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Impact of CYP3A5 Gene Polymorphism on Efficacy of Simvastatin.

ABSTRACT: BACKGROUND:One of the promises of human genetics is individualized therapy. Therefore, we evaluated the impact of CYP3A5 gene polymorphism on the effectiveness of simvastatin (a HMG-CoA reductase inhibitor). METHODS:Patients (n = 191) with hypercholesterolemia were treated with simvastatin for at least 6 months and were genotyped for the CYP3A5 polymorphism. RESULTS:The frequency of CYP3A5 polymorphism was 0.5% for WT (wild-type), 15.6% for HT (heterozygous, expressors) and 83.9% for HM (homozygous, non-expressors). Differences in lipid profile before and after dose-response of simvastatin treatment were described as % difference {[(variable after-variable before)/variable before]*100}. There was a trend towards the decrease of low density lipoprotein cholesterol (LDL-C) in HT individuals who had a -35.2% reduction with a dose of 20 mg simvastatin and HM individuals who had a slightly higher decrease (-37.5%) despite the lower dose of simvastatin (10 mg, p = 0.07). Furthermore, HT genotype individuals had significantly higher than expected (6-8%) LDL-C % difference between 20 and 40 mg of simvastatin (-35.2 vs -49.2%, p = 0.037). In individuals with HM genotype a significant LDL-C % difference was found between 10 and 40 mg of simvastatin (-37.5 vs -48.4%, p = 0.023). CONCLUSION:The individuals with HM polymorphism display a trend towards higher LDL-C reductions compared with HT polymorphism. Within the same genotype, differences between doses were also observed. These findings need to be confirmed in larger studies.

SUBMITTER: Kolovou G

PROVIDER: S-EPMC3959175 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Impact of CYP3A5 Gene Polymorphism on Efficacy of Simvastatin.

Kolovou Genovefa G Ragia Georgia G Kolovou Vana V Mihas Constantinos C Katsiki Niki N Vasiliadis Ioannis I Mavrogeni Sophie S Vartela Vassiliki V Tavridou Anna A Manolopoulos Vangelis G VG

The open cardiovascular medicine journal 20140207

<h4>Background</h4>One of the promises of human genetics is individualized therapy. Therefore, we evaluated the impact of CYP3A5 gene polymorphism on the effectiveness of simvastatin (a HMG-CoA reductase inhibitor).<h4>Methods</h4>Patients (n = 191) with hypercholesterolemia were treated with simvastatin for at least 6 months and were genotyped for the CYP3A5 polymorphism.<h4>Results</h4>The frequency of CYP3A5 polymorphism was 0.5% for WT (wild-type), 15.6% for HT (heterozygous, expressors) and ...[more]

PMID: 24653785

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Project description:Atorvastatin, prescribed for the treatment of hypercholesterolemia, demonstrated overwhelming benefits in reducing cardiovascular morbidity and mortality. However, many patients discontinue therapy due to adverse reactions, especially myopathy. The Dutch Pharmacogenetics Working Group (DPWG) recommends an alternative agent to atorvastatin and simvastatin or a dose adjustment depending on other risk factors for statin-induced myopathy in SLCO1B1 rs4149056 CC or TC carriers. In contrast, the Clinical Pharmacogenetics Implementation Consortium (CPIC) published their guideline on simvastatin, but not on atorvastatin. In this work, we aimed to demonstrate the effect of SLCO1B1 phenotype and other variants (e.g., in CYP3A4/5, UGT enzymes or SLC transporters) on atorvastatin pharmacokinetics. For this purpose, a candidate-gene pharmacogenetic study was proposed. The study population comprised 156 healthy volunteers enrolled in atorvastatin bioequivalence clinical trials. The genotyping strategy comprised a total of 60 variants in 15 genes. Women showed higher exposure to atorvastatin compared to men (p = 0.001), however this difference disappeared after dose/weight (DW) correction. The most relevant pharmacogenetic differences were the following: AUC/DW and Cmax /DW based on (a) SLCO1B1 phenotype (p < 0.001 for both) and (b) CYP3A5*3 (p = 0.004 and 0.018, respectively). As secondary findings: SLC22A1 *2/*2 genotype was related to higher Cmax/DW (ANOVA p = 0.030) and SLC22A1 *1/*5 genotype was associated with higher Vd/F (ANOVA p = 0.032) compared to SLC22A1 *1/*1, respectively. Finally, UGT2B7 rs7439366 *1/*1 genotype was associated with higher tmax as compared with the *1/*3 genotype (ANOVA p = 0.024). Based on our results, we suggest that SLCO1B1 is the best predictor for atorvastatin pharmacokinetic variability and that prescription should be adjusted based on it. We suggest that the CPIC should include atorvastatin in their statin-SLCO1B1 guidelines. Interesting and novel results were observed based on CYP3A5 genotype, which should be confirmed with further studies.

Project description:To assess the impact of the loss-of-function CYP3A5*3 allele (rs776746, 6986A>G SNP) on darunavir (DRV) plasma concentrations.135 HIV-1 infected patients treated with DRV-based therapy were included in the study and plasma samples were obtained immediately before drug intake in order to determine DRV trough concentrations using an ultra performance liquid chromatography method (UPLC) with diode-array detection (DAD). Noteworthy is the fact that in 16 (11.9%) patients, etravirine (ETR) was combined with DRV. CYP3A5 genotypes were determined using real time PCR method (TaqMan® genotyping assay). The patients were then classified into CYP3A5 expressors (CYP3A5*1 allele carriers) and non-expressors (CYP3A5*3 homozygous). Subsequently, the association between DRV plasma trough concentration ([DRV]plasma) and CYP3A5 genotype-based expression status was analyzed.45% of the patients were classified as CYP3A5 expressors. In the whole cohort, mean [DRV]plasma was not different between CYP3A5 expressors and non-expressors (1894ng/ml [CI95%: 1566-2290] versus 1737ng/ml [CI95%: 1468-2057], p = 0.43). However, in the subgroup of the 16 patients receiving DRV combined with ETR, a significantly lower [DRV]plasma was observed for CYP3A5 expressors when compared to non-expressors (1385ng/ml [CI95%:886.3-2165] versus 3141ng/ml [CI95%:2042-4831], p = 0.007).Interaction between DRV and ETR is partly mediated by CYP3A5 polymorphism with lower DRV plasma trough concentrations in CYP3A5 expressors suggesting a specific ETR-driven CYP3A5 activation only in CYP3A5 expressors. Consequently, these patients might be more at risk of infra-therapeutic [DRV]plasma. This potentially important observation is a good illustration of a genotype-based drug interaction, which could also have considerable consequences if translated to other CYP3A5-metabolized drugs. Further investigations are thus needed to confirm this association and to explore its clinical impact, mainly in the African population among whom CYP3A5 expressors are more frequent, before recommending systematic CYP3A5 pre-emptive genotyping for DRV-ETR co-administration.

Project description:IntroductionTacrolimus (TAC) is the mainstay immunosuppressant for renal transplantation. A narrow therapeutic index, multiple drug interactions, and interindividual variability in pharmacokinetics make it obligatory to monitor therapeutic drug levels. The Multidrug resistance gene 1 (MDR1) and CYP3A5 gene polymorphism may blend to achieve the optimal level. The optimal dose as per body weight is difficult to single out in the early posttransplantation period. In this study, we aimed to analyze the melding effect of both gene polymorphisms and to elicit the dose depending on the combination of genetic single nucleotide polymorphisms (SNPs) in northern Indian transplant recipients, for whom data are limited.MethodsThe daily TAC dose, weight-adjusted doses (mg/kg per day), TAC trough blood concentration (average of at least 3 levels), dose normalized with a corresponding dose using TAC concentration/weight-adjusted dose ratio (ng/ml per mg/kg per day) of 248 patients were recorded. All recipients were genotyped for the SNPs of CYP3A5 at intron 3 A6986G (the *3 or *1 allele), MDR1 at exons 12 (C1236T), 21 (G2677A/T), and 26 (C3435T). We analyzed the blending effect of mutant SNPs of the MDR gene and CYP3A5 for optimized TAC levels.ResultsAmong CYP3A5 genotypic variants, the dose-adjusted TAC level was significantly lower, and the TAC dose required to achieve the target level was significantly higher, in CYP3A5*1*1 (expressor) than that of CYP3A5*1*3 and CYP3A5*3*3. Of the MDR1 gene SNPs, only the G2677T/A homozygous mutant was significantly associated with TAC level, and it was strongly correlated with P-gp expression.The daily TAC dose requirement was highest with a combination of CYP3A5*1*1 and homozygous mutant TT+AA genotype of G2677T/A, and was lowest with CYP3A5*3*3 and wild-type GG of the G2677T/A genotype.ConclusionBoth CYP gene and MDR1 gene polymorphism affect TAC dose requirements, and there is a need to look for both in an individual to achieve the target trough concentration.

Project description:ObjectiveSimvastatin is primarily metabolized by CYP3A4. A combined CYP3A4/5 genotype classification, combining the decrease-of-function CYP3A4*22 and the loss-of-function CYP3A5*3, has recently been reported. We aim to determine whether CYP3A4*22 and CYP3A5*3 alleles are associated with increased plasma concentrations of simvastatin lactone (SV) and simvastatin acid (SVA). This is the first report evaluating associations between in-vivo simvastatin concentrations and CYP3A4*22, alone or in a combined CYP3A4/5 genotype-defined classification.Participants and methodsGenotypes and simvastatin concentrations were determined for 830 participants (555 Whites and 275 African-Americans) in the Cholesterol and Pharmacogenomics clinical trial with 40 mg/day simvastatin for 6 weeks. Concentrations were determined in 12-h postdose samples. Associations between simvastatin concentrations and CYP3A4*22 and CYP3A5*3 alleles were tested separately and in a combined CYP3A4/5 genotype-defined classification system.ResultsIn Whites, CYP3A4*22 carriers (n=42) had 14% higher SVA (P=0.04) and 20% higher SV (P=0.06) compared with noncarriers (n=513). CYP3A5*3 allele status was not significantly associated with SV or SVA in Whites. In African-Americans, CYP3A4*22 carriers (n=8) had 170% higher SV (P<0.01) than noncarriers (n=267), but no significant difference was detected for SVA. African-American CYP3A5 nonexpressors (n=28) had 33% higher SV (P=0.02) than CYP3A5 expressors (n=247), but no significant difference was detected for SVA. For both races, SV appeared to decrease across the rank-ordered combined CYP3A4/5 genotype-defined groups (poor, intermediate, and extensive metabolizers); however, similar trends were not observed for SVA.ConclusionGenetic variation in CYP3A4 was associated with plasma simvastatin concentrations in self-reported Whites. Genetic variations in CYP3A4 and CYP3A5 were associated with plasma simvastatin concentrations in self-reported African-Americans.

Dataset Information

Impact of CYP3A5 Gene Polymorphism on Efficacy of Simvastatin.

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Impact of CYP3A5 Gene Polymorphism on Efficacy of Simvastatin.

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