Impact of the CYP2C8 *3 polymorphism on the drug–drug interaction between gemfibrozil and pioglitazone. (14th December 2012)

• Record Type: Journal Article
• Authors: Aquilante, Christina L.; Kosmiski, Lisa A.; Bourne, David W. A.; Bushman, Lane R.; Daily, Elizabeth B.; Hammond, Kyle P.; Hopley, Charles W.; Kadam, Rajendra S.; Kanack, Alexander T.; Kompella, Uday B.; Le, Merry; Predhomme, Julie A.; Rower, Joseph E.; Sidhom, Maha S.
• Is Part Of: British journal of clinical pharmacology. Volume 75:Number 1(2013:Jan.)
• Page Start: 217
• Page End: 226
• Publication Date: 2012-12-14
• Subjects: Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/j.1365-2125.2012.04343.x
• Languages: English
• ISSNs: 0306-5251

Abstract

<abstract abstract-type="main" xml:lang="en"> <title> <x xml:space="preserve">Abstract</x> </title> <p> <bold>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT</bold> </p> <p> A drug–drug interaction exists between gemfibrozil (CYP2C8 inhibitor) and pioglitazone (CYP2C8 substrate), whereby gemfibrozil increases pioglitazone plasma exposure. Substantial interindividual variability exists in the pharmacokinetic magnitude of this drug–drug interaction.</p> <p> <italic>CYP2C8</italic>*<italic>3</italic> is associated with increased metabolism and decreased plasma exposure of pioglitazone.</p> <p> Polymorphisms in CYP metabolizing enzyme genes, namely <italic>CYP2C19</italic> and <italic>CYP2D6</italic>, have been shown to influence the magnitude of inhibitory drug–drug interactions. However, the extent to which <italic>CYP2C8</italic> polymorphisms (e.g. <italic>CYP2C8</italic>*<italic>3</italic>) affect the interaction between gemfibrozil and pioglitazone is not known.</p> <p> <bold>WHAT THIS STUDY ADDS</bold> </p> <p> The <italic>CYP2C8</italic>*<italic>3</italic> allele influences pharmacokinetic variability in the drug–drug interaction between gemfibrozil and pioglitazone. <italic>CYP2C8</italic>*<italic>3</italic> carriers experienced a larger relative increase in pioglitazone plasma exposure following gemfibrozil administration than wild‐type homozygotes.</p> <p> Consideration should be given to the contribution of polymorphic <italic>CYP2C8</italic> alleles to interindividual variability in the pharmacokinetic magnitude of CYP2C8‐mediated drug–drug interactions.</p> <p> <bold>AIM</bold> The objective of this study was to determine the extent to which the <italic>CYP2C8</italic>*<italic>3</italic> allele influences pharmacokinetic variability in the drug–drug interaction between gemfibrozil (CYP2C8 inhibitor) and pioglitazone (CYP2C8 substrate).</p> <p> <bold>METHODS</bold> In this randomized, two phase crossover study, 30 healthy Caucasian subjects were enrolled based on <italic>CYP2C8</italic>*<italic>3</italic> genotype (<italic>n</italic>= 15, <italic>CYP2C8</italic>*<italic>1</italic>/*<italic>1</italic>; <italic>n</italic>= 15, <italic>CYP2C8</italic>*<italic>3</italic> carriers). Subjects received a single 15 mg dose of pioglitazone or gemfibrozil 600 mg every 12 h for 4 days with a single 15 mg dose of pioglitazone administered on the morning of day 3. A 48 h pharmacokinetic study followed each pioglitazone dose and the study phases were separated by a 14 day washout period.</p> <p> <bold>RESULTS</bold> Gemfibrozil significantly increased mean pioglitazone AUC(0, ∞) by 4.3‐fold (<italic>P</italic> < 0.001) and there was interindividual variability in the magnitude of this interaction (range, 1.8‐ to 12.1‐fold). When pioglitazone was administered alone, the mean AUC(0, ∞) was 29.7% lower (<italic>P</italic>= 0.01) in <italic>CYP2C8</italic>*<italic>3</italic> carriers compared with <italic>CYP2C8</italic>*<italic>1</italic> homozygotes. The relative change in pioglitazone plasma exposure following gemfibrozil administration was significantly influenced by <italic>CYP2C8</italic> genotype. Specifically, <italic>CYP2C8</italic>*<italic>3</italic> carriers had a 5.2‐fold mean increase in pioglitazone AUC(0, ∞) compared with a 3.3‐fold mean increase in <italic>CYP2C8</italic>*<italic>1</italic> homozygotes (<italic>P</italic>= 0.02).</p> <p> <bold>CONCLUSION</bold> <italic>CYP2C8</italic>*<italic>3</italic> is associated with decreased pioglitazone plasma exposure <italic>in vivo</italic> and significantly influences the pharmacokinetic magnitude of the gemfibrozil–pioglitazone drug‐drug interaction. Additional studies are needed to evaluate the impact of <italic>CYP2C8</italic> genetics on the pharmacokinetics of other CYP2C8‐mediated drug–drug interactions.</p> </abstract>