A (N = 26) received atorvastatin (40 mg) on days 1 and 9 and CP-778 875 (1.0 mg QD) on days 5–12. Group B was designed to examine the effects of multiple doses of atorvastatin on the single dose pharmacokinetics of CP-778 875. Subjects in group B (N = 29) received CP-778 875 (0.3 mg) on days 1 and 9 and atorvastatin (40 mg QD) on days 5–12.3. Mean maximum serum concentration (C_max) and area under the curve of atorvastatin were increased by 45% and 20%, respectively, upon co-administration with CP-778 875. Statistically significant increases in the systemic exposure of ortho- and para-hydroxyatorvastatin were also observed upon concomitant dosing with CP-778 875. CP-778 875 pharmacokinetics, however, were not impacted upon concomitant dosing with atorvastatin.4. Inhibition of organic anion transporting polypeptide 1B1 by CP-778 875 (IC₅₀ = 2.14 ±0.40 μM) could be the dominant cause of the pharmacokinetic interaction as CP-778 875 did not exhibit significant inhibition of cytochrome P450 3A4/3A5, multidrug resistant protein 1 or breast cancer resistant protein, which are also involved in the hepatobiliary disposition of atorvastatin.