Cyp2c19 Polymorphisms in Drug Metabolism and Response

Individuals vary widely in their response to drug treatment. After receiving doses of a drug that are recommended based on a population average, some patients could have an insufficient response, whereas others may experience adverse effects. Of the many factors causing variability in drug response across individuals, genetic polymorphism of drug-metabolizing enzymes is deemed to be one of the valuable independent predictors of this variability. CYP2C19 is an important polymorphically expressed enzyme known to catalyze the metabolism of several widely prescribed drugs, including omeprazole, warfarin (R-enantiomer), and citalopram/escitalopram. The impact of CYP2C19 polymorphisms on the pharmacokinetics (PK) of its substrates and corresponding clinical relevance are of great interest. The aim of this thesis is to investigate the influence of CYP2C19 polymorphisms on PK and pharmacodynamics (PD) of clinically important CYP2C19 substrates (e.g., omeprazole, citalopram, and warfarin), and to advance the understanding of their inter-individual variability in drug therapy. We quantified the effect of functional CYP2C19 allele variants, including the gain-offunction allele (CYP2C19*17), on drug exposure and response in order to facilitate personalized dose selection. In Paper I, we studied the disposition of omeprazole and its effect on plasma gastrin levels following single and multiple doses in the three phenotype groups (extensive metabolisers [EMs], intermediate metabolisers [IMs], and poor metabolisers [PMs]) of Smephenytoin hydroxylation. When 20 mg of omeprazole was given orally for 8 days on a once-daily (QD) regimen, the relative AUC ratios in EMs, IMs, and PMs were 1:5.3:13.1. Differences in the plasma gastrin levels (used as a PD marker) were also significant between the three groups and the increase was in an omeprazole-concentration-dependent fashion. Suitability of omeprazole as a probe for CYP2C19 was also explored. The metabolic ratio (MR) of omeprazole was correlated significantly with S/R ratio of mephenytoin. Paper II further studied the use of omeprazole as a probe for CYP2C19 activity in a population of 160 unrelated Swedish subjects. There was a close correlation between MRs of omeprazole and S/R ratios of mephenytoin. A good agreement was also demonstrated between the CYP2C19 phenotypes (both by omeprazole and mephenytoin) and the genotype with respect to CYP2C19*2, indicating that genotype is a valid predictor of CYP2C19 activity. Since omeprazole is a substrate for both CYP2C19 and CYP3A4, the potential advantage also includes using it as a dual-substrate probe. In Paper III, we used omeprazole as a dual substrate probe to assess the potential for PK interactions between carbamazepine (CBZ) and omeprazole and, particularly, the inducibility of CYP3A4 and CYP2C19 by CBZ. Both omeprazole and hydroxyomeprazole decreased by approximately 40% in mean AUC after coadministration of omeprazole with CBZ, while the sulphone metabolite increased by 44%. None of the AUC changes were statistically significant due to the large variation and small sample size. A significant decrease in the AUC ratio between hydroxyomeprazole and sulphone metabolite was observed, suggesting induction was more pronounced for CYP3A4 than for CYP2C19. The potential contribution of the CYP2C19 genotypes on R-warfarin clearance with special focus on the gain-of-function allele (CYP2C19*17) was the primary objective for Paper IV. Compared to CYP2C19*2 carriers, the mean R-warfarin clearance increased by 32% in CYP2C19*17 carriers, 26% in the CYP2C19*2/*17 genotype, and 11% in CYP2C19*1/*1 genotype. CYP2C19 genotypes also contributed to the variability of INR/daily dose where VKORC1 (Vitamin K epoxide reductase subcomplex 1) and CYP2C9 genotypes are the major determinants in warfarin treatment. About 52% of variance can be explained by the combinations of VKORC1, CYP2C9, CYP2C19, age, gender, and bodyweight, of which CYP2C19 genotypes accounted for 7%. Paper V pooled data from16 published studies to quantify the effect of functional CYP2C19 allele variants on citalopram/escitalopram exposure by means of meta-analysis. Compared to subjects with EM/EM (*1/*1) genotype, the exposure to (es)citalopram increased by 95% in the PM/PM (*2/*2, *2/*3, or *3/*3), 30% in the EM/PM (*1/*2 or *1/*3), and 25% in the UM (ultrarapid metaboliser)/PM (*17/*2 or *17/*3) groups. In contrast, the exposure to (es)citalopram decreased by 36% in the UM/UM (*17/*17) and by 14% in the UM/EM (*17/*1) groups. All functional CYP2C19 genotypes showed significant effects on citalopram/escitalopram exposure compared to the CYP2C19*1/*1 genotype. In conclusion, there are significant effects of CYP2C19 polymorphisms on PK and PD of drugs that are metabolized by the CYP2C19 enzyme. The results of this thesis demonstrate that CYP2C19 genotype is an important independent predictor of the exposure to omeprazole, R-warfarin, and citalopram/escitalopram. Increased knowledge and understanding of inter-individual variability, genotype-phenotype correlation, and the impact of CYP2C19 polymorphisms on clinical practice are helpful in optimizing personalized drug therapy. LIST OF SCIENTIFIC PAPERS I. Chang M, Tybring G, Dahl ML, Götharson E, Sagar M, Seensalu R, Bertilsson L. Interphenotype differences in disposition and effect on gastrin levels of omeprazole suitability of omeprazole as a probe for CYP2C19. Br J Clin Pharmacol. 1995; 39(5): 511-8. II. Chang M, Dahl ML, Tybring G, Götharson E, Bertilsson L. Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians: comparison with smephenytoin hydroxylation phenotype and CYP2C19 genotype. Pharmacogenetics 1995; 5: 358-63. III. Bertilsson L Tybring G, Widen J, Chang M, Tomson T. Carbamazepine treatment induces the CYP3A4 catalyzed sulphoxidation of omeprazole, but has no or less effect on hydroxylation via CYP2C19. Br J Clin Pharmacol. 1997; 44(2): 186-9. IV. Chang M, Söderberg MM, Scordo MG, Tybring G, Dahl ML. CYP2C19 genotypes including CYP2C19*17 affect R-warfarin plasma clearance and dose-INR relationship in patients treated with warfarin. [Submitted to Eur J Clin Pharmacol] V. Chang M, Tybring G, Dahl ML, Lindh JD. Impact of CYP2C19 polymorphisms on citalopram/escitalopram exposure: a systematic review and meta-analysis. Clin Pharmacokinet 2014; 53(9): 801-11 CONTENTS