CYP2C19 Intermediate Metabolizers Research Articles

PS 05-55 IMPACT OF CYP2C19 VARIANTS ON DRUG EFFICACY OF CLOPIDOGREL AND 1-YEAR CLINICAL OUTCOMES IN CORONARY HEART PATIENTS UNDERGOING PCI

Objective: To investigate the following: 1) the association between CYP2C19 variants involved in clopidogrel-mediated platelet effects; 2) the association between CYP2C19 variants involved in clopidogrel-mediated inflammatory, endothelial effects; 3) CYP2C19 variants involved in the risk of major adverse cardiovascular events(MACE). Design and Method: We detected the residual platelet aggregation rate (RPA), maximal aggregation rate (MAR) and the plasma levels of sCD40L, sP-selectin, MMP-9, sVCAM-1 and sE-selectin after 24 hours of PCI in 559 patients undergoing PCI treated with clopidogrel, and followed up for one year for MACE. Results: The levels of RPA, MAR, sE-selectin, sCD40l, sP-selectin, MMP-9 and sVCAM-1 in CYP2C19 intermediate metabolizers (IM), poor metabolizers (PM) or both together patients were higher than those in extensive metabolizers (EM) patients. During one-year follow-up, there were 69 cases (13.3%) suffering MACE. The risk of MACE in CYP2C19 IM + PM patients is 2.664 times higher than that in CYP2C19 EM patients (OR = 2.664(1.397–5.193), P = 0.004). Our results suggest that CYP2C19 metabolizers modulate clopidogrel drug efficacy in coronary heart patients undergoing PCI and further impact on the risk of MACE. Conclusions: Thus it is benefit for coronary heart patients undergoing PCI treated with clopidogrel if carried out individualized treatment according to CYP2C19 metabolizers.

Interaction between sulthiame and clobazam: Sulthiame inhibits the metabolism of clobazam, possibly via an action on CYP2C19

The aim of this study was to investigate the effect of sulthiame (STM) on the pharmacokinetics of clobazam (CLB) by determining the concentration to dose (CD) ratio (serum level (ng/ml) divided by dose (mg/kg)) of CLB and that of N-desmethyl-clobazam (DMCLB).We evaluated five patients (an adult and four children) whose serum CLB and DMCLB concentrations were monitored after the addition or discontinuation of STM. Four of the five patients were CYP2C19 intermediate metabolizers, and one patient was an extensive metabolizer. When the patients were taking STM (100–275mg/day), the mean CD ratio of DMCLB increased by 82.6 to 248.5%, which was higher than when they were not using STM. The increase was dose-dependent. In contrast, the CD ratio of CLB remained stable after addition or discontinuation of STM.These data suggest that STM has the potential to inhibit CYP2C19 enzyme activity. During combination therapy with STM and CLB in patients with CYP2C19 intermediate or extensive metabolizer phenotypes, monitoring of DMCLB concentrations may be helpful in ascertaining CLB-related adverse effects.

CYP2C19 Poor Metabolizer Is Associated With Clinical Outcome of Clopidogrel Therapy in Acute Myocardial Infarction But Not Stable Angina

More intensive platelet suppression is required in patients with acute myocardial infarction (AMI) than in those with stable angina because of differential platelet activation between AMI and stable angina. In this context, CYP2C19 genotype leading to reduced active metabolite formation may profoundly affect the clinical outcome of clopidogrel therapy in patients with AMI compared with those with stable angina. Effects of CYP2C19 genotypes on the clinical outcome of clopidogrel therapy were evaluated in 2188 patients (532 patients with AMI and 1656 patients with stable angina) undergoing percutaneous coronary intervention. The primary clinical outcome was a composite of major adverse cardiac and cerebrovascular events defined as death from any cause, nonfatal myocardial infarction, or stroke during 1 year of clopidogrel therapy. Compared with extensive metabolizer, the CYP2C19 poor metabolizer was significantly associated with higher risk of major adverse cardiac and cerebrovascular events in patients with AMI (hazard ratio, 2.88; 95% confidence interval, 1.27-6.53; P=0.011). However, this finding was not seen in patients with stable angina. A significant interaction between CYP2C19 genotypes and disease subsets of AMI and stable angina was identified with respect to major adverse cardiac and cerebrovascular events (adjusted interaction P=0.045). The patients with AMI showed lower percent inhibition of P2Y12 compared with patients with stable angina in CYP2C19 poor metabolizer or CYP2C19 intermediate metabolizer genotype groups but not in CYP2C19 extensive metabolizer genotype group. CYP2C19 poor metabolizer is associated with poor clinical outcome of clopidogrel therapy in Asian patients with AMI but not in those with stable angina possibly because of differential requirement of platelet suppression in patients with AMI and stable angina. URL: clinicaltrials.gov. Identifier: NCTO1239914.

Analysis of cytochrome P450 gene polymorphism in a lupus nephritis patient in whom tacrolimus blood concentration was markedly elevated after administration of azole antifungal agents

Both itraconazole (ITCZ) and voriconazole (VCZ) are potent inhibitors of cytochrome P450 (CYP) 3A, and their effects have been reported to be equal. However, ITCZ is metabolized by CYP3A, whereas VCZ is mainly metabolized by CYP2C9 and CYP2C19 and only partially by CYP3A. We experienced the case of a patient who showed a 5-fold increase in trough levels of tacrolimus (FK) level after switching from ITCZ to VCZ. Our objective is to discuss the mechanism of the increase drug-drug interaction in terms of serum concentration of the azole drugs and patient pharmacogenomics. A 53-year-old woman was treated with FK (1 mg/day) for lupus nephritis. Because fungal infection was suspected, she received ITCZ (100 mg/day). When ITCZ was replaced with VCZ (400 mg/day), the blood concentration of FK increased markedly from 6·1 to 34·2 ng/mL. During coadministration with FK, the levels of ITCZ and VCZ were 135·5 ng/mL and 5·5 μg/mL, respectively, with the VCZ level around 3-fold higher than the previously reported level (1·4-1·8 μg/mL). Her CYP genotypes were CYP2C19*1/*2, CYP3A4*1/*1 and CYP3A5*3/*3. The patient was a CYP2C19 intermediate metabolizer (IM) and deficient in CYP3A5. The increase in plasma VCZ level appears to have been at least in part, associated with the CYP2C19 IM phenotype. One possible explanation for the marked increase in blood FK concentration was increased inhibition of CYP3A because of the impaired metabolism and subsequent increased plasma concentration of VCZ. This case shows that the severity of drug interactions may be influenced by metabolic gene polymorphism.

Abstract 760: A randomized, crossover, phase 1 study to evaluate the effect of a strong CYP3A4 inhibitor on tivantinib (ARQ 197) pharmacokinetics in healthy subjects

Abstract Background: Tivantinib is a selective, oral, non-ATP-competitive, small-molecule inhibitor of c-MET. In vitro data suggest that CYP2C19 and CYP3A4 are the major enzymes involved in tivantinib metabolism. Therefore, there is potential that CYP3A4 inhibitors may affect tivantinib pharmacokinetics (PK) leading to increased exposure. During the course of their disease, cancer patients receive multiple drugs, some of which may be strong CYP3A4 inhibitors. This open-label, 2-stage study evaluated the effect of ketoconazole, a strong inhibitor of CYP3A4, on tivantinib metabolism in adults with different CYP2C19 activity. Methods: Healthy adults (age 18 to 45 years) with no clinical conditions were eligible. In stage 1, healthy subjects who were either an extensive metabolizer (EM) or intermediate metabolizer (IM) based on CYP2C19 activity were randomized to 1 of 2 sequences, each consisting of two 8-day treatment periods under fed conditions with a 14-day washout between periods. In sequence 1, tivantinib (120 mg) was administered alone on day 4 of period 1 followed by ketoconazole (400 mg/day) with concomitant tivantinib (120 mg) on day 4 of period 2. The treatments were reversed in sequence 2. If there was no interaction, poor metabolizer (PM) subjects were to be analyzed in stage 2. Serial blood samples were collected for 96 hours after tivantinib administration, and area under the curve (AUC), maximum concentration (Cmax), and time to peak concentration (tmax) were calculated and statistically compared. Results: Sixteen subjects were randomized equally to 1 of 2 treatment sequences. When tivantinib was combined with ketoconazole, total exposure to tivantinib (AUC) was increased 2.1-fold and Cmax was increased 1.4-fold compared with tivantinib alone. Median tmax was similar for ketoconazole + tivantinib and tivantinib alone (4.75 vs 4.50 hours, respectively). Exposure to tivantinib was 2- to 3-fold higher in CYP2C19 IM subjects compared with CYP2C19 EM subjects, with or without ketoconazole. The median tmax for tivantinib was comparable for IM and EM subjects with or without ketoconazole (tivantinib, 4.50 vs 4.49 hours, respectively and ketoconazole + tivantinib, 5.00 vs 4.50 hours, respectively). A total of 10 adverse events (AEs) were reported in 5 subjects (31%); 4 AEs were considered related to ketoconazole and the remaining AEs were unrelated to study treatment. Two subjects discontinued the study because of elevated creatinine (related to ketoconazole) and elevated neutrophils (unrelated to treatment), respectively. Stage 2 assessment in CYP2C19 PM subjects was not performed. Conclusions: Concurrent administration of ketoconazole substantially increased tivantinib exposure. Therefore, caution should be exercised when strong CYP3A4 inhibitors are coadministered with tivantinib. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 760. doi:1538-7445.AM2012-760

Association of CYP2B6, CYP3A5, and CYP2C19 Genetic Polymorphisms With Sibutramine Pharmacokinetics in Healthy Korean Subjects

We assessed the association of CYP2B6, CYP3A5, and CYP2C19 polymorphisms with sibutramine pharmacokinetics. Forty six healthy male subjects were enrolled, and their CYP2B6 (*4 and *6), CYP3A5 (*3), and CYP2C19 (*2, and *3) genotypes were analyzed. After a single 15-mg dose of sibutramine was administered, plasma concentrations of sibutramine and its metabolites, M1 and M2, were measured. CYP2B6 and CYP3A5 polymorphisms did not affect the pharmacokinetics of sibutramine and its metabolites. However, the CYP2C19 genotype substantially influenced plasma levels of sibutramine and its metabolites. The mean area under the curve (AUC) of sibutramine in CYP2C19 intermediate metabolizers (IMs; *1/*2 or *1/*3) and poor metabolizers (PMs; *2/*2, *2/*3)) was 18.5 and 252.2% higher, respectively, than the AUC in extensive metabolizers (EMs, *1/*1) (P < 0.001). The AUC of M1 metabolite in IMs and PMs was 22.5 and 148.0% higher, respectively, than that of EMs (P < 0.001). Our findings indicate that the CYP2C19 genotype substantially affects the pharmacokinetics of sibutramine.