Influence of novel CYP2C-haplotype on proton pump inhibitor pharmacokinetics in children.

In this brief report, we provide an analysis of the influence of a novel CYP2C haplotype (CYP2C:TG) on proton pump inhibitor (PPI) pharmacokinetics (PK) in children. The CYP2C:TG haplotype has been proposed to be associated with increased CYP2C19 activity. We sought to determine if this CYP2C:TG haplotype resulted in similar alterations in metabolism for proton pump inhibitors, which are primarily metabolized by CYP2C19. In a cohort of 41 children aged 6-21 participating in a PPI pharmacokinetic study, effects of the CYP2C:TG allele were assessed by fitting two linear regression models for each of the six PK outcomes assessed, the second of which accounted for the presence of the CYP2C:TG allele. The difference in R2 values between the two models was computed to quantify the variability in the outcome that could be accounted for by the CYP2C:TG allele after adjustment for the CYP2C19 genotype. We found the CYP2C:TG haplotype to have no measurable additive impact on CYP2C19-mediated metabolism of PPIs in vivo in older children and adolescents. The findings of this study do not support the clinical utility of routine testing for the CYP2C:TG haplotype to guide PPI dose adjustments in children.

Association between gene polymorphisms and initial warfarin therapy in patients after heart valve surgery.

BACKGROUND: Warfarin is widely used for the prevention and treatment of thrombotic events. This study aimed to examine the influence of gene polymorphisms on the early stage of warfarin therapy in patients following heart valve surgery. METHODS: Nine single nucleotide polymorphisms were genotyped using microarray chips, categorizing patients into three groups: normal responders (Group I), sensitive responders (Group II), and highly sensitive responders (Group III). The primary clinical outcomes examined were time in therapeutic range (TTR) and international normalized ratio (INR) variability. To investigate potential influencing factors, a generalized linear regression model was employed. RESULTS: Among 734 patients, the prevalence of CYP2C9*3-1075A > C, CYP2C19*3-636G > A, and CYP2C19*17-806C > T variants were 11.2%, 9.9%, and 1.9% of patients, respectively. VKORC1-1639G > A or the linked -1173C > T variant was observed in 99.0% of the patients. Generalized linear model analysis revealed an impact of sensitivity grouping on INR variability. Compared to Group I, Group II showed higher TTR values (p = 0.023), while INR variability was poorer in Group II (p < 0.001) and Group III (p < 0.001). Individual gene analysis identified significant associations between CYP2C9*3-1075A > C (p < 0.001), VKORC1-1639G > A or the linked -1173 C > T (p = 0.009) and GGCX-3261G > A (p = 0.019) with INR variability. CONCLUSION: The genotypes of CYP2C9, VKORC1, and GGCX were found to have a significant impact on INR variability during the initial phase of warfarin therapy. However, no significant association was observed between TTR and gene polymorphisms. These findings suggest that focusing on INR variability is crucial in clinical practice, and preoperative detection of gene polymorphisms should be considered to assist in the initiation of warfarin therapy.

The diversity and clinical implications of genetic variants influencing clopidogrel bioactivation and response in the Emirati population.

BACKGROUND: Clopidogrel is a widely prescribed prodrug that requires activation via specific pharmacogenes to exert its anti-platelet function. Genetic variations in the genes encoding its transporter, metabolizing enzymes, and target receptor lead to variability in its activation and platelet inhibition and, consequently, its efficacy. This variability increases the risk of secondary cardiovascular events, and therefore, some variations have been utilized as genetic biomarkers when prescribing clopidogrel. METHODS: Our study examined clopidogrel-related genes (CYP2C19, ABCB1, PON1, and P2Y12R) in a cohort of 298 healthy Emiratis individuals. The study used whole exome sequencing (WES) data to comprehensively analyze pertinent variations of these genes, including their minor allele frequencies, haplotype distribution, and their resulting phenotypes. RESULTS: Our data shows that approximately 37% (n = 119) of the cohort are likely to benefit from the use of alternative anti-platelet drugs due to their classification as intermediate or poor CYP2C19 metabolizers. Additionally, more than 50% of the studied cohort exhibited variants in ABCB1, PON1, and P2YR12 genes, potentially influencing clopidogrel's transport, enzymatic clearance, and receptor performance. CONCLUSIONS: Recognizing these alleles and genotype frequencies may explain the clinical differences in medication response across different ethnicities and predict adverse events. Our findings underscore the need to consider genetic variations in prescribing clopidogrel, with potential implications for implementing personalized anti-platelet therapy among Emiratis based on their genetic profiles.

Association Study of Esomeprazole Pharmacokinetics and CYP2C19 Gene Polymorphisms.

To investigate the association between esomeprazole pharmacokinetics and CYP2C19 gene polymorphisms in a cohort of 95 healthy Chinese participants. A cohort of 95 participants was assembled and stratified into 2 distinct groups, receiving either 20 or 40 mg of esomeprazole through oral administration. The subjects encompassed 17 poor metabolizers, 47 intermediate metabolizers, and 31 rapid metabolizers, and their genotypes were ascertained using the polymerase chain reaction-restriction fragment length polymorphism technique. Esomeprazole plasma concentrations were quantified employing a high-performance liquid chromatography-ultraviolet method. Pharmacokinetic parameters were computed via Phoenix WinNonlin 6.1 software, while SPSS 26.0 facilitated statistical analysis to contrast the pharmacokinetics and the CYP2C19 genotypes. In the aftermath of administering 20 or 40 mg esomeprazole, marked differences were discerned between terminal elimination half-life, maximum concentration/dose, and area under the plasma concentration-time curve from time zero to infinity/dose of esomeprazole (P < .05), with the exception of time to maximum concentration. The findings of this investigation signify a significant association between esomeprazole metabolism and CYP2C19 gene polymorphisms. There were no unprecedented adverse events documented subsequent to the administration of 20 and 40 mg esomeprazole dosages. Esomeprazole has manifested promising safety and tolerability profiles in pertinent clinical trials.

Acute kidney injury interacts with VKORC1 genotype on initiative warfarin dose among heart surgery recipients: a real-world research.

Patients who receive heart valve surgery need anticoagulation prophylaxis to reduce the risk of thrombosis. Warfarin often is a choice but its dosage varies due to gene and clinical factors. We aim to study, among them, if there is an interaction between acute kidney injury and two gene polymorphisms from this study. We extracted data of heart valve surgery recipients from the electronic health record (EHR) system of a medical center. The primary outcome is about the average daily dose of warfarin, measured as an additive interaction effect (INTadd) between acute kidney injury (AKI) and warfarin-related gene polymorphisms. The confounders, including age, sex, body surface area (BSA), comorbidities (i.e., atrial fibrillation [AF], hypertension [HTN], congestive heart failure [CHF]), serum albumin level, warfarin-relevant gene polymorphism (i.e., CYP2C9, VKORC1), prosthetic valve type (i.e., metal, bio), and warfarin history were controlled via a multivariate-linear regression model. The study included 200 patients, among whom 108 (54.00%) are female. Further, the mean age is 54.45 years, 31 (15.50%) have CHF, and 40 (20.00%) patients were prescribed concomitant amiodarone, which potentially overlays with the warfarin prophylaxis period. During the follow-up, AKI occurred in 30 (15.00%) patients. VKORC1 mutation (1639G>A) occurred in 25 (12.50%) patients and CYPC29 *2 or *3 mutations presented in 20 patients (10.00%). We found a significant additive interaction effect between AKI and VKORC1 (- 1.17, 95% CI - 1.82 to - 0.53, p = 0.0004). This result suggests it is probable that there is an interaction between acute kidney injury and the VKORC1 polymorphism for the warfarin dose during the initial period of anticoagulation prophylaxis.

The influence of temperature on the metabolic activity of CYP2C9, CYP2C19, and CYP3A4 genetic variants in vitro.

1. Temperature is considered to affect the activity of drug-metabolizing enzymes; however, no previous studies have compared temperature dependency among cytochrome P450 genetic variants. This study aimed to analyse warfarin 7-hydroxylation by CYP2C9 variants; omeprazole 5-hydroxylation by CYP2C19 variants; and midazolam 1-hydroxylation by CYP3A4 variants at 34 °C, 37 °C, and 40 °C.2. Compared with that seen at 37 °C, the intrinsic clearance rates (Vmax/Km) of CYP2C9.1 and .2 were decreased (76 ∼ 82%), while that of CYP2C9.3 was unchanged at 34 °C. At 40 °C, CYP2C9.1, .2, and .3 exhibited increased (121%), unchanged and decreased (87%) intrinsic clearance rates, respectively. At 34 °C, the clearance rates of CYP2C19.1A and .10 were decreased (71 ∼ 86%), that of CYP2C19.1B was unchanged, and those of CYP2C19.8 and .23 were increased (130 ∼ 134%). At 40 °C, the clearance rates of CYP2C19.1A, .1B, .10, and .23 remained unaffected, while that of CYP2C19.8 was decreased (74%). At 34 °C, the clearance rates of CYP3A4.1 and .16 were decreased (79 ∼ 84%), those of CYP3A4.2 and .7 were unchanged, and that of CYP3A4.18 was slightly increased (112%). At 40 °C, the clearance rate of CYP3A4.1 remained unaffected, while those of CYP3A4.2, .7, .16, and .18 were decreased (58 ∼ 82%).3. These findings may be clinically useful for dose optimisation in patients with hypothermia or hyperthermia.

Warfarin pharmacogenetics in a black Zimbabwean cohort: an observational prospective study.

Aim: A prospective observational study was conducted to evaluate the feasibility of implementing clinical guidelines for warfarin dosing in black Zimbabwean patients. Methods: CYP2C9*5, CYP2C9*6, CYP2C9*8 and CYP2C9*11 and VKORC1 c. 1639 G>A variations were observed in 62 study patients. Results & Conclusion: Overall, 39/62 (62.90%) participants did not receive a warfarin starting dose as would have been recommended by Clinical Pharmacogenetics Implementation Consortium guidelines. US FDA and Dutch Pharmacogenetics Working Group guidelines are based on CYP2C9*2 and CYP2C9*3 only, hence, unlikely useful in this cohort, where such variants were not detected. Clinical Pharmacogenetics Implementation Consortium guidelines, on the other hand, have a specific recommendation on the African-specific variants CYP2C9*5, CYP2C9*6 and CYP2C9*11, and are hence suitable for implementation in Zimbabwe and would help optimize warfarin doses in patients in the study cohort.

FREQUENCY OF VKORC1 AND CYP2C9 GENES POLYMORPHISM IN ABKHAZIAN POPULATION.

The aim of the research was to study the frequency of VKROC1 and CYP2C9 genes different alleles for healthy donors and for patients with thrombosis, in Abkhazian population and to reveal the interdependence of the studied genes products in the treatment of thrombosis with warfarin. Warfarin is an anticoagulant, causing the inactivation of the VKORC1 gene product, which is one of the clotting factors. The protein product of CYP2C9 gene is involved in the metabolism of warfarin. Genotyping of blood samples for studied genes alleles was carried out using a tube scanner (ESE Quant Tube Scaner), allowing to identify SNPs. With the highest frequency in the studied group of healthy donors of Abkhazian population, by VKROC1 gene found Heterozygous (AG genotype) (74,5 %). The distribution of homozygous of "wild" (GG) and mutant genotype (AA) accounted for 13,5% and 11,8%, respectively. In the group of patients with Thrombosis, wild-type homozygotes accounted for 32.5%, which is significantly high compared to the control group. The percentage of heterozygotes was significantly lower than in the control group and accounted 56,25%. as for the homozygous mutant genotype, it was practically the same as in control group (11,2%). Regarding the rate of polymorphic variants of the CYP2C9 gene, quite large differences between diseased and healthy individuals were detected according to some of them. CYP2C9 *1/*1 genotype (wild- type homozygote) was observed in 32.9% of healthy individuals, while the same genotype was detected in only 14.5% of patients with thrombosis. The percentage of CYP2C9 *1/*2 genotype was slightly different between healthy and thrombotic subjects and corresponded to 27.5% in healthy individuals and 30.4% in thrombotic patients. CYP2C9 *1/*3 genotype accounted for 16.1% in healthy individuals. The mentioned indicator was significantly different from the similar indicator of patients with thrombosis, which corresponded to 24.1%. The largest difference between the percentages was observed according to the CYP2C9 *2/*3 (mutant heterozygote) genotype. In healthy individuals, this rate corresponded to 40.3%, and in thrombotic individuals - 11.4%. The CYP2C9 *2/*2 genotype was not observed in any of the study groups, while the percentage of CYP2C9 *3/*3 (mutant homozygous) individuals did not differ and amounted to 1.6% (in healthy individuals) and 1.2% (in thrombotic patients). VKORC1 and / or CYP2C9 genes polymorphisms are presented in a number of clinical dosing algorithms and in prospective clinical trials. In conclusion, it should be noted that the present work revealed a significant variability of genotypes between the groups of patients with thrombosis and healthy individuals, in Abkhazian population. The results obtained in determining the polymorphic variants of the VKORC1 and CYP2C9 genes, studied by us, should be taken into account when using algorithms to determine the optimal dosage for warfarin treatment in thrombotic individuals of the Abkhazian population, both during treatment and for the prevention of thrombosis.

Development of an electrochemical DNA-based biosensor for the detection of the cardiovascular pharmacogenetic-altering SNP CYP2C9*3.

Cardiovascular diseases are among the major causes of mortality and morbidity. Warfarin is often prescribed for these disorders, an anticoagulant with inter and intra-dosage variability dose required to achieve the target international normalized ratio. Warfarin presents a narrow therapeutic index, and due to its variability, it can often be associated with the risk of hemorrhage, or in other patients, thromboembolism. Single-nucleotide polymorphisms are included in the causes that contribute to this variability. The Cytochrome P450 (CYP) 2C9*3 genetic polymorphism modifies its enzymatic activity, and hence warfarin's plasmatic concentration. Thus, the need for a selective, rapid, low-cost, and real-time detection device is crucial before prescribing warfarin. In this work, a disposable electrochemical DNA-based biosensor capable of detecting CYP2C9*3 polymorphism was developed. By analyzing genomic databases, two specific 78 base pairs DNA probes; one with the wild-type adenine (Target-A) and another with the cytosine (Target-C) single-nucleotide genetic variation were designed. The biosensor implied the immobilization on screen-printed gold electrodes of a self-assembled monolayer composed by mercaptohexanol and a linear CYP2C9*3 DNA-capture probe. To improve the selectivity and avoid secondary structures a sandwich format of the CYP2C9*3 allele was designed using complementary fluorescein isothiocyanate-labeled signaling DNA probe and enzymatic amplification of the electrochemical signal. Chronoamperometric measurements were performed at a range of 0.015-1.00 nM for both DNA targets achieving limit of detection of 42 p.m. The developed DNA-based biosensor was able to discriminate between the two synthetic target DNA targets, as well as the targeted denatured genomic DNA, extracted from volunteers genotyped as non-variant homozygous (A/A) and heterozygous (A/C) of the CYP2C9*3 polymorphism.

VARIANTS OF THE FORMATION AND COURSE OF DRUG-RESISTANT EPILEPSY IN CHILDREN WITH GENETIC POLYMORPHISMS OF CYP2C9, CYP2C19, CYP3A4.

OBJECTIVE: The aim: To clarify the frequency with which various variants of the formation and course of drug-resistant epilepsy occur in children with genetic polymor¬phisms of cytochromes CYP2C9, CYP2C19, CYP3A4. PATIENTS AND METHODS: Materials and methods: The genotyping of CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP3A4*1B by the allele-specific polymerase chain reaction was performed in 116 children with drug-resistant epilepsy aged from 2 to 17 years. Thirty cases (boys-15; girls-15) with a follow-up period of more than 5 years were analyzed in detail. RESULTS: Results: Of 30 cases analyzed, polymorphisms were not detected in 8 (26.67%) children, and 22 (73.33%) had polymorphisms of the CYP2C9, CYP2C19 and CYP3A4 genes associated with a slow metabolism of AED. In children with polymorphisms of the CYP450 genes, the wave-like course of the disease with the periods of remission and its failures was characteristic, while for children with a presumably normal metabolism there was the initial resistance to the treatment with AED. CONCLUSION: Conclusions: Individual changes in the AED metabolism affect the course of drug-resistant epilepsies. For patients with a slow metabolism of AED the wave-like course of the disease and the "slipping off" phenomenon were more characteristic.

CYP2C19 loss-of-function alleles are not associated with higher prevalence of gastrointestinal bleeds in those who have been prescribed antidepressants: Analysis in a British-South Asian cohort.

AIMS: CYP2C19 is a hepatic enzyme involved in the metabolism of antidepressants associated with increased gastrointestinal bleed (GIB) risk. The aim of our study was to explore a possible association between loss-of-function CYP2C19 genotypes and GIB in South Asian ancestry participants prescribed antidepressants. METHODS: Genes & Health participants with a record in Barts Health NHS Trust (N 22 753) were studied using a cross-sectional approach. CYP2C19 diplotypes were assessed and metabolizer type inferred from consortia guidance. Fisher's exact test was used to compare the prevalence of GIB in different metabolizer categories. Multivariable regression was used to test for association between antidepressant prescriptions and GIB, and between CYP2C19 metabolizer state and GIB in the subcohort prescribed antidepressants. RESULTS: Antidepressants were frequently prescribed (47%, N = 10 612). A total of 864 participants (4%) had a GIB; 534 (62%) had been prescribed a CYP2C19 metabolized antidepressant. There was an independent association between antidepressant prescriptions and GIB events (odds ratio 1.8, confidence interval 1.5-2.0, P < 0.0001). There was no relationship between CYP2C19 inferred poor (P 0.56) or intermediate (P 0.53) metabolizer status and GIB in those prescribed an antidepressant in unadjusted analysis. A multivariable logistic regression model did not show an independent association between poor (P 0.54) or intermediate (P 0.62) CYP2C19 metabolizers and GIB in the subcohort prescribed antidepressants. CONCLUSIONS: CYP2C19 dependent antidepressants are associated with increased GIB prevalence. GIB appeared independent from CYP2C19 metabolizer genotype in individuals who had been prescribed antidepressants. Precision dosing based on CYP2C19 genetic information alone is unlikely to reduce GIB prevalence.

Integrated analysis of clinical and genetic factors on the interindividual variation of warfarin anticoagulation efficacy in clinical practice.

AIM: The anticoagulation effect of warfarin is usually evaluated by percentage of time in therapeutic range (PTTR), which is negatively correlated with the risk of warfarin adverse reactions. This study aimed to explore the effects of genetic and nongenetic factors on anticoagulation efficacy of warfarin during different therapeutic range. METHODS: We conducted an observational retrospective study aiming at evaluating the impact of clinical and genetic factors on PTTR from initial to more than six months treatment. This analysis included patients with heart valve replace (HVR) surgery who underwent long-term or life-long time treatment with standard-dose warfarin for anticoagulation control in Second Xiangya Hospital. All patients were followed for at least 6 months. We genotyped single nucleotide polymorphisms in VKORC1 and CYP2C9 associated with altered warfarin dose requirements and tested their associations with PTTR. RESULTS: A total of 629 patients with intact clinical data and available genotype data were enrolled in this study, and only 38.63% patients achieved good anticoagulation control (PTTR > 0.6). Clinical factors, including male gender, older age, overweight, AVR surgery and stroke history, were associated with higher PTTR. Patients with VKORC1 -1639AA genotype had significantly higher PTTR level compared with GA/GG genotype carriers only in the first month of treatment. Patients with CYP2C9*3 allele had higher PTTR compared with CYP2C9*1*1 carriers. Moreover, compared with VKORC1 -1639 AG/GG carriers, INR > 4 was more likely to be present in patients with AA genotype. The frequency of CYP2C9*1*3 in patients with INR > 4 was significantly higher than these without INR > 4. CONCLUSION: We confirmed the relevant factors of warfarin anticoagulation control, including genetic factors (VKORC1 -1639G > A and CYP2C9*3 polymorphisms) and clinical factors (male gender, older age, overweight, AVR surgery and stroke history), which could be helpful to individualize warfarin dosage and improve warfarin anticoagulation control during different treatment period.

Prediction of Omeprazole Pharmacokinetics and its Inhibition on Gastric Acid Secretion in Humans Using Physiologically Based Pharmacokinetic-Pharmacodynamic Model Characterizing CYP2C19 Polymorphisms.

PURPOSE: To develop a whole physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model to describe the pharmacokinetics and anti-gastric acid secretion of omeprazole in CYP2C19 extensive metabolizers (EMs), intermediate metabolizers (IMs), poor metabolizers (PMs) and ultrarapid metabolizers (UMs) following oral or intravenous administration. METHODS: A PBPK/PD model was built using Phoenix WinNolin software. Omeprazole was mainly metabolized by CYP2C19 and CYP3A4 and the CYP2C19 polymorphism was incorporated using in vitro data. We described the PD by using a turn-over model with parameter estimates from dogs and the effect of a meal on the acid secretion was also implemented. The model predictions were compared to 53 sets of clinical data. RESULTS: Predictions of omeprazole plasma concentration (72.2%) and 24 h stomach pH after administration (85%) were within 0.5-2.0-fold of the observed values, indicating that the PBPK-PD model was successfully developed. Sensitivity analysis demonstrated that the contributions of the tested factors to the plasma concentration of omeprazole were Vmax,2C19 ≈ Papp > Vmax,3A4 > Kti, and contributions to its pharmacodynamic were Vmax,2C19 > kome > kms > Papp > Vmax,3A4. The simulations showed that while the initial omeprazole dose in UMs, EMs, and IMs increased 7.5-, 3- and 1.25-fold compared to those of PMs, the therapeutic effect was similar. CONCLUSIONS: The successful establishment of this PBPK-PD model highlights that pharmacokinetic and pharmacodynamic profiles of drugs can be predicted using preclinical data. The PBPK-PD model also provided a feasible alternative to empirical guidance for the recommended doses of omeprazole.

Substantiation of a clopidogrel metabolism-associated gene (CYP2C19) variation among healthy individuals.

BACKGROUND: It is essential to investigate the prevalence of CYP2C19 alleles that affect drug metabolism. This study measures the allelic and genotypic frequencies of CYP2C19 loss-of-function (LoF) alleles CYP2C19∗2, CYP2C19∗3, and gain-of-function (GoF) alleles CYP2C19∗17 in the general population. METHODOLOGY: The study involved 300 healthy subjects between the ages of 18 and 85 recruited by simple random sampling. Allele-specific touchdown PCR was employed to identify the various alleles. The genotype and allele frequencies were calculated and checked for Hardy-Weinberg equilibrium. The phenotypic prediction of ultra-rapid metabolizer (UM = ∗17/∗17), extensive metabolizer (EM = ∗1/∗17, ∗1/∗1), intermediate metabolizer (IM = ∗1/∗2, ∗1/∗3, ∗2/∗17) and poor metabolizer (PM = ∗2/∗2, ∗2/∗3, ∗3/∗3) was made based on their genotype. RESULTS: The allele frequency of CYP2C19∗2, CYP2C19∗3, and CYP2C19∗17 was 0.365, 0.0033, and 0.18, respectively. The IM phenotype predominated with an overall frequency of 46.67%, including 101 subjects with ∗1/∗2, two subjects with ∗1/∗3, and 37 subjects with ∗2/∗17 genotype. This was followed by EM phenotype with an overall frequency of 35%, including 35 subjects with ∗1/∗17 and 70 subjects with ∗1/∗1 genotype. PM phenotype had an overall frequency of 12.67%, including 38 subjects with ∗2/∗2 genotype, and UM phenotype had an overall frequency of 5.67%, including 17 subjects with ∗17/∗17 genotype. CONCLUSION: Given the high allelic frequency of PM in the study population, a pre-treatment test to identify the individual's genotype may be recommended to decide the dosage, monitor the drug response, and avoid adverse drug reactions.

Effects of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide in healthy subjects.

Gliclazide metabolism is mediated by genetically polymorphic CYP2C9 and CYP2C19 enzymes. We investigated the effects of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide. Twenty-seven Korean healthy volunteers were administered a single oral dose of gliclazide 80 mg. The plasma concentration of gliclazide was quantified for the pharmacokinetic analysis and plasma concentrations of glucose and insulin were measured as pharmacodynamic parameters. The pharmacokinetics of gliclazide showed a significant difference according to the number of defective alleles of combined CYP2C9 and CYP2C19. The two defective alleles group (group 3) and one defective allele group (group 2) showed 2.34- and 1.46-fold higher AUC0-∞ (P < 0.001), and 57.1 and 32.3% lower CL/F (P < 0.001), compared to those of the no defective allele group (group 1), respectively. The CYP2C9IM-CYP2C19IM group had AUC0-∞ increase of 1.49-fold (P < 0.05) and CL/F decrease by 29.9% (P < 0.01), compared with the CYP2C9 Normal Metabolizer (CYP2C9NM)-CYP2C19IM group. The CYP2C9NM-CYP2C19PM group and CYP2C9NM-CYP2C19IM group showed 2.41- and 1.51-fold higher AUC0-∞ (P < 0.001), and 59.6 and 35.4% lower CL/F (P < 0.001), compared to those of the CYP2C9NM-CYP2C19NM group, respectively. The results represented that CYP2C9 and CYP2C19 genetic polymorphisms significantly affected the pharmacokinetics of gliclazide. Although the genetic polymorphism of CYP2C19 had a greater effect on the pharmacokinetics of gliclazide, the genetic polymorphism of CYP2C9 also had a significant effect. On the other hand, plasma glucose and insulin responses to gliclazide were not significantly affected by the CYP2C9-CYP2C19 genotypes, requiring further well-controlled studies with long-term dosing of gliclazide in diabetic patients.

Development and validation wise assessment of genotype guided warfarin dosing algorithm in Indian population.

OBJECTIVES: A study was conducted to develop and validate the warfarin pharmacogenetic dose optimization algorithm considering the clinical pharmacogenetic implementation consortium (CPIC) recommendations for the Asian ethnicity population. METHODS: The present prospective observational study recruited warfarin-receiving patients. We collected a three ml blood sample for VKORC1, CYP2C9*2, CYP2C9*3, and CYP4F2 polymorphism assessment during the follow-up visits. Clinical history, sociodemographic and warfarin dose details were noted. RESULTS: The study recruited 300 patients (250 in derivation and 50 in validation timed cohort) receiving warfarin therapy. The baseline characteristics were similar in both cohorts. BMI, presence of comorbidity, VKORC1, CYP2C9*2, and CYP2C9*3 were identified as covariates significantly affecting the warfarin weekly maintenance dose (p<0.001 for all) and the same were included in warfarin pharmacogenetic dose optimization algorithm building. The algorithm built-in the present study showed a good correlation with Gage (r=0.57, p<0.0001), and IWPC (r=0.51, p<0.0001) algorithms, widely accepted in western side of the globe. The receiver operating characteristic curve analysis showed a sensitivity of 73 %, a positive predictive value of 96 %, and a specificity of 89 %. The algorithm correctly identified the validation cohort's warfarin-sensitive, intermediate reacting, and resistant patient populations. CONCLUSIONS: Validation and comparisons of the warfarin pharmacogenetic dose optimization algorithm have made it ready for the clinical trial assessment.

Prevalence of CYP2C9 and CYP2C19 variants and the impact on clopidogrel efficacy in patients having CYPC19*2 variant.

OBJECTIVE: Human cytochrome p450 enzymes play an important role in the metabolism of various substances. The CYP2C subfamily consists of various important drug-metabolizing enzymes such as CYP2C9 and CYP2C19. The objectives of the study include the determination of the frequency of genetic variants (CYP2C9*2, CYP2C9*3, and CYP2C19*2) of selected enzymes using allele-specific polymerase chain reaction (ASPCR) and its comparison with Indian as well as global past frequencies. We also aimed to study the impact of genetic mutation on clopidogrel efficacy and compare the efficacies between patients with and without CYP2C19*2 genetic variant. METHODOLOGY: In this study, the prevalence of variants CYP2C19*2, CYP2C9*2, and CYP2C9*3, the most popular variants of the respective enzymes, was determined using the ASPCR method. The correlation between the CYP2C19*2 variant and the antiplatelet activity of clopidogrel was studied using platelet aggregation assay (PAA). RESULTS: The determined frequencies of CYP2C19*2, CYP2C9*2, and CYP2C9*3 are 46%, 9%, and 12%. These frequencies are indicative of homozygous as well as heterozygous mutations. Reduced clopidogrel efficacy was observed in patients with a heterozygous mutation of CYP2C19*2 variant. CONCLUSIONS: The observed frequencies are not significantly different from that observed in earlier reported studies conducted across India and the world. Antiplatelet activity, as measured using the PAA method, was significantly lesser in patients having the CYP2C19*2 variant. The therapy failure in these patients can lead to serious cardiovascular consequences, and we propose determining the presence of the CYP2C19*2 variant before initiation of clopidogrel therapy.

Time-to-event modeling for achieving a stable warfarin dose using genetic and non-genetic covariates.

BACKGROUND: Time-to-event modeling is gaining importance in drug dosage determination, particularly using pharmacometrics approaches. OBJECTIVES: To evaluate the various time-to-event models for estimating the time to achieve a stable warfarin dose in the Bahraini population. MATERIAL AND METHODS: A cross-sectional study evaluating the non-genetic and genetic covariates (single nucleotide polymorphisms (SNPs) in CYP2C9, VKORC1 and CYP4F2 genotypes) was conducted in patients receiving warfarin for at least 6 months. Time to achieving a stable dose of warfarin was defined as the duration (in days) from the day of initiating warfarin until 2 consecutive prothrombin time-international normalized ratio (PT-INR) values were observed in the therapeutic range with a gap of at least 7 days. Exponential, Gompertz, log-logistics, and Weibull models were tested, and the model with the lowest objective function value (OFV) was chosen. The covariate selection was carried out using the Wald test and OFV. A hazard ratio (HR) with a 95% confidence interval (95% CI) was estimated. RESULTS: A total of 218 participants were included in the study. The Weibull model was observed to have the lowest OFV (1989.82). The expected time to reach a stable dose in the population was 21.35 days. The CYP2C9 genotypes were identified as the only significant covariate. The HR (95% CI) for achieving a stable warfarin dose within 6 months of initiation for individuals with CYP2C9 *1/*2 was 0.2 (0.09, 0.3), 0.2 (0.1, 0.5) for CYP2C9 *1/*3, 0.14 (0.04, 0.6) for CYP2C9 *2/*2, 0.2 (0.03, 0.9) for CYP2C9 *2/*3, and 0.8 (0.45, 0.9) for those with the C/T genotype for CYP4F2. CONCLUSION: We estimated the population time-to-event parameters for achieving a stable warfarin dose in our population and observed CYP2C9 genotypes to be the main predictor covariate followed by CYP4F2. The influence of these SNPs needs to be validated in a prospective study and an algorithm to predict a stable warfarin dose and the time to achieve it needs to be developed.

The prevalence of pharmacogenetic variants of vitamin K epoxide reductase complex subunit 1 gene (rs9923231), cytochrome P450 family 2 subfamily C member 9 gene (rs1799853) and cytochrome P450 family 3 subfamily-A member-5 gene (rs776746) among 13 ethnic groups of Pakistan.

BACKGROUND: Pharmacogenomics (PGx) plays a central role in the selection of targeted therapies that underpins precision-medicine. We investigated the prevalence of three important pharmacogenetic variants of VKORC1, CYP2C9, and CYP3A5 genes among Pakistani populations. METHODS: A total of 1104 individuals were included representing thirteen major ethnicities. Samples were genotyped by using PCR-RFLP analysis. The allelic and genotypic frequencies of the three SNV's were calculated and were compared with the world's population data (ALFA, gnomAD, and 1000Genome, 1 K databases), using the chi-square test. RESULTS: We found overall frequencies of functional-alleles of VKORC1 0.43, CYP2C9 0.94, and CYP3A5 0.14 in our population. Data showed a low prevalence of homozygous functional genotypes of VKORC1 (0.18; 0.0-0.45) and CYP3A5 (0.04; 0.0-0.22), and a high frequency of CYP2C9 (0.885; 0.80-1.0) across ethnicities. Genotyping distribution of VKCOR1 functional genotype was varied across ethnic groups such as 0.0-0.10 in Brahuis and Mohanas, Sindhis, Rajputs, and Gujjars populations, 0.11-0.20 in Makranis, Parsis, and Burusho populations, and 0.20-0.30 in Kalash, Kashmiris and Baloch populations. The highest VKORC1 (CC) was found in Pathans (0.45) and Hazaras (0.39) populations. Interestingly, we found a high prevalence of functional genotype CYP2C9 (rs1799853; C) and non-functional genotype of CYP3A5 (rs776746; T) across various ethnic groups of Pakistan. CONCLUSION: Data regarding prevalence of clinically important pharmacogenomics SNVs could be useful in drug adjustment and avoiding adverse drug reactions in a specific ethnic population. This could help in moving current medical practices toward precision medicine in our part of the world.