Search

Introduction: The decreasing Helicobacter pylori eradication rate is primarily attributed to antibiotic resistance, and further exacerbated by uniform drug administration disregarding a host's metabolic capability. Consequently, applying personalized treatment based on antibiotic resistance-associated variants and the host's metabolic phenotype can potentially increase the eradication rate. Method: A custom next-generation sequencing panel for personalized H. pylori eradication treatment (NGS-PHET) was designed which targeted the regions for amoxicillin, clarithromycin, metronidazole, tetracycline, and levofloxacin-resistance in H. pylori and human proton-pump inhibitor (PPI) metabolism. The libraries were constructed following customized methods and sequenced simultaneously. The customized framework criteria, grounded in previously reported antibiotic resistance associated variants and the host's PPI metabolism, was applied to the NGS-PHET results and suggested a personalized treatment for each subject, which was validated through each subject's actual eradication outcome. Results: Both previously reported and novel variants were identified from H. pylori sequencing results. Concurrently, five CYP2C19 homozygous extensive metabolizers and three CYP3A4 intermediate metabolizers were identified. Among the total of 12 subjects, clarithromycin triple therapy was suggested for five subjects, bismuth quadruple therapy was suggested for six subjects, and rifabutin triple therapy was suggested for one subject by following the customized framework criteria. The treatment suggestion for nine of the 12 subjects was consistent with the treatment that each subject achieved eradication with. Discussion: Applying the methodology using the NGS-PHET and customized framework helps to perform eradication treatment quickly and effectively in most patients with antibiotic-resistant H. pylori strains, and is also useful in research to find novel antibiotic-resistance candidates. [ABSTRACT FROM AUTHOR]

AbstractThe drug-drug interaction (DDI) and CYP2C19 genetic variation can lead to a high blood concentration of voriconazole. CYP2C19 is a highly genetically polymorphic enzyme, and CYP2C19*2 is more frequent among Asians associated with reduced metabolism of drugs. Clinical study found that co-administration with omeprazole significantly increased voriconazole concentrations and there was an additive effect in CYP2C19*2 allele.CYP2C19 rs4244285 (681G>A) is the key polymorphism of CYP2C19*2 allele. This study aims to describe the in vitro effects of omeprazole on CYP2C19*1 and *2 (681G>A), and determine how CYP2C19 polymorphisms influence the DDI between omeprazole and voriconazole.Using the lentiviral expression system, we successfully generated HepG2-derived cell lines stably expressing CYP2C19*1 and *2 (681G>A). The results showed that the CYP2C19 mRNA level, protein level, and enzymatic activity were lower in HepG2-CYP2C19*2 (681G>A) than HepG2-CYP2C19*1 cells. Our study also showed that the inhibition rates of omeprazole on voriconazole had no significantly differences between CYP2C19*1 and *2 (681G>A). But the IC50 of omeprazole on CYP2C19*1 slightly lower than CYP2C19*2 (681G>A).Moreover, omeprazole inhibited CYP2C19 protein level in cells carrying CYP2C19*1 and CYP2C19*2 (681G>A). Our study demonstrated that omeprazole could inhibit voriconazole metabolism in both CYP2C19*1 and CYP2C19*2 (681G>A).The drug-drug interaction (DDI) and CYP2C19 genetic variation can lead to a high blood concentration of voriconazole. CYP2C19 is a highly genetically polymorphic enzyme, and CYP2C19*2 is more frequent among Asians associated with reduced metabolism of drugs. Clinical study found that co-administration with omeprazole significantly increased voriconazole concentrations and there was an additive effect in CYP2C19*2 allele.CYP2C19 rs4244285 (681G>A) is the key polymorphism of CYP2C19*2 allele. This study aims to describe the in vitro effects of omeprazole on CYP2C19*1 and *2 (681G>A), and determine how CYP2C19 polymorphisms influence the DDI between omeprazole and voriconazole.Using the lentiviral expression system, we successfully generated HepG2-derived cell lines stably expressing CYP2C19*1 and *2 (681G>A). The results showed that the CYP2C19 mRNA level, protein level, and enzymatic activity were lower in HepG2-CYP2C19*2 (681G>A) than HepG2-CYP2C19*1 cells. Our study also showed that the inhibition rates of omeprazole on voriconazole had no significantly differences between CYP2C19*1 and *2 (681G>A). But the IC50 of omeprazole on CYP2C19*1 slightly lower than CYP2C19*2 (681G>A).Moreover, omeprazole inhibited CYP2C19 protein level in cells carrying CYP2C19*1 and CYP2C19*2 (681G>A). Our study demonstrated that omeprazole could inhibit voriconazole metabolism in both CYP2C19*1 and CYP2C19*2 (681G>A). [ABSTRACT FROM AUTHOR]

Omeprazole (OME) is a CYP2C19 phenotyping probe, marketed as a racemic (S)/(R) mixture or as an S‐enantiomer. Both CYP2C19 and CYP3A4 enzymes mediate (R)‐OME hydroxylation to (R)‐5‐hydroxyomeprazole, while (S)‐OME is exclusively hydroxylated via CYP2C19. This study investigates OME and its 5‐hydroxymetabolite enantiomers' pharmacokinetics using data from two studies involving healthy volunteers. In Study A, volunteers received OME alone in Session 1, OME combined with voriconazole and fluvoxamine in Session 2 and finally OME with rifampicin in Session 3. In Study B, volunteers received OME alone in Session 1, OME combined with voriconazole in Session 2 and finally OME with fluvoxamine in Session 3. Despite low metabolic ratio values of (S)‐OME, detectable modulation of CYP2C19 activity suggests both (R)‐ and (S)‐OME isomers could effectively assess CYP2C19 activity. Further research is needed for precise cut‐offs in different phenotype groups. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications DT‐678 is a novel antiplatelet prodrug, capable of releasing the antiplatelet active metabolite of clopidogrel (AM) upon exposure to glutathione. In this study, we investigated factors responsible for clopidogrel high on‐treatment platelet reactivity (HTPR) in acute coronary syndrome (ACS) patients and evaluated the capacity of DT‐678 to overcome HTPR.A total of 300 consecutive ACS patients naive to P2Y12 receptor inhibitors were recruited and genotyped for CYP2C19 alleles. Blood samples were drawn before and after administration of 600‐mg clopidogrel. Platelet reactivity index (PRI) and plasma AM concentrations were determined and grouped according to their CYP2C19 genotypes. DT‐678 was applied ex vivo to whole blood samples to examine its inhibitory effects. To further examine the antiplatelet effectiveness of DT‐678 in vivo, 20 healthy human subjects were recruited in a Phase I clinical trial, and each received a single dose of either 3‐mg DT‐678 or 75‐mg clopidogrel. The pharmacokinetics and pharmacodynamics in different CYP2C19 genotype groups were compared.Statistical analyses revealed that CYP2C19 genotype, body mass index, hyperuricaemia, and baseline PRI were significantly associated with a higher risk of clopidogrel HTPR in ACS patients. The addition of DT‐678 ex vivo decreased baseline PRI regardless of CYP2C19 genotypes, overcoming clopidogrel HTPR. This observation was further confirmed in healthy volunteers receiving 3 mg of DT‐678.These results suggest that DT‐678 effectively overcomes clopidogrel HTPR resulting from genetic and/or clinical factors in Chinese ACS patients, demonstrating its potential to improve antiplatelet therapy. [ABSTRACT FROM AUTHOR]

Abrocitinib is a selective Janus kinase 1 inhibitor approved for the treatment of atopic dermatitis. It is metabolized primarily by cytochrome P450 (CYP) 2C19 (approximately 53%) and CYP2C9 (approximately 30%), which form 2 active metabolites. The pharmacologic activity of abrocitinib is attributable to the unbound exposures of abrocitinib and those metabolites with active moiety area under the plasma concentration–time curve (AUC) considered the best measure of the total pharmacological effect. The effect of CYP2C19 and/or CYP2C9 genotypes on abrocitinib and active moiety exposures were evaluated using a meta‐analysis of the noncompartmental estimates of exposure pooled from 10 clinical studies. A linear mixed‐effects model was developed on the basis of the power model to evaluate the effect of CYP2C19 and/or CYP2C9 genotypes on exposure (i.e., abrocitinib AUC and peak plasma concentration, active moiety AUC and peak plasma concentration). The genotypes were evaluated individually and as a combined phenotype effect. When evaluating the poor metabolizers of CYP2C19 or CYP2C9 individually, the estimated increases were 44.9% and 42.0% in active moiety AUC, respectively. The combined phenotype models showed a 0.6% decrease, and 25.1% and 10.5% increases in the active moiety AUC for "elevated," "mixed," and "reduced" metabolizers, respectively. Overall, the active moiety exposures did not appear to be affected to a clinically meaningful extent by different genotypes of CYP2C19 and/or CYP2C9. [ABSTRACT FROM AUTHOR]

Aims: The aim of the present study was to investigate the impact of CYP2D6 genotype on exposure and metabolism of escitalopram in patients stratified by CYP2C19 genotype in a large real‐world population. Methods: Patients were included from a therapeutic drug monitoring service if they had measured serum concentration of escitalopram and the metabolite, N‐desmethyl escitalopram, and performed CYP2C19 and CYP2D6 genotyping. Patients were divided into 16 combined genotype‐predicted phenotype subgroups (poor [PM], intermediate [IM], normal [NM] and ultrarapid metabolizers [UM]) of CYP2C19/CYP2D6. The concentration‐to‐dose (CD) ratio and metabolite‐to‐parent ratio (metabolic ratio) of escitalopram were compared across subgroups using the Kruskal–Wallis test followed by Dunn's test with CYP2D6 NMs as the reference group. Results: A total of 5067 patients were included in the study. A stepwise increase in escitalopram CD ratio by decreasing CYP2D6 activity was observed in all CYP2C19 subgroups, except for in CYP2C19 UMs. The percentage differences in escitalopram CD ratio between CYP2D6 PMs and NMs were 24% in CYP2C19 NMs (P <.001), 28% in CYP2C19 IMs (P <.001) and 31% in CYP2C19 PMs (P =.04). As for the CD ratio, CYP2D6 genotype effect on metabolic ratio increased stepwise by decreasing CYP2C19 metabolism. Conclusions: CYP2D6 genotype is of significant importance for the individual variation in escitalopram pharmacokinetics. The most relevant increase in escitalopram concentration is seen in individuals with decreased and/or absent CYP2C19 activity. By combining CYP2C19 and CYP2D6 genotypes, the optimal dose for patients may be predicted with greater precision than for CYP2C19 genotype alone. [ABSTRACT FROM AUTHOR]

Purpose: A physiologically based pharmacokinetic (PBPK) model for fedratinib was updated and revalidated to bridge a gap between the observed drug–drug interaction (DDI) of a single sub-efficacious dose in healthy participants and the potential DDI in patients with cancer at steady state. The study aimed to establish an appropriate dose for fedratinib in patients coadministered with dual CYP3A4 and CYP2C19 inhibitors, providing quantitative evidence to inform dosing guidance. Methods: The original minimal PBPK model was developed using Simcyp® Simulator v17. The model was updated by substituting a single distribution rate (Qsac) with 2 separate rates (CLin/CLout) and transitioning to v20. Model parameter updates were further informed with 3 clinical studies, and 3 more studies served as independent validation data. The validated model was applied to simulate potential DDIs between fedratinib and a known dual inhibitor of CYP3A4 and CYP2C19 (fluconazole). Results: Coadministration of fedratinib with fluconazole in patients was predicted to increase fedratinib exposure by < 2-fold in all simulated scenarios. For patients with cancer receiving the approved dose of fedratinib 400 mg once daily along with fluconazole 200 mg daily, the model predicted an approximate 50% increase in fedratinib exposure at steady state. Conclusions: The updated PBPK model improved description of the observed pharmacokinetics and predicted a low risk of clinically significant DDIs between fedratinib and fluconazole. The quantitative evidence serves as a primary foundation for providing dose guidance in clinical practice for the coadministration of fedratinib with dual CYP3A4 and CYP2C19 inhibitors. [ABSTRACT FROM AUTHOR]

To compensate for drug response variability, drug metabolism phenotypes are determined based on the results of genetic testing, and if necessary, drug dosages are adjusted. In some cases, discrepancies between predicted and observed phenotypes (phenoconversion) may occur due to drug–drug interactions caused by concomitant medications. We conducted a prospective, exploratory study to evaluate the risk of CYP2C19 phenoconversion in genotyped healthy volunteers exposed to CYP2C19 inhibitors. Three groups of volunteers were enrolled: CYP2C19 g‐RM, g‐NM, and g‐IM (g‐ for genetically predicted). All volunteers received as CYP2C19 phenotyping substrate 10 mg omeprazole (OME) alone at the control session and in co‐administration with CYP2C19 inhibitors: voriconazole 400 mg and fluvoxamine 50 mg in second and third study sessions, respectively. Phenoconversion occurred in over 80% of healthy volunteers, with variations among genotypic groups, revealing distinct proportions in response to fluvoxamine and voriconazole. Statistically significant differences were observed in mean metabolic ratios between CYP2C19 intermediate metabolizers (g‐IMs) with *1/*2 and *2/*17 genotypes, with the *2/*17 group exhibiting lower ratios, and distinctions were noted between genotypic groups, emphasizing the impact of genetic variations on drug metabolism. When reclassified according to CYP2C19 baseline‐measured phenotype into p‐RM, p‐NM, and p‐IM (p‐ for measured phenotype), we observed 100% phenoconversion of p‐RMs and a significant phenotype switch in p‐NMs, p‐IMs, and p‐PMs after fluvoxamine and voriconazole, and complete phenoconversion of p‐IMs to p‐PMs on both inhibitors, emphasizing the impact of genetic variations on the vulnerability to CYP2C19 phenoconversion and the importance of considering both genotyping and phenotyping in predicting drug response. [ABSTRACT FROM AUTHOR]

The ability of freely available in silico tools to predict the effect of non‐synonymous single nucleotide polymorphisms (nsSNPs) in pharmacogenes on protein function is not well defined. We assessed the performance of seven sequence‐based (SIFT, PolyPhen2, mutation accessor, FATHMM, PhD‐SNP, MutPred2, and SNPs & Go) and five structure‐based (mCSM, SDM, DDGun, CupSat, and MAESTROweb) tools in predicting the impact of 118 nsSNPs in the CYP2C19, CYP2C9, CYP2B6, CYP2D6, and DPYD genes with known function (24 normal, one increased, 42 decreased, and 51 no‐function). Sequence‐based tools had a higher median (IQR) positive predictive value (89% [89–94%] vs. 12% [10–15%], P < 0.001) and lower negative predictive value (30% [24–34%] vs. 90% [80–93%], P < 0.001) than structure‐based tools. Accuracy did not significantly differ between sequence‐based (59% [37–67%]) and structure‐based (34% [23–44%]) tools (P = 0.070). Notably, the no‐function CYP2C9*3 allele and decreased function CYP2C9*8 allele were predicted incorrectly as tolerated by 100% of sequenced‐based tools and as stabilizing by 60% and 20% of structure‐based tools, respectively. As a case study, we performed mutational analysis for the CYP2C9*1, *3 (I359L), and *8 (R150H) proteins through molecular dynamic (MD) simulations using S‐warfarin as the substrate. The I359L variant increased the distance of the major metabolic site of S‐warfarin to the oxy‐ferryl center of CYP2C9, and I359L and R150H caused shifts in the conformation of S‐warfarin to a position less favorable for metabolism. These data suggest that MD simulations may better capture the impact of nsSNPs in pharmacogenes than other tools. [ABSTRACT FROM AUTHOR]

Zastaprazan (JP‐1366) is a novel potassium‐competitive acid blocker for the treatment of acid‐related disorders. We aimed to establish a population pharmacokinetic (PK) model of zastaprazan, thereby characterizing the PK of zastaprazan in patients with gastroesophageal reflux disease (GERD) as well as evaluating the impact of various covariates, including CYP2C19 phenotypes, on zastaprazan PK. This population PK analysis included zastaprazan plasma concentration–time data from 92 patients with erosive GERD and 68 healthy volunteers without any gastrointestinal disorders and was performed using nonlinear mixed‐effect modeling. Simulations were conducted to predict zastaprazan PK under various dosing regimens in patients with GERD. The plasma PK of zastaprazan was adequately described by a two‐compartment model with Erlang‐type absorption (six sequential compartments) and first‐order elimination. CYP2C19 phenotypes had no significant effect on zastaprazan PK. The disease status was identified as a significant covariate on apparent clearance of zastaprazan, showing lower values in patients with GERD compared to healthy volunteers. However, the model‐based simulation indicated that the impact of disease status on zastaprazan exposure was not clinically meaningful. Overall, the current population PK model successfully characterized the observed zastaprazan PK in both patients with GERD and healthy volunteers. [ABSTRACT FROM AUTHOR]

Introduction: The decreasing Helicobacter pylori eradication rate is primarily attributed to antibiotic resistance, and further exacerbated by uniform drug administration disregarding a host's metabolic capability. Consequently, applying personalized treatment based on antibiotic resistance-associated variants and the host's metabolic phenotype can potentially increase the eradication rate. Method: A custom next-generation sequencing panel for personalized H. pylori eradication treatment (NGS-PHET) was designed which targeted the regions for amoxicillin, clarithromycin, metronidazole, tetracycline, and levofloxacinresistance in H. pylori and human proton-pump inhibitor (PPI) metabolism. The libraries were constructed following customized methods and sequenced simultaneously. The customized framework criteria, grounded in previously reported antibiotic resistance associated variants and the host's PPI metabolism, was applied to the NGS-PHET results and suggested a personalized treatment for each subject, which was validated through each subject's actual eradication outcome. Results: Both previously reported and novel variants were identified from H. pylori sequencing results. Concurrently, five CYP2C19 homozygous extensive metabolizers and three CYP3A4 intermediate metabolizers were identified. Among the total of 12 subjects, clarithromycin triple therapy was suggested for five subjects, bismuth quadruple therapy was suggested for six subjects, and rifabutin triple therapy was suggested for one subject by following the customized framework criteria. The treatment suggestion for nine of the 12 subjects was consistent with the treatment that each subject achieved eradication with. Discussion: Applying the methodology using the NGS-PHET and customized framework helps to perform eradication treatment quickly and effectively in most patients with antibiotic-resistant H. pylori strains, and is also useful in research to find novel antibiotic-resistance candidates. [ABSTRACT FROM AUTHOR]

Mavacamten is a selective, allosteric, reversible cardiac myosin inhibitor that has been developed for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM). A population pharmacokinetic (PopPK) model was developed to characterize mavacamten pharmacokinetics (PK) and the variation in mavacamten exposure associated with intrinsic and extrinsic factors. Data from 12 clinical studies (phases 1, 2, and 3) were used. Evaluable participants were those who had at least one mavacamten concentration measurement with associated sampling time and dosing information. The base model included key covariates: body weight, cytochrome P450 isozyme 2C19 (CYP2C19) phenotype with respect to PK, and formulation. The final model was generated using stepwise covariate testing and refinement processes. Simulations were performed to evaluate PK: apparent clearance (CL/F); apparent central and peripheral volumes of distribution; and steady‐state average, trough, and maximum concentrations. Overall, 9244 measurable PK observations from 497 participants were included. A two‐compartment model structure was selected. After stepwise covariate model building and refinement, additional covariates included were: specified mavacamten dose, omeprazole or esomeprazole administration, health/disease status, estimated glomerular filtration rate, fed status, and sex. The final PopPK model accurately characterized mavacamten concentrations. At any given dose, CYP2C19 phenotype was the most influential covariate on exposure parameters (e.g., median CL/F was reduced by 72% in CYP2C19:poor metabolizers compared with the reference participant [CYP2C19:normal metabolizer]). CL/F was also approximately 16% higher in women than in men but lower in participants receiving concomitant omeprazole or esomeprazole (by 33% and 42%, respectively) than in participants not receiving such concomitant therapy. [ABSTRACT FROM AUTHOR]

This study employed physiologically‐based pharmacokinetic–pharmacodynamics (PBPK/PD) modeling to predict the effect of obesity and gastric bypass surgery on the pharmacokinetics and intragastric pH following omeprazole treatment. The simulated plasma concentrations closely matched the observed data from non‐obese, morbidly obese, and post‐gastric bypass populations. Obesity significantly reduces CYP3A4 and CYP2C19 activities, as reflected by the metabolic ratio [omeprazole sulphone]/[omeprazole] and [5‐hydroxy‐omeprazole]/[omeprazole]. The morbidly obese model accounted for the down‐regulation of CYP2C19 and CYP3A4 to recapitulate the observed data. Sensitivity analysis showed that intestinal CYP3A4, gastric pH, small intestine bypass, and the delay in bile release do not have a major influence on omeprazole exposure. Hepatic CYP3A4 had a significant impact on the AUC of (S)‐omeprazole, while hepatic CYP2C19 affected both (R)‐ and (S)‐omeprazole AUC. After gastric bypass surgery, the activity of CYP3A4 and CYP2C19 is restored. The PBPK model was linked to a mechanism‐based PD model to assess the effect of omeprazole on intragastric pH. Following 40 mg omeprazole, the mean intragastric pH was 4.3, 4.6, and 6.6 in non‐obese, obese, and post‐gastric bypass populations, and the daily time with pH >4 was 14.7, 16.4, and 24 h. Our PBPK/PD approach provides a comprehensive understating of the impact of obesity and weight loss on CYP3A4 and CYP2C19 activity and omeprazole pharmacokinetics. Given that simulated intragastric pH is relatively high in post‐RYGB patients, irrespective of the dose of omeprazole, additional clinical outcomes are imperative to assess the effect of proton pump inhibitor in preventing marginal ulcers in this population. [ABSTRACT FROM AUTHOR]

Mavacamten is the first cardiac myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM). The phase III EXPLORER‐HCM (NCT03470545) study used a dose‐titration scheme based on mavacamten exposure and echocardiographic assessment of Valsalva left ventricular outflow tract gradient (VLVOTg) and left ventricular ejection fraction (LVEF). Using population pharmacokinetic/exposure‐response modeling and simulations of virtual patients, this in silico study evaluated alternative dose‐titration regimens for mavacamten, including regimens that were guided by echocardiographic measures only. Mavacamten exposure‐response models for VLVOTg (efficacy) and LVEF (safety) were developed using patient data from five clinical studies and characterized using nonlinear mixed‐effects models. Simulations of five echocardiography‐guided regimens were performed in virtual cohorts constructed based on either expected or equal population distributions of cytochrome P450 2C19 (CYP2C19) metabolizer phenotypes. Each regimen aimed to maximize the proportions of patients who achieved a VLVOTg below 30 mm Hg while maintaining LVEF above 50% over 40 weeks and 104 weeks, respectively. The exposure‐response models successfully characterized mavacamten efficacy and safety parameters. Overall, the simulated regimen with the optimal benefit–risk profile across CYP2C19 phenotypes had steps for down‐titration at weeks 4 and 8 (for VLVOTg <20 mm Hg), and up‐titration at week 12 (for VLVOTg ≥30 mm Hg and LVEF ≥55%), and every 12 weeks thereafter. This simulation‐optimized regimen is recommended in the mavacamten US prescribing information. [ABSTRACT FROM AUTHOR]

Voriconazole pharmacokinetics (PK) are known to be affected by genetic polymorphisms of drug-metabolizing enzymes such as CYP2C19 ; however, such information is limited for the pediatric population. The primary aim of this study is to establish a voriconazole PK model incorporating CYP2C19 phenotypes in Japanese children with malignancy or inborn errors of immunity. CYP2C19 genotypes were assessed by whole-genome genotyping and defined as follows: *17/*17: ultrarapid metabolizer (URM), *1/*17: rapid metabolizer (RM), *1/*1:normal metabolizer (NM), *1/*2, *1/*3, *2/*17:intermediate metabolizer (IM), and *2/*2, *2/*3, *3/*3: poor metabolizer (PM). Population PK analysis was performed. The voriconazole serum concentration profile was described by a two-compartment model with first-order absorption, mixed linear and nonlinear (Michaelis-Menten) elimination. Voriconazole concentration data were available from 60 patients with a median age of 5.3 years. The phenotypes predicted from CYP2C19 genotypes were RM in 1 (2 %), NM in 21 (35 %) patients, IM in 27 (45 %) patients, and PM in 11 (18 %) patients. Underlying diseases included 38 (63%) patients with hematological malignancy and 18 (30 %) patients with inborn errors of immunity. Among the CYP2C19 phenotypes, PM was predicted to show complete inhibition (the degree of V max inhibition [V max, inh ] = 100 %; V max = 0). The estimated parameters of V max,inh were +0.8 higher in patients with gamma-glutamyl transpeptidase (γ-GTP) Grade 2 or higher and +2.7 higher when C -reactive protein (CRP) levels were 2.0 mg/dL or higher. CYP2C19 genetic polymorphisms, γ-GTP, and CRP affect V max,inh of voriconazole in children with malignancy or inborn errors of immunity. [ABSTRACT FROM AUTHOR]

We developed and evaluated several new fused imidazo[1,2‐d][1,2,4]thiadiazolo[1,2,3]triazoles to see how they perform against bacteria and biofilms. Some compounds showed acceptable activity compared to the primary standard, Dicloxacillin. Some of the compounds demonstrated significant antibacterial activity against S. aureus, with MIC values ranging from 1.56–12.5 μg/mL. We also found anti‐biofilm properties in the potent compounds. The results showed that derivatives 3‐(4‐fluorophenyl)imidazo[1,2‐d] [1,2,3] triazolo[1,5‐b][1,2,4]thiadiazole 8,8‐dioxide and 3‐(3,5‐difluorophenyl)imidazo[1,2‐d][1,2,3]triazolo[1,5‐b][1,2,4] thiadiazole 8,8‐dioxide were strong antibacterial agents and effective MSSA and MRSA biofilm growth inhibitors. We conducted in silico studies to assess the molecular interactions of more potent compounds with TLR4 proteins (PDB: 3FXI, 3VQ1, 3RG1). Our findings revealed that 3‐(4‐chloro‐3,5‐dimethoxyphenyl)imidazo[1,2‐d][1,2,3]triazolo[1,5‐b] [1,2,4]thiadiazole 8,8‐dioxide, 3‐(3,5‐dichlorophenyl)imidazo[1,2‐d] [1,2,3]triazolo[1,5‐b][1,2,4] thiadiazole 8,8‐dioxide, and 3‐(4‐(trifluoromethyl)phenyl)imidazo[1,2‐d][1,2,3]triazolo[1,5‐b][1,2,4] thiadiazole 8,8‐dioxide exhibited more binding interactions than dicloxacillin. ADME of more potent compounds examined in this study and compounds could potentially inhibit the cytochrome P450 CYP2C19 isoform. [ABSTRACT FROM AUTHOR]

This article presents a study on the distribution of cytochrome P450 (CYP450) alleles in the Danish population. CYP450 enzymes are important for drug metabolism, and genetic variations in the genes encoding these enzymes can impact drug response. The study compared genotype data from different genotyping platforms and found that the CYP2C19*17 and CYP2C9*2 alleles were more common than the CYP2C19*2 and CYP2C9*3 alleles. The results provide valuable insights into the genetic variability of these enzymes in the Danish population and suggest that the Illumina GSA platform could be useful for identifying drug-gene interactions. [Extracted from the article]

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor (clopidogrel, prasugrel, or ticagrelor) is indicated after percutaneous coronary intervention (PCI) to reduce the risk of atherothrombotic events. Approximately 30% of the US population has a CYP2C19 no‐function allele that reduces the effectiveness of clopidogrel, but not prasugrel or ticagrelor, after PCI. We have shown improved outcomes with the integration of CYP2C19 genotyping into clinical care to guide the selection of prasugrel or ticagrelor in CYP2C19 no‐function allele carriers. However, the influence of patient‐specific demographic, clinical, and other genetic factors on outcomes with genotype‐guided DAPT has not been defined. In addition, the impact of genotype‐guided de‐escalation from prasugrel or ticagrelor to clopidogrel in patients without a CYP2C19 no‐function allele has not been investigated in a diverse, real‐world clinical setting. The Precision Antiplatelet Therapy after Percutaneous Coronary Intervention (Precision PCI) Registry is a multicenter US registry of patients who underwent PCI and clinical CYP2C19 testing. The registry is enrolling a diverse population, assessing atherothrombotic and bleeding events over 12 months, collecting DNA samples, and conducting platelet function testing in a subset of patients. The registry aims to define the influence of African ancestry and other patient‐specific factors on clinical outcomes with CYP2C19‐guided DAPT, evaluate the safety and effectiveness of CYP2C19‐guided DAPT de‐escalation following PCI in a real‐world setting, and identify additional genetic influences of clopidogrel response after PCI, with the ultimate goal of establishing optimal strategies for individualized antiplatelet therapy that improves outcomes in a diverse, real‐world population. [ABSTRACT FROM AUTHOR]

Introduction: Clopidogrel remains widely utilized in patients undergoing percutaneous coronary intervention despite compelling evidence that genetic variation impacts patient response to clopidogrel. Clinical decision support (CDS) is frequently used to aid in precision medicine; however, limitations within the electronic medical record can hinder reliable CDS. Procedural areas where standard order entry is not utilized create a barrier to CDS implementation. Objectives: We aimed to evaluate the implementation of a novel alerting mechanism on genotype‐guided antiplatelet prescribing within the cardiac catheterization laboratory procedural setting. Methods: A retrospective cohort study was conducted to assess the rate of antiplatelet ordering in patients with one or two loss‐of‐function cytochrome P450 2C19 (CYP2C19) alleles before and after alert implementation. Pharmacogenomic congruence was measured before and after the alert via chart abstraction that included the CYP2C19 genotype and antiplatelet medications ordered within that encounter. Results: A total of 236 patients were included in analyses, 127 encounters within the cohort before alert implementation and 136 encounters in the cohort after alert implementation. Prior to alert implementation, 40.9% (n = 127) were prescribed clopidogrel compared with 25.7% (n = 136) post implementation. After implementing a genotype‐guided alert within the cardiac catheterization laboratory procedural setting, providers were 2.22 times more likely to prescribe an alternative antiplatelet (p = 0.024). Clopidogrel‐naïve patients were 9.75 times more likely to receive a genotype‐guided antiplatelet order following alert implementation (p < 0.05). Conclusion: Providers were responsive to a novel alert within the cardiac catheterization laboratory procedural setting. Genotype‐guided antiplatelet prescribing significantly increased following the alert implementation. [ABSTRACT FROM AUTHOR]

The Department of Veterans Affairs (VA) utilizes a pharmacogenomic (PGx) program that analyzes specific "pharmacogenes." This study evaluates the effect that pharmacogenes may have on prevalence of polypharmacy. This retrospective cohort study included patients with VA prescriptions who underwent PGx testing. We quantified prescriptions active or recently expired at the time of PGx testing. We constructed two co‐primary polypharmacy (≥10 medications) end points: (i) based on all medications and (ii) requiring that at least one medication was affected by a pharmacogene of interest. Pharmacogenes and actionable phenotypes of interest included poor and ultrarapid metabolizers for CYP2D6, CYP2C9, and CYP2C19 and intermediate and normal metabolizers for CYP3A5. Patients were classified as having 0, 1, and 2+ total phenotypes across all genes. Of the 15,144 patients screened, 13,116 met eligibility criteria. Across phenotype cohorts, there was no significant association with polypharmacy using all medications, number of total medications, or number of medications affected by phenotypes. However, there was a significant difference in patients with polypharmacy prescribed ≥1 medication impacted by PGx across phenotype groups: 2,514/4,949 (51%), 1,349/2,595 (52%), 204/350 (58%) (P = 0.03, OR 1.31, 95% CI 1.02–1.67). The median number of medications affected by PGx phenotypes with ≥1 PGx‐impacted medication across phenotype groups was a median of 0 (IQR 0, 0), 0 (IQR 0, 0), and 1 (IQR 0, 1) (P < 0.001). In patients prescribed ≥1 medication impacted by PGx, those with more actionable pharmacogenomic phenotypes were more likely to meet polypharmacy criteria. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19)‐associated pulmonary aspergillosis superinfection with cytokine storm is associated with increased mortality. This study aimed to establish a physiologically‐based pharmacokinetic (PK) model to investigate the disease‐drug–drug interactions between voriconazole and nirmatrelvir/ritonavir in patients with COVID‐19 with elevated interleukin‐6 (IL‐6) levels carrying various CYP2C19 phenotypes. The model was constructed and validated using PK data on voriconazole, ritonavir, and IL‐6, and was subsequently verified against clinical data from 78 patients with COVID‐19. As a result, the model predicted voriconazole, ritonavir, and IL‐6 PK parameters and drug–drug interaction‐related fold changes in healthy subjects and patients with COVID‐19 with acceptable prediction error, demonstrating its predictive capability. Simulations indicated ritonavir could increase voriconazole exposure to CYP2C19 intermediate and poor metabolizers rather than decrease it, in contrast to what is indicated in the drug package insert. However, the predicted ritonavir exposures were comparable across subjects. In patients with COVID‐19, both ritonavir and IL‐6 increased voriconazole trough concentrations, which may lead to CYP2C19 phenotype‐dependent overexposure. In conclusion, COVID‐19‐induced IL‐6 elevation and ritonavir increased voriconazole exposure, and the magnitude of interactions was influenced by CYP2C19 phenotype. Thus, caution is warranted when prescribing voriconazole concomitantly with Paxlovid in patients with COVID‐19. [ABSTRACT FROM AUTHOR]

Background: Helicobacter pylori eradication therapy based on antimicrobial susceptibility in Vietnamese children currently get low efficiency. There are causes of treatment failure, among host genetic factors namely MDR1 C3435T and CYP2C19 affect the absorption and metabolism of proton pump inhibitors - a crucial component of eradication therapy. The study aimed to investigate the effect of MDR1 C3435T and CYP2C19 genetic polymorphisms on the cure rate. Methods: 207 pediatric patients with gastritis and peptic ulcer infecting Helicobacter pylori completed the eradication therapy based on antimicrobial susceptibility with proton pump inhibitor esomeprazole. Eradication efficacy was assessed after at least 4 weeks by the urease breath test. MDR1 C3435T genetic polymorphism and CYP2C19 genotype were determined using a sequencing method based on Sanger's principle. Results: Among 207 children recruited in this study, the ratio of CYP2C19 EM, IM, and PM phenotypes was 40.1%, 46.4%, and 16.9%, respectively. The patient with MDR1 3435 C/C polymorphism accounted for 43.0%, MDR1 3435 C/T was 40.1%, and MDR1 3435T/T was 16.9%. The cure rate of Helicobacter pylori infection in patients with CYP2C19 EM genotype was 78.3%; 83.3% of those with the IM genotype, and PM genotype was 96,4% (p = 0.07). Successful eradication rates for Helicobacter pylori were 85.4%, 86.7%, and 68.6% in patients with the MDR1 3435 C/C, C/T, and T/T, respectively (p = 0.02). Multiple logistic regression analysis found that MDR1 C3435T genetic polymorphisms of patients were significant independent risk factors for treatment failure, and CYP2C19 genotype did not affect Helicobacter pylori eradication. Conclusions: The Helicobacter pylori eradication rates by regimens based on antibiotic susceptibility and esomeprazole were not significantly different between the CYP2C19 phenotypes. The MDR1 C3435T polymorphism is one of the factors impacting Helicobacter pylori eradication results in children. [ABSTRACT FROM AUTHOR]

Voriconazole is the cornerstone of the treatment and prevention of fungal infections. While there is a good correlation between CYP2C19 genotype and voriconazole exposure during prophylactic treatment, no correlation was found in patients with invasive aspergillosis. Proinflammatory cytokines result in inhibition of CYP2C19 enzyme activity (and may result in phenoconversion). Here we investigated the relationship between inflammation, CYP2C19 genotype‐predicted‐phenotype, and CYP2C19 activity in patients receiving voriconazole. Data were obtained from two prospective studies investigating voriconazole treatment (NCT02074462 and NCT00893555). Dose‐corrected voriconazole plasma concentration and C‐reactive protein (CRP) were used as proxies for CYP2C19 activity and inflammation, respectively. After data extraction and synthesis, data from 39 patients with paired voriconazole and CRP measurements were available. The distribution of CYP2C19 genotype‐predicted metabolizer phenotypes was 31% intermediate (IM), 41% normal (NM), and 28% rapid metabolizer (RM). During inflammation, dose‐corrected voriconazole levels were increased by 245%, 278%, and 486% for CYP2C19 NMs IMs and RMs, respectively. Patients with moderate or high CRP levels (>50 mg/L) were phenoconverted to a lower metabolizer phenotype irrespective of their CYP2C19 genotype. In a subgroup analysis of eight patients with longitudinal data available with and without inflammation, the pattern of the dose‐corrected voriconazole and CRP measurements were similar, with CYP2C19 activity following decreasing or increasing CRP levels. In conclusion, voriconazole plasma concentrations increase during inflammation due to downregulation of CYP2C19 activity. While this effect appears largest for CYP2C19 RMs, no clinically relevant differences were observed between the CYP2C19 genotypes. [ABSTRACT FROM AUTHOR]

Obstructive hypertrophic cardiomyopathy (oHCM) is a subtype of HCM characterized by left ventricular outflow tract obstruction resulting from cardiac muscle hypertrophy and anatomic alterations in the mitral valve and apparatus. Mavacamten, a cardiac myosin inhibitor metabolized primarily by CYP2C19 in the liver, is the first and only targeted medication approved for the treatment of symptomatic New York Heart Association (NYHA) class II–III oHCM. Previous pharmacokinetic (PK) results of mavacamten in healthy Caucasian, Japanese, and Asian participants demonstrated that mavacamten exposure was affected by CYP2C19 metabolism status. This open‐label, parallel‐group, phase I trial aimed to determine the PK and safety of mavacamten in healthy Chinese participants with different CYP2C19 genotypes. The primary outcome was to define the PK of mavacamten in healthy Chinese participants; the secondary outcome was to examine safety and tolerability. After a single oral dose of 15 or 25 mg mavacamten in fasted healthy adult Chinese individuals, Cmax was reached within a median Tmax of 0.6–1.5 h, indicating rapid absorption. Inter‐individual variability was moderate, and individuals carrying non‐functional CYP2C19 alleles (*2/*2, *3/*3, or *2/*3) exhibited longer half‐life and increased total exposure. After stratification of CYP2C19 genotypes, total mavacamten exposures were similar among different ethnic groups when compared with prior PK studies. No significant adverse events were observed in this study. Single oral administration of mavacamten at 15 mg was well tolerated across all CYP2C19 genotypes, and 25 mg dose was well tolerated in healthy participants with CYP2C19 genotypes UM/RM/NM. The PK profile of mavacamten in the healthy Chinese population was consistent with that in other healthy populations. [ABSTRACT FROM AUTHOR]

Copyright of Traditional Chinese Drug Research & Clinical Pharmacology is the property of Traditional Chinese Drug Research & Clinical Pharmacology Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Although great progress has been made in the fine‐tuning of diplotypes, there is still a need to further improve the predictability of individual phenotypes of pharmacogenetically relevant enzymes. The aim of this study was to analyze the additional contribution of sex and variants identified by exome chip analysis to the metabolic ratio of five probe drugs. A cocktail study applying dextromethorphan, losartan, omeprazole, midazolam, and caffeine was conducted on 200 healthy volunteers. CYP2D6, 2C9, 2C19, 3A4/5, and 1A2 genotypes were analyzed and correlated with metabolic ratios. In addition, an exome chip analysis was performed. These SNPs correlating with metabolic ratios were confirmed by individual genotyping. The contribution of various factors to metabolic ratios was assessed by multiple regression analysis. Genotypically predicted phenotypes defined by CPIC discriminated very well the log metabolic ratios with the exception of caffeine. There were minor sex differences in the activity of CYP2C9, 2C19, 1A2, and CYP3A4/5. For dextromethorphan (CYP2D6), IP6K2 (rs61740999) and TCF20 (rs5758651) affected metabolic ratios, but only IP6K2 remained significant after multiple regression analysis. For losartan (CYP2C9), FBXW12 (rs17080138), ZNF703 (rs79707182), and SLC17A4 (rs11754288) together with CYP diplotypes, and sex explained 50% of interindividual variability. For omeprazole (CYP2C19), no significant influence of CYP2C:TG haplotypes was observed, but CYP2C19 rs12777823 improved the predictability. The comprehensive genetic analysis and inclusion of sex in a multiple regression model significantly improved the explanation of variability of metabolic ratios, resulting in further improvement of algorithms for the prediction of individual phenotypes of drug‐metabolizing enzymes. [ABSTRACT FROM AUTHOR]

Introduction: CYP2C19 plays a major role in the metabolism of various drugs. The most common genetic variants were the CYP2C19*2 and *3 alleles (rs4244285 and rs4986893, non-functional variants). In previous studies, we found that genetic polymorphisms in CYP2C19 variants influenced the active metabolites of clopidogrel and caused major adverse cardiovascular and cerebrovascular effects. However, the distribution of CYP2C19 varies among ethnic groups and according to adverse drug reactions. This study aimed to investigate the frequency of CYP2C19 genetic polymorphisms in the Thai population and analyze the differences in the frequency of CYP2C19 genetic polymorphisms between Thai and other populations. Methods: This study enrolled 211 unrelated healthy Thai individuals in total. We performed a real-time polymerase chain reaction to genotype CYP2C19*2 (681G > A) and CYP2C19*3 (636G > A). Results: In the Thai population, the CYP2C19*1 allele was the most prevalent at 70.14%, while the CYP2C19*2 and *3 alleles were found at frequencies of 25.36% and 4.50%, respectively. Conversely, the CYP2C19*3 allele was not detected in Caucasian, Hispanic, African, Italian, Macedonian, Tanzanian, or North Indian populations. The phenotypic profile of this gene revealed that the frequency of intermediate metabolizers (IMs) is nearly equal to that of extensive metabolizers (EMs), at 42.65% and 48.82% respectively, with genotypes *1/*2 (36.02%) and *1/*3 (6.63%). Likewise, poor metabolizers (PMs) with genotypes *2/*2 (6.16%), *2/*3 (2.37%), and *3/*3 (< 1%) are more prevalent in our population as well. Conclusion: The distribution of CYP2C19 genotype and phenotype influenced by non-functional alleles has potential as a pharmacogenomics biomarker for precision medicine and is dependent on an ethnic-specific genetic variation database. [ABSTRACT FROM AUTHOR]

Background: Despite Antiplatelet therapy (APT), cardiovascular patients undergoing revascularisation remain at high risk for thrombotic events. Individual response to APT varies substantially, resulting in insufficient protection from thrombotic events due to high on-treatment platelet reactivity (HTPR) in ≤40% of patients. Individual variation in platelet response impairs APT guidance on a single patient level. Unfortunately, little is known about individual platelet response to APT over time, timing for accurate residual platelet reactivity measurement, or the optimal test to monitor residual platelet reactivity. Aims: To investigate residual platelet reactivity variability over time in individual patients undergoing carotid endarterectomy (CEA) treated with clopidogrel. Methods: Platelet reactivity was determined in patients undergoing CEA in a prospective, single-centre, observational study using the VerifyNow (change in turbidity from ADP-induced binding to fibrinogen-coated beads), the VASP assay (quantification of phosphorylation of vasodilator-stimulated phosphoprotein), and a flow-cytometry-based assay (PACT) at four perioperative time points. Genotyping identified slow (CYP2C19*2 and CYP2C19*3) and fast (CYP2C19*17) metabolisers. Results: Between December 2017 and November 2019, 50 patients undergoing CEA were included. Platelet reactivity measured with the VerifyNow (p = <.001) and VASP (p =.029) changed over time, while the PACT did not. The VerifyNow identified patients changing HTRP status after surgery. The VASP identified patients changing HTPR status after eight weeks (p =.018). CYP2C19 genotyping identified 13 slow metabolisers. Conclusion: In patients undergoing CEA, perioperative platelet reactivity measurements fluctuate over time with little agreement between platelet reactivity assays. Consequently, HTPR status of individual patients measured with the VerifyNow and VASP assay changed over time. Therefore, generally used perioperative platelet reactivity measurements seem unreliable for adjusting perioperative APT strategy. [ABSTRACT FROM AUTHOR]

Antiplatelet therapy is an important factor influencing the postterm patency rate of carotid artery stenting (CAS). Clopidogrel is a platelet aggregation inhibitor mediated by the adenosine diphosphate receptor and is affected by CYP2C19 gene polymorphisms in vivo. When the CYP2C19 gene has a nonfunctional mutation, the activity of the encoded enzyme will be weakened or lost, which directly affects the metabolism of clopidogrel and ultimately weakens its antiplatelet aggregation ability. Therefore, based on network pharmacology, analyzing the influence of CYP2C19 gene polymorphisms on the antiplatelet therapeutic effect of clopidogrel after CAS is highly important for the formulation of individualized clinical drug regimens. The effect of the CYP2C19 gene polymorphism on the antiplatelet aggregation of clopidogrel after CAS was analyzed based on network pharmacology. A total of 100 patients with ischemic cerebrovascular disease who were confirmed by the neurology department and required CAS treatment were studied. CYP2C19 genotyping was performed on all patients via a gene chip. All patients were classified into the wild-type (WT) group (*1/*1), heterozygous mutation (HTM) group (CYP2C19*1/*2, CYP2C19*1/*3), and homozygous mutation (HMM) group (CYP2C19*2/*2, CYP2C19*2/*3, and CYP2C19*3/*3). High-performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) was used to detect the blood concentration of clopidogrel and the plasma clopidogrel clearance (CL) rate in different groups of patients before and after clopidogrel treatment. The platelet aggregation rate of patients with different genotypes was measured by turbidimetry. The incidences of clopidogrel resistance (CR) and stent thrombosis in different groups after three months of treatment were analyzed. The results showed that among the different CYP2C19 genotypes, patients from the HTM group accounted for the most patients, while patients from the HTM group accounted for the least patients. Similarly, the clopidogrel CL of patients in the HMM group was lower than that of patients in the WT group and HTM group (P < 0.01). The platelet inhibition rate of patients in the HMM group was evidently inferior to that of patients in the WT group and HTM group (P < 0.01). The incidence of CR and stent thrombosis in the WT group was notably lower than that in the HTM and HMM groups (P < 0.01). These results indicate that the CYP2C19 gene can affect CR occurrence and stent thrombosis after CAS by influencing clopidogrel metabolism and platelet count. [ABSTRACT FROM AUTHOR]

Medical economics is essential in cardiac genetics for the clinical application and development of research results. However, related economic evaluations are unclear, and limited systematic reviews are available on the cost-effectiveness of drug selection based on the CYP2C19 LOF allele. This review analyzed research in the MEDLINE database from January 2012 to June 2023 using more evidence than a well-designed cohort study, owing to the lack of relevant research in the database. For example, cost-effectiveness analyses are often reported as simulation assays, and were included in this analysis. No conditions related to patient background or antiplatelet drug therapy were selected. This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (2020). Twenty-one cardiac genetic studies were selected, of which nineteen involved antiplatelet therapy after PCI. A universal group consisting of clopidogrel and other drugs was used as the baseline and compared with the drug selection groups based on the CYP2C19 LOF allele. The incremental cost–effectiveness ratio was generally below 50,000 (US$/Qaly), and drug selection based on the CYP2C19 LOF allele was the most cost-effective, followed by universal clopidogrel. Although cardiac genetic and economic data are rudimentary, this review indicates that antiplatelet therapy (drug selection based on the CYP2C19 LOF allele) after PCI is generally cost-effective. [ABSTRACT FROM AUTHOR]

Pseudoginsenoside DQ (PDQ), an ocotillol-type ginsenoside, is synthesized with protopanaxadiol through oxidative cyclization. PDQ exhibits good anti-arrhythmia activity. However, the inhibitory effect of PDQ on the cytochrome 450 (CYP450) enzymes and major drug transporters is still unclear. Inhibition of CYP450 and drug transporters may affect the efficacy of the drugs being used together with PDQ. These potential drug–drug interactions (DDIs) are essential for the clinical usage of drugs. In this study, we investigated the inhibitory effect of PDQ on seven CYP450 enzymes and seven drug transporters with in vitro models. PDQ has a significant inhibitory effect on CYP2C19 and P-glycoprotein (P-gp) with a half-inhibitory concentration (IC50) of 0.698 and 0.41 μM, respectively. The inhibition of CYP3A4 and breast cancer-resistant protein (BCRP) is less potent, with IC50 equal to 2.02–6.79 and 1.08 μM, respectively. [ABSTRACT FROM AUTHOR]

Variability in hepatic cytochrome P450 (CYP) enzymes such as 2C19 and 2D6 may influence side-effect and efficacy outcomes for antipsychotics. Aripiprazole and risperidone are two commonly prescribed antipsychotics, metabolized primarily through CYP2D6. Here, we aimed to provide an overview of the effect of CYP2C19 and CYP2D6 on side-effects of aripiprazole and risperidone, and expand on existing literature by critically examining methodological issues associated with pharmacogenetic studies. A PRISMA compliant search of six electronic databases (Pubmed, PsychInfo, Embase, Central, Web of Science, and Google Scholar) identified pharmacogenetic studies on aripiprazole and risperidone. 2007 publications were first identified, of which 34 were included. Quality of literature was estimated using Newcastle-Ottowa Quality Assessment Scale (NOS) and revised Cochrane Risk of Bias tool. The average NOS score was 5.8 (range: 3–8) for risperidone literature and 5 for aripiprazole (range: 4–6). All RCTs on aripiprazole were rated as high risk of bias, and four out of six for risperidone literature. Study populations ranged from healthy volunteers to inpatient individuals in psychiatric units and included adult and pediatric samples. All n = 34 studies examined CYP2D6. Only one study genotyped for CYP2C19 and found a positive association with neurological side-effects of risperidone. Most studies did not report any relationship between CYP2D6 and any side-effect outcome. Heterogeneity between and within studies limited the ability to synthesize data and draw definitive conclusions. Studies lacked statistical power due to small sample size, selective genotyping methods, and study design. Large-scale randomized trials with multiple measurements, providing robust evidence on this topic, are suggested. • Personalizing psychiatric medication may be achieved through pharmacogenetics. • Metabolic enzymes CYP2C19 and CYP2D6 are of interest for psychopharmacology. • Combining all available data suggests that empirical evidence remains mixed. • Some evidence exists for a link between CYP2D6 and side-effects of risperidone. • Research on CYP2C19 and antipsychotic medication is lacking. [ABSTRACT FROM AUTHOR]

Introduction: The activity changes of cytochrome P450 (CYP450) enzymes, along with the complicated medication scenarios in diabetes mellitus (DM) patients, result in the unanticipated pharmacokinetics (PK), pharmacodynamics (PD), and drug–drug interactions (DDIs). Physiologically based pharmacokinetic (PBPK) modeling has been a useful tool for assessing the influence of disease status on CYP enzymes and the resulting DDIs. This work aims to develop a novel diabetic PBPK population model to facilitate the prediction of PK and DDI in DM patients. Methods: First, mathematical functions were constructed to describe the demographic and non-CYP physiological characteristics specific to DM, which were then incorporated into the PBPK model to quantify the net changes in CYP enzyme activities by comparing the PK of CYP probe drugs in DM versus non-DM subjects. Results: The results show that the enzyme activity is reduced by 32.3% for CYP3A4/5, 39.1% for CYP2C19, and 27% for CYP2B6, while CYP2C9 activity is enhanced by 38% under DM condition. Finally, the diabetic PBPK model was developed through integrating the DM-specific CYP activities and other parameters and was further used to perform PK simulations under 12 drug combination scenarios, among which 3 combinations were predicted to result in significant PK changes in DM, which may cause DDI risks in DM patients. Conclusions: The PBPK modeling applied herein provides a quantitative tool to assess the impact of disease factors on relevant enzyme pathways and potential disease-drug–drug-interactions (DDDIs), which may be useful for dosing regimen optimization and minimizing the DDI risks associated with the treatment of DM. [ABSTRACT FROM AUTHOR]

This cohort study aims to assess the connection between cytochrome P450 family 2 subfamily C member 19 (CYP2C19) genotyping, platelet aggregability following oral clopidogrel administration, and the occurrence of postoperative atrial fibrillation (POAF) after off‐pump coronary artery bypass graft (CABG) surgery. From May 2017 to November 2022, a total of 258 patients undergoing elective first‐time CABG surgery, receiving 100 mg/day oral aspirin and 75 mg/day oral clopidogrel postoperatively, was included for analysis. These patients were categorized based on CYP2C19 genotyping. Platelet aggregability was assessed serially using multiple‐electrode aggregometry before CABG, 1 and 5 days after the procedure, and before discharge. The incidences of POAF were compared using the log‐rank test for cumulative risk. CYP2C19 genotyping led to categorization into CYP2C19*1*1 (WT group, n = 123) and CYP2C19*2 or *3 (LOF group, n = 135). Baseline characteristics and operative data showed no significant differences between the two groups. The incidence of POAF after CABG was 42.2% in the LOF group, contrasting with 22.8% in the WT group (hazard risk [HR]: 2.061; 95% confidence interval [CI]: 1.347, 3.153; p = 0.0013). Adenosine diphosphate‐stimulated platelet aggregation was notably higher in the LOF group compared to the WT group 5 days after CABG (30.4% ± 6.5% vs. 17.9% ± 4.1%, p < 0.001), remaining a similar higher level at hospital discharge (25.6% ± 6.1% vs. 12.2% ± 3.5%, p < 0.001). The presence of CYP2C19 LOF was linked to a higher incidence of POAF and relatively elevated platelet aggregation after CABG surgery under the same oral clopidogrel regimen. [ABSTRACT FROM AUTHOR]

Loss-of-function CYP2C19 variants are associated with increased cumulative ischemic outcomes warranting CYP2C19 genotyping prior to clopidogrel administration. TAILOR-PCI was an international, multicenter (40 sites), prospective, randomized trial comparing rapid point of care (POC) genotype-guided vs. conventional anti-platelet therapy. The performance of buccal-based rapid CYP2C19 genotyping performed by non-laboratory-trained staff in TAILOR-PCI was assessed. Pre-trial training and evaluation involved rapid genotyping of 373 oral samples, with 99.5% (371/373) concordance with Sanger sequencing. During TAILOR-PCI, 5302 patients undergoing PCI were randomized to POC rapid CYP2C19 *2, *3, and *17 genotyping versus no genotyping. At 12 months post-PCI, TaqMan genotyping determined 99.1% (2,364/2,385) concordance with the POC results, with 90.7-98.8% sensitivity and 99.2-99.6% specificity. In conclusion, non-laboratory personnel can be successfully trained for on-site instrument operation and POC rapid genotyping with analytical accuracy and precision across multiple international centers, thereby supporting POC genotyping in patient-care settings, such as the cardiac catheterization laboratory.Clinical Trial Registration: https://www.clinicalTrials.gov (Identifier: NCT01742117).

The effectiveness of lipid-lowering therapies may be insufficient in high-risk cardiovascular patients and depends on the genetic variability of drug-metabolizing enzymes. Customizing statin therapy, including treatment with atorvastatin, may improve clinical outcomes. Currently, there is a lack of guidelines allowing the prediction of the therapeutic efficacy of lipid-lowering statin therapy. This study aimed to determine the effects of clinically significant gene variants of CYP2C19 on atorvastatin therapy in patients with acute coronary syndromes. In total, 92 patients with a confirmed diagnosis of ST-elevation myocardial infarction (STEMI) or non-ST-elevation myocardial infarction (NSTEMI) were sequenced for target regions within the CYP2C19 gene on the Illumina Miniseq system. The CYP2C19 poor metabolizer phenotype (carriers of CYP2C19*2, CYP2C19*4, and CYP2C19*8 alleles) was detected in 29% of patients. These patients had significantly lower responses to treatment with atorvastatin than patients with the normal metabolizer phenotype. CYP2C19-metabolizing phenotype, patient age, and smoking increased the odds of undertreatment in patients (∆LDL-C (mmol/L) < 1). These results revealed that the CYP2C19 phenotype may significantly impact atorvastatin therapy personalization in patients requiring LDL lipid-lowering therapy. [ABSTRACT FROM AUTHOR]

A recently discovered haplotype—CYP2C:TG—determines the ultrarapid metabolism of several CYP2C19 substrates. The platelet inhibitor clopidogrel requires CYP2C19-mediated activation: the risk of ischemic events is increased in patients with a poor (PM) or intermediate (IM) CYP2C19 metabolizer phenotype (vs. normal, NM; rapid, RM; or ultrarapid, UM). We investigated whether the CYP2C:TG haplotype affected efficacy/bleeding risk in clopidogrel-treated patients. Adults (n = 283) treated with clopidogrel over 3–6 months were classified by CYP2C19 phenotype based on the CYP2C19*2*17 genotype, and based on the CYP2C19/CYP2C cluster genotype, and regarding carriage of the CYP2:TG haplotype, and were balanced on a number of covariates across the levels of phenotypes/haplotype carriage. Overall, 45 (15.9%) patients experienced ischemic events, and 49 (17.3%) experienced bleedings. By either classification, the incidence of ischemic events was similarly numerically higher in PM/IM patients (21.6%, 21.8%, respectively) than in mutually similar NM, RM, and UM patients (13.2–14.8%), whereas the incidence of bleeding events was numerically lower (13.1% vs. 16.6–20.5%). The incidence of ischemic events was similar in CYP2C:TG carries and non-carries (14.1% vs. 16.1%), whereas the incidence of bleedings appeared mildly lower in the former (14.9% vs. 20.1%). We observed no signal to suggest a major effect of the CYP2C19/CYP2C cluster genotype or CYP2C:TG haplotype on the clinical efficacy/safety of clopidogrel. [ABSTRACT FROM AUTHOR]

This document summarizes a pilot study conducted in Denmark to assess the agreement between publicly funded genotyping tests and phenotype classification for certain genes. The study found inconsistencies in genotype and phenotype agreement between three laboratories, highlighting the need for standardization in pharmacogenetic testing. The document also discusses the lack of national alignment between laboratories in Denmark, which poses challenges in the use and implementation of pharmacogenetic testing. The study recommends continuous updating of the phenotype approach and alignment of genotyping and phenotyping classifications to ensure consistent implementation of pharmacogenetic testing in Denmark. The document also references various guidelines and studies related to pharmacogenetic testing in mental health care settings. [Extracted from the article]

Various CYP2C19-mediated metabolizer groups may arise as a result of inter-individual variability, which potentially influences the efficacy and safety of escitalopram. Hence, it is crucial to establish a comprehensive collection of information relevant to each phenotype regarding the efficacy and tolerability of therapy. This will enable psychiatrists to make optimal decisions for individual patients. The aim of the study. The aim of this study is to classify MDD patients into various CYP2C19 metabolizer groups and to determine the association between phenotype and treatment outcome. Materials and Methods. The study enrolled 119 escitalopram monotherapy-treated MDD patients aged 18-58. MADRS, HDRS-17, and CGI were used to measure efficacy at baseline, weeks 4, 8, and 12. Safety and tolerability outcomes were examined from occurring ADRs. Clinical outcomes were compared among phenotypes based on changes in HDRS-17 and CGI scores from week 4 to week 12. Results. Subjects were categorized by CYP2C19 genotype: 20 poor (PM), 64 intermediate (IM), 24 extensive (EM), and 11 ultra-rapid (UM) metabolizers. Response and remission occurred in 67.2 % and 26.8 % of the 119 subjects at the end of the 12th week of the study. The response rate in PM was much lower (21.6 %) compared to EM. There were 312 adverse drug reactions (ADRs), and 88 (73.94 %) individuals had at least one. In safety data, nervousness was the most common ADR among the four groups 66 (55.4 %), followed by decreased appetite 48 (40.3 %). There were no severe ADRs. Men had more ADRs than women. Conclusions. CYP2C19 genotyping may help personalize escitalopram medication. The study found that the reduced ability of PM to metabolize escitalopram is probably associated with the decreased efficacy and tolerance shown in PM compared to EM and IM. The relationship between metabolizer status and treatment response followed the anticipated direction. Our findings should guide future clinical studies that include pharmacokinetic assessments [ABSTRACT FROM AUTHOR]

Proton pump inhibitors (PPIs) have recently been reported to be linked with nephrotoxicity. PPIs are metabolized mainly or partly by cytochrome P450 2C19 (CYP2C19). However, the relationship between CYP2C19 genetic polymorphism and PPI‐induced nephrotoxicity is unclear. In this study, we aimed to analyze the association between the time of occurrence of renal injury by PPIs, including lansoprazole, esomeprazole, rabeprazole, and vonoprazan, and CYP2C19 metabolizer status classified by CYP2C19 genotypes. Patients prescribed PPIs were reviewed in this retrospective cohort study. The primary outcome was the time to a 30% decrease in estimated glomerular filtration rate (eGFR) from baseline. In patients treated with lansoprazole, the time to a 30% decrease in eGFR for the CYP2C19 poor metabolizer (PM) group was significantly shorter than that for the non‐PM group (hazard ratio for PM vs. non‐PM, 2.43, 95% confidence interval, 1.21 to 4.87, P = 0.012). In contrast, in patients that received esomeprazole, rabeprazole, or vonoprazan, no significant differences were found in the time to a 30% decrease in eGFR between non‐PM and PM groups. The adjusted hazard ratios for the time to a 30% eGFR decrease in patients treated with lansoprazole were significantly higher for CYP2C19 PM, hypertension, and a history of myocardial infarction. In conclusion, this retrospective study showed that CYP2C19 metabolizer status was associated with the time to a 30% eGFR decrease in patients treated with lansoprazole, but not with esomeprazole, rabeprazole, or vonoprazan. [ABSTRACT FROM AUTHOR]

Objective: To study the distribution characteristics of CYP2C19 polymorphisms in patients suffering from stroke in Han Chinese patients. Method: PCR and DNA microarray chip technology were used to detect the CYP2C19 genotype of 549 patients with stroke, and the genotype, allele frequency and metabolic type of patients with different sexes, ages and types of infarctions and the independent risk factors for clopidogrel resistance were analyzed. Results: Six genotypes were detected in these 549 patients. A total of 233 (42.44%) patients had the heterozygous allele *1/*2, which was the most prevalent, followed by the homozygous wild-type allele *1/*1 (191, 34.79%). A total of 30 (5.46%) patients possessed the heterozygous allele *1/*3, and 65 (11.84%) patients had the homozygous mutant allele *2/*2. Twenty-nine (5.28%) patients had the compound heterozygous mutant allele *2/*3, and only 1 patient had the homozygous mutant allele *3/*3. The distribution of genotypes, alleles, and metabolic types did not change significantly (P > 0.05) by sex, age, or type of stroke. In addition, no independent risk factors for clopidogrel resistance were found in this analysis. Conclusion: The distribution of CYP2C19 genotypes, allele frequencies, and metabolic types in patients with stroke in Han Chinese patients were not correlated with sex, age, or infarction type. The possibilities of hyperglycemia, hypercholesterolemia, hypertriglyceridemia, hypo-HDL-cholesterolemia, hyper-LDL-cholesterolemia and high blood pressure were not statistically associated with CYP2C19 genotypes. CYP2C19 gene polymorphism detection is recommended for patients who are available, and during treatment, the CYP2C19 genotype can be used to guide personalized precise medication use in patients with stroke. [ABSTRACT FROM AUTHOR]

An ABCD-GENE (age, body mass index, chronic kidney disease, diabetes, and CYP2C19 genetic variants) score ≥10 predicts reduced clopidogrel effectiveness, but its association with response to alternative therapy remains unclear. The aim of this study was to evaluate the association between ABCD-GENE score and the effectiveness of clopidogrel vs alternative P2Y 12 inhibitor (prasugrel or ticagrelor) therapy after percutaneous coronary intervention (PCI). A total of 4,335 patients who underwent PCI, CYP2C19 genotyping, and P2Y 12 inhibitor treatment were included. The primary outcome was major atherothrombotic events (MAE) within 1 year after PCI. Cox regression was performed to assess event risk in clopidogrel-treated (reference) vs alternatively treated patients, with stabilized inverse probability weights derived from exposure propensity scores after stratifying by ABCD-GENE score and further by CYP2C19 loss-of-function (LOF) genotype. Among patients with scores <10 (n = 3,200), MAE was not different with alternative therapy vs clopidogrel (weighted HR: 0.89; 95% CI: 0.65-1.22; P = 0.475). The risk for MAE also did not significantly differ by treatment among patients with scores ≥10 (n = 1,135; weighted HR: 0.75; 95% CI: 0.51-1.11; P = 0.155). Among CYP2C19 LOF allele carriers, MAE risk appeared lower with alternative therapy in both the group with scores <10 (weighted HR: 0.50; 95% CI: 0.25-1.01; P = 0.052) and the group with scores ≥10 (weighted HR: 0.48; 95% CI: 0.29-0.80; P = 0.004), while there was no difference in the group with scores <10 and no LOF alleles (weighted HR: 1.03; 95% CI: 0.70-1.51; P = 0.885). These data support the use of alternative therapy over clopidogrel in CYP2C19 LOF allele carriers after PCI, regardless of ABCD-GENE score, while clopidogrel is as effective as alternative therapy in non-LOF patients with scores <10. [Display omitted] [ABSTRACT FROM AUTHOR]

Peripheral arterial disease (PAD) affects approximately 236 million people worldwide. Therefore, this study aimed to investigate the relationship between CYP2C19 genotype polymorphisms and clopidogrel resistance (CR) following revascularization in patients with PAD. In total, 345 patients who underwent PAD revascularization were monitored for five years and risk factors for ischemic events were identified. Platelet reactivity and CYP2C19 genotypes were measured, and patients were classified as normal, intermediate, or poor metabolizers based on their genotypes. The study endpoint was defined as an ischemic event, that encompassed major adverse cardiovascular or limb events, or all-cause death. In this study, ischemic events following PAD revascularization were associated with patient age, prior minor amputation, the Rutherford category before revascularization, indications for revascularization, index ankle-branchial index before revascularization, CYP2C19 phenotypes, and CR. Intermediate and poor metabolism, the Rutherford category before revascularization, and CR were independent risk factors for ischemic events in patients after PAD revascularization. Similarly, intermediate and poor metabolism, the Rutherford category before revascularization, and CR were independent risk factors for ischemic events in patients with PAD after revascularization within five years. Intermediate and poor metabolizers had a higher platelet reactivity and risk of CR than normal metabolizers. However, poor metabolizers had a higher platelet reactivity and risk of CR than intermediate metabolizers. Furthermore, the hazard ratio for ischemic events increased with platelet reactivity. This effect was more prevalent in intermediate and poor metabolizers than in normal metabolizers. Ischemic events in patients after PAD revascularization were affected by independent risk factors. Decreased clopidogrel metabolism increased the platelet reactivity and CR in patients after PAD revascularization. Furthermore, high platelet reactivity was associated with an increased risk of ischemic events in patients with intermediate and poor metabolism. [Display omitted] • CYP2C19 phenotype and CR effects after revascularization for PAD remain unclear. • We evaluated these effects on ischemic events after revascularization over 5 years. • CYP2C19 phenotype and CR were independent risk factors for ischemic events. • Patients with impaired clopidogrel metabolism had a higher risk of CR. [ABSTRACT FROM AUTHOR]

Proton-pump inhibitors (PPIs) are the most administered first-line treatment for eosinophilic esophagitis (EoE). However, only around half of EoE patients respond histologically to a double dosage of PPI. In addition, 70% of responders maintain EoE in remission after tapering the PPI dose. In order to avoid endoscopy with biopsies—the only accurate method of assessing PPI response—efforts have been made to identify PPI responder patients. The clinical or endoscopic features and biomarkers evaluated so far, however, have not proven to be sufficient in predicting PPI response. Although new approaches based on omics technologies have uncovered promising biomarkers, the specialized and complex procedures required are difficult to implement in clinical settings. Alternatively, PPI pharmacogenetics based on identifying variations in CYP2C19 and STAT6 genes have shown promising results in EoE, and could easily be performed in most laboratories. Other genetic variations have also been associated with PPI response and may explain those cases not related to CYP2C19 or STAT6. Here, we provide an overview of PPI treatment in EoE and evidence of how genetic variations in CYP2C19 and other genes could affect PPI effectiveness, and also discuss studies evaluating the role of pharmacogenetics in predicting PPI response in patients with EoE. [ABSTRACT FROM AUTHOR]

Background: Venlafaxine (VEN) is a commonly utilized medication for alleviating depression and anxiety disorders. The presence of genetic polymorphisms gives rise to considerable variations in plasma concentrations across different phenotypes. This divergence in phenotypic responses leads to notable differences in both the efficacy and tolerance of the drug. Purpose: A physiologically based pharmacokinetic (PBPK) model for VEN and its metabolite O-desmethylvenlafaxine (ODV) to predict the impact of CYP2D6 and CYP2C19 gene polymorphisms on VEN pharmacokinetics (PK). Methods: The parent-metabolite PBPK models for VEN and ODV were developed using PK-Sim® and MoBi®. Leveraging prior research, derived and implemented CYP2D6 and CYP2C19 activity score (AS)-dependent metabolism to simulate exposure in the drug-gene interactions (DGIs) scenarios. The model's performance was evaluated by comparing predicted and observed values of plasma concentration–time (PCT) curves and PK parameters values. Results: In the base models, 91.1%, 94.8%, and 94.6% of the predicted plasma concentrations for VEN, ODV, and VEN + ODV, respectively, fell within a twofold error range of the corresponding observed concentrations. For DGI scenarios, these values were 81.4% and 85% for VEN and ODV, respectively. Comparing CYP2D6 AS = 2 (normal metabolizers, NM) populations to AS = 0 (poor metabolizers, PM), 0.25, 0.5, 0.75, 1.0 (intermediate metabolizers, IM), 1.25, 1.5 (NM), and 3.0 (ultrarapid metabolizers, UM) populations in CYP2C19 AS = 2.0 group, the predicted DGI AUC0-96 h ratios for VEN were 3.65, 3.09, 2.60, 2.18, 1.84, 1.56, 1.34, 0.61, and for ODV, they were 0.17, 0.35, 0.51, 0.64, 0.75, 0.83, 0.90, 1.11, and the results were similar in other CYP2C19 groups. It should be noted that PK differences in CYP2C19 phenotypes were not similar across different CYP2D6 groups. Conclusions: In clinical practice, the impact of genotyping on the in vivo disposition process of VEN should be considered to ensure the safety and efficacy of treatment. [ABSTRACT FROM AUTHOR]

Lipophilicity is one of the most important properties of compounds required to estimate the absorption, distribution, and transport in biological systems, in addition to solubility, stability, and acid–base nature. It is crucial in predicting the ADME profile of bioactive compounds. The study assessed the usefulness of computational and chromatographic methods (thin-layer chromatography in a reversed-phase system, RP-TLC) for estimating the lipophilicity of 21 newly synthesized compounds belonging to diquinothiazines and quinonaphthiazines. In order to obtain reliable values of the relative lipophilicities of diquinothiazines and quinonaphthiazines, the partition coefficients obtained using different algorithms such as AlogPs, AClogP, AlogP, MLOGP, XLOGP2, XLOGP3, logP, and ClogP were compared with the chromatographic RM0 values of all the tested compounds measured by the experimental RP-TLC method (logPTLC). Additionally, logPTLC values were also correlated with other descriptors, as well as the predicted ADME and drug safety profiling parameters. The linear correlations of logPTLC values of the tested compounds with other calculated molecular descriptors such as molar refractivity, as well as ADME parameters (Caco-2 substrates, P-gp inhibitors, CYP2C19, and CYP3A4) generally show poor predictive power. Therefore, in silico ADME profiling can only be helpful at the initial step of designing these new candidates for drugs. The compliance of all discussed diquinothiazines and naphthoquinothiazines with the rules of Lipiński, Veber, and Egan suggests that the tested pentacyclic phenothiazine analogs have a chance to become therapeutic drugs, especially orally active drugs. [ABSTRACT FROM AUTHOR]

Juvenile myoclonic epilepsy (JME) is the most common of the generalized genetic epilepsies, with multiple causal and susceptibility genes; however, its etiopathogenesis is mainly unknown. The toxic effects caused by xenobiotics in cells occur during their metabolic transformation, mainly by enzymes belonging to cytochrome P450. The elimination of these compounds by transporters of the ABC type protects the central nervous system, but their accumulation causes neuronal damage, resulting in neurological diseases. The present study has sought the association between single nucleotide genetic variants of the CYP2C9, CYP2C19, and ABCB1 genes and the development of JME in patients compared to healthy controls. The CC1236 and GG2677 genotypes of ABCB1 in women; allele G 2677, genotypes GG 2677 and CC 3435 in men; the CYP2C19*2A allele, and the CYP2C19*3G/A genotype in both sexes were found to be risk factors for JME. Furthermore, carriers of the TTGGCC genotype combination of the ABCB1 gene (1236/2677/3435) have a 10.5 times higher risk of developing JME than non-carriers. Using the STRING database, we found an interaction between the proteins encoded by these genes and other possible proteins. These findings indicate that the CYP450 system and ABC transporters could interact with other genes in the JME. [ABSTRACT FROM AUTHOR]

Previous results demonstrated that CYP2D6 and CYP2C19 gene variants affect serum concentrations of antidepressants. We implemented a PGx service determining gene variants in CYP2D6 and CYP2C19 in our clinical routine care and report on our first patient cohort. We analysed CYP2D6 and CYP2C19 allele, genotype, and phenotype frequencies, and actionable pharmacogenetic variants in this German psychiatric inpatient cohort. Two-tailed z-test was used to investigate for differences in CYP2D6 and CYP2C19 phenotypes and actionable/non-actionable genetic variant frequencies between our cohort and reference cohorts. Out of the 154 patients included, 44.8% of patients were classified as CYP2D6 normal metabolizer, 38.3% as intermediate metabolizers, 8.4% as poor metabolizers, and 2.6% as ultrarapid metabolizers. As for CYP2C19, 40.9% of patients were classified as normal metabolizers, 19.5% as intermediate metabolizers, 2.6% as poor metabolizers, 31.2% as rapid metabolizers, and 5.8% as ultrarapid metabolizers. Approximately, 80% of patients had at least one actionable PGx variant. There is a high prevalence of actionable PGx variants in psychiatric inpatients which may affect treatment response. Physicians should refer to PGx-informed dosing guidelines in carriers of these variants. Pre-emptive PGx testing in general may facilitate precision medicine also for other drugs metabolised by CYP2D6 and/or CYP2C19. [ABSTRACT FROM AUTHOR]

Background: We investigated the effect of a 5-day low-dose ritonavir therapy, as it is used in the treatment of COVID-19 with nirmatrelvir/ritonavir, on the pharmacokinetics of three factor Xa inhibitors (FXaI). Concurrently, the time course of the activities of the cytochromes P450 (CYP) 3A4, 2C19, and 2D6 was assessed. Methods: In an open-label, fixed sequence clinical trial, the effect and duration of a 5-day oral ritonavir (100 mg twice daily) treatment on the pharmacokinetics of three oral microdosed FXaI (rivaroxaban 25 µg, apixaban 25 µg, and edoxaban 50 µg) and microdosed probe drugs (midazolam 25 µg, yohimbine 50 µg, and omeprazole 100 µg) was evaluated in eight healthy volunteers. The plasma concentrations of all drugs were quantified using validated liquid chromatography–tandem mass spectrometry (LC-MS/MS) methods and pharmacokinetics were analysed using non-compartmental analyses. Results: Ritonavir increased the exposure of apixaban, edoxaban, and rivaroxaban, but to a different extent the observed area under the plasma concentration–time curve (geometric mean ratio 1.29, 1.46, and 1.87, respectively). A strong CYP3A4 inhibition (geometric mean ratio > 10), a moderate CYP2C19 induction 2 days after ritonavir (0.64), and no alteration of CYP2D6 were observed. A CYP3A4 recovery half-life of 2.3 days was determined. Conclusion: This trial with three microdosed FXaI suggests that at most the rivaroxaban dose should be reduced during short-term ritonavir, and only in patients receiving high maintenance doses. Thorough time series analyses demonstrated differential effects on three different drug-metabolising enzymes over time with immediate profound inhibition of CYP3A4 and only slow recovery after discontinuation. Clinical Trial Registration: EudraCT number: 2021-006643-39. [ABSTRACT FROM AUTHOR]