CYP2C19 Poor Metabolizers Research Articles

Can CYP2C19 genotyping improve antiplatelet therapy efficacy in real-life practice? Recent advances.

Clopidogrel remains the most widely used P2Y₁₂ receptor inhibitor worldwide and is often used in combination with aspirin for secondary prevention in patients with arterial disease. The drug is associated with a wide response variability with one on three patients exhibiting little or no inhibition of adenosine diphosphate-induced platelet aggregation. It is a prodrug that is mainly metabolized by hepatic cytochrome P450 (CYP) 2C19. Patients who carry a CYP2C19 loss-of-function (LoF) allele have reduced metabolism of clopidogrel that is associated with reduced platelet inhibition compared to non-carriers that is associated with increased risk for thrombotic event occurrences, particularly, stent thrombosis. The United States Food and Drug Administration (US FDA) issued a black box warning in the clopidogrel label highlighting the importance of presence of CYP2C19 LOF allele during the insufficient metabolism of clopidogrel and availability of other potent P2Y₁₂ inhibitor for the treatment in CYP2C19 poor metabolizers. Clinical trials have conclusively demonstrated greater anti-ischemic benefits of prasugrel/ticagrelor in the treatment of patients carrying the CYP2C19 LoF allele. However, uniform use of these more potent P2Y₁₂ inhibitors has been associated with greater bleeding and cost, and lower adherence. The latter information provides a strong rationale for personalizing P2Y₁₂ inhibitor therapy based on the laboratory determination of CYP2C19 genotype. However, cardiologists have been slow to take up pharmacogenetic testing possibly due to lack of provider and patient education, clear cardiology guidelines and, and lack of positive results from adequately sized randomized clinical trials. However, current evidence strongly supports genotyping of patients who are candidates for clopidogrel. Physicians should strongly consider performing genetic tests to identify LoF carriers and treat these patients with more pharmacodynamically predictable P2Y₁₂ inhibitors than clopidogrel.

Meta-Analysis of Noncompartmental Pharmacokinetic Parameters to Evaluate the Impact of CYP2C19 and CYP2C9 Genetic Polymorphisms on Abrocitinib Exposure.

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.

Influence of C-reactive protein on the pharmacokinetics of voriconazole in relation to the CYP2C19 genotype: a population pharmacokinetics analysis.

Voriconazole is a broad-spectrum triazole antifungal agent. A number of studies have revealed that the impact of C-reactive protein (CRP) on voriconazole pharmacokinetics was associated with the CYP2C19 phenotype. However, the combined effects of CYP2C19 genetic polymorphisms and inflammation on voriconazole pharmacokinetics have not been considered in previous population pharmacokinetic (PPK) studies, especially in the Chinese population. This study aimed to analyze the impact of inflammation on the pharmacokinetics of voriconazole in patients with different CYP2C19 genotypes and optimize the dosage of administration. Data were obtained retrospectively from adult patients aged ≥16years who received voriconazole for invasive fungal infections from October 2020 to June 2023. Plasma voriconazole levels were measured via high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). CYP2C19 genotyping was performed using the fluorescence in situ hybridization method. A PPK model was developed using the nonlinear mixed-effect model (NONMEM). The final model was validated using bootstrap, visual predictive check (VPC), and normalized prediction distribution error (NPDE). The Monte Carlo simulation was applied to evaluate and optimize the dosing regimens. A total of 232 voriconazole steady-state trough concentrations from 167 patients were included. A one-compartment model with first order and elimination adequately described the data. The typical clearance (CL) and the volume of distribution (V) of voriconazole were 3.83L/h and 134L, respectively. The bioavailability was 96.5%. Covariate analysis indicated that the CL of voriconazole was substantially influenced by age, albumin, gender, CRP, and CYP2C19 genetic variations. The V of voriconazole was significantly associated with body weight. An increase in the CRP concentration significantly decreased voriconazole CL in patients with the CYP2C19 normal metabolizer (NM) and intermediate metabolizer (IM), but it had no significant effect on patients with the CYP2C19 poor metabolizer (PM). The Monte Carlo simulation based on CRP levels indicated that patients with high CRP concentrations required a decreased dose to attain the therapeutic trough concentration and avoid adverse drug reactions in NM and IM patients. These results indicate that CRP affects the pharmacokinetics of voriconazole and is associated with the CYP2C19 phenotype. Clinicians dosing voriconazole should consider the patient's CRP level, especially in CYP2C19 NMs and IMs.

Metabolic activity of CYP2C19 and CYP2D6 on antidepressant response from 13 clinical studies using genotype imputation: a meta-analysis

Cytochrome P450 enzymes including CYP2C19 and CYP2D6 are important for antidepressant metabolism and polymorphisms of these genes have been determined to predict metabolite levels. Nonetheless, more evidence is needed to understand the impact of genetic variations on antidepressant response. In this study, individual clinical and genetic data from 13 studies of European and East Asian ancestry populations were collected. The antidepressant response was clinically assessed as remission and percentage improvement. Imputed genotype was used to translate genetic polymorphisms to metabolic phenotypes (poor, intermediate, normal, and rapid+ultrarapid) of CYP2C19 and CYP2D6. CYP2D6 structural variants cannot be imputed from genotype data, limiting the determination of metabolic phenotypes, and precluding testing for association with response. The association of CYP2C19 metabolic phenotypes with treatment response was examined using normal metabolizers as the reference. Among 5843 depression patients, a higher remission rate was found in CYP2C19 poor metabolizers compared to normal metabolizers at nominal significance but did not survive after multiple testing correction (OR = 1.46, 95% CI [1.03, 2.06], p = 0.033, heterogeneity I2 = 0%, subgroup difference p = 0.72). No metabolic phenotype was associated with percentage improvement from baseline. After stratifying by antidepressants primarily metabolized by CYP2C19, no association was found between metabolic phenotypes and antidepressant response. Metabolic phenotypes showed differences in frequency, but not effect, between European- and East Asian-ancestry studies. In conclusion, metabolic phenotypes imputed from genetic variants using genotype were not associated with antidepressant response. CYP2C19 poor metabolizers could potentially contribute to antidepressant efficacy with more evidence needed. Sequencing and targeted pharmacogenetic testing, alongside information on side effects, antidepressant dosage, depression measures, and diverse ancestry studies, would more fully capture the influence of metabolic phenotypes.

A population pharmacokinetic model for sertraline in women during the perinatal period-A contribution from the ConcePTION project.

Sertraline is frequently prescribed for mental health conditions in both pregnant and breastfeeding women. According to the limited available data, only small amounts of sertraline are transferred into human milk, yet with a large amount of unexplained interindividual variability. This study aimed to develop a population pharmacokinetic (popPK) model to describe the pharmacokinetics of sertraline during the perinatal period and explain interindividual variability. Pregnant women treated with sertraline were enrolled in the multicenter prospective cohort SSRI-Breast Milk study. A popPK model for sertraline maternal plasma and breast milk concentrations was developed and allowed estimating the milk-to-plasma ratio (MPR). An additional fetal compartment allowed cord blood concentrations to be described. Several covariates were tested for significance. Ultimately, model-based simulations allowed infant drug exposure through placenta and breast milk under various conditions to be predicted. Thirty-eight women treated with sertraline were included in the study and provided 89 maternal plasma, 29 cord blood and 107 breast milk samples. Sertraline clearance was reduced by 42% in CYP2C19 poor metabolizers compared to other phenotypes. Doubling milk fat content increased the MPR by 95%. Simulations suggested a median daily infant dosage of 6.9μg kg-1 after a 50 mg maternal daily dose, representing 0.95% of the weight-adjusted maternal dose. Median cord blood concentrations could range from 3.29 to 33.23 ng mL-1 after maternal daily doses between 25 and 150 mg. Infant exposure to sertraline, influenced by CYP2C19 phenotype and breast milk fat content, remains low, providing reassurance regarding the use of sertraline during pregnancy and breastfeeding.

The impact of CYP2C19 genotypes on steady-state plasma concentration of escitalopram in South Indian population with Major Depressive Disorder

Background: Among depressed patients, escitalopram plasma levels differed between those who were considered as extensive metabolizers and poor metabolizers of CYP2C19. However, the majority of research utilized the dose-response relationship. Consequently, we investigated the effect of variations in the CYP2C19 gene on the levels of drug in the bloodstream of individuals suffering from Major Depressive Disorder (MDD) in south India. Methods: A total of 109 individuals with MDD who were prescribed escitalopram at doses of 5, 10, 15, or 20 mg daily participated in this research. We used HPLC with SPD-10AVP UV-Visible detector to measure the escitalopram concentrations in the blood. The polymorphisms of the CYP2C19 were determined by employing the PCR techniques. Results: Our study found that 55% of the subjects were intermediate metabolizers, followed by extensive (19.3%), poor (17.4%), and ultra-rapid (8.3%). The significant correlation is identified between the steady state plasma concentration and Sex with (P - Value < 0.05), insignificant correlation was seen in Age and BMI with (P - Value > 0.05). The majority of gene variants seen in the study population were CYP2C19*1/*2, accounting for 49 individuals (44.9%). Conclusion: These findings showed that sex had a substantial impact on the CYP2C19 genetic variation. Medication administration to individuals with CYP2C19PM requires special caution.

Interaction of age and CYP2C19 genotypes on voriconazole steady-state trough concentration in Chinese patients.

Both age and CYP2C19 genotypes affect voriconazole plasma concentration; the interaction of age and CYP2C19 genotypes on voriconazole plasma concentration remains unknown. This study aims to investigate the combined effects of age and CYP2C19 genotypes on voriconazole plasma concentration in Chinese patients. A total of 480 patients who received voriconazole treatment were recruited. CYP2C19*2 (rs4244285) and CYP2C19*3 (rs4986893) polymorphisms were genotyped. Patients were divided into the young and the elderly groups by age of 60 years old. Influence of CYP2C19 genotype on steady-state trough concentration (C ss-min ) in overall patients and in age subgroups was analyzed. Voriconazole C ss-min correlated positively with age, and mean voriconazole C ss-min was significantly higher in the elderly group ( P < 0.001). CYP2C19 poor metabolizers showed significantly increased mean voriconazole C ss-min in the young but not the elderly group. The percentage of patients with subtherapeutic voriconazole C ss-min (<1.0 mg/l) was higher in the young group and that of supratherapeutic voriconazole C ss-min (>5.5 mg/l) was higher in the elderly patients. When the average C ss-min in the CYP2C19 normal metabolizer genotype was regarded as a reference, CYP2C19 genotypes showed greater impact on voriconazole C ss-min in the young group, while the influence of age on voriconazole C ss-min exceeded CYP2C19 genotypes in the elderly. CYP2C19 genotypes affects voriconazole exposure is age dependent. Influence of CYP2C19 poor metabolizer genotype on increased voriconazoleexposure is prominent in the young, while age is a more important determinant factor for increased voriconazole exposure in the elderly patients.

Impact of CYP2C19 Gene Variants on Long-Term Treatment with Atorvastatin in Patients with Acute Coronary Syndromes.

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.

84 Using Opportunistic Sampling and Remnant Blood Samples to Develop Pediatric Pharmacokinetic Models to Inform Antidepressant Dosing

OBJECTIVES/GOALS: Developing pharmacokinetic (PK) models to guide selective serotonin reuptake inhibitor (SSRI) dosing in youth is costly, time-intensive, and requires large numbers of participants. We evaluated the use of remnant blood samples from SSRI-treated youth and developed precision PK dosing strategies. METHODS/STUDY POPULATION: Following IRB approval, we used a clinical surveillance platform to identify patients with routine phlebotomy within 24 hours of escitalopram or sertraline dosing. Remnant blood samples were obtained from youth aged 5–18 years, escitalopram and sertraline concentrations were determined, and clinical characteristics (e.g., age, sex, weight, concomitant medications that inhibit sertraline or escitalopram metabolism) and phenotypes for CYP2C19, the predominant enzyme that metabolizes these SSRIs, were extracted from the electronic medical record (EMR). A population PK analysis of escitalopram and sertraline was performed using NONMEM. The influence of clinical variables, CYP2C19, and dosing was evaluated from simulated concentration-time curves. RESULTS/ANTICIPATED RESULTS: Over 21 months, we collected315 samples from escitalopram-treated patients (N=288) and 265 samples from sertraline-treated patients (N=255). In youth, escitalopram and sertraline exposure (concentrations over time) and specific pharmacokinetic parameters (e.g., clearance) were influenced by CYP2C19 phenotype, concomitant CYP2C19 inhibitors, and patient-specific characteristics. Escitalopram and sertraline concentrations from remnant blood samples were 3.98-fold higher and 3.23-fold higher, respectively, in poor metabolizers compared to normal metabolizers (escitalopram, p&lt;0.001) and compared to normal, rapid, and ultrarapid metabolizers combined (sertraline, p&lt;0.001). DISCUSSION/SIGNIFICANCE: Combining remnant blood sampling with pharmacogenetic-integrated EMR data can facilitate large-scale population PK analyses of escitalopram and sertraline in youth. This real-world approach can be used to rapidly develop precision SSRI dosing strategies, including slower titration and reduced target doses in CYP2C19 poor metabolizers.

Physiologically Based Pharmacokinetic Modeling to Investigate the Disease-Drug-Drug Interactions between Voriconazole and Nirmatrelvir/Ritonavir in COVID-19 Patients with CYP2C19 Phenotypes.

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.

Tizanidine: Advances in Pharmacology & Therapeutics and Drug Formulations.

Skeletal muscle relaxants (SMRs) are widely used in treating musculoskeletal conditions. All SMRs, with the exception of baclofen and tizanidine, are on the list of 2023 American Geriatrics Society Beers Criteria® for potentially inappropriate medication use in older adults. In our geriatric practice, off-label use of tizanidine as preemptive analgesia drove us to find recent advances in its pharmacology and therapeutics. An update review of tizanidine was thus presented, aiming to bring the latest knowledge to clinicians and promote further research and practical exploration. Relevant literature up to December 2023 was identified through searches of PubMed, Web of Science, and Embase. Tizanidine, a centrally acting alpha-2 adrenoceptor agonist with both antispastic and antispasmodic activity, shows efficacy in the common indications for all SMRs. From the perspective of drug safety, tizanidine has lower incidences of adverse events (injury, delirium, encephalopathy, falls, and opioid overdose) compared to baclofen, no association with risk of Alzheimer's disease as with orphenadrine, no risk of serotonin syndrome like metaxalone when comedicated with serotonergic drugs, no significant pharmacokinetic changes in CYP2C19 poor metabolizers unlike diazepam and carisoprodol, and no physically addictive or abuse properties like carisoprodol and diazepam. From the perspective of new and potential therapeutic uses, tizanidine has additional benefits (eg, gastroprotection that can improve patient tolerance to nonsteroidal anti-inflammatory agents, anti-neuropathic pain, a key component of multimodal analgesia strategy to reduce early postoperative pain, and anti-tumor effects). New delivery systems of tizanidine are developing to improve the pharmacokinetics of oral products, including buccal patches, transdermal delivery systems, nasal spray, and in situ rectal gel. Tizanidine is an SMR with unique features and may be an optimal initial choice for older adults. There would be more scientific studies, wider therapeutic applications, and new drug formulations in the future.

Implementation of clopidogrel pharmacogenetic clinical decision support for a preemptive return of results program.

To describe our experiences implementing and iterating CYP2C19 genotype-guided clopidogrel pharmacogenetic clinical decision support (CDS) tools over time in the setting of a large health system-wide, preemptive pharmacogenomics program. Clopidogrel-treated patients who are genetically predicted cytochrome P450 isozyme 2C19 (CYP2C19) intermediate or poor metabolizers have an increased risk of atherothrombotic events, some of which can be life-threatening. The Clinical Pharmacogenetics Implementation Consortium provides guidance for the use of clopidogrel based on CYP2C19 genotype in patients with cardiovascular and cerebrovascular diseases. Our multidisciplinary team implemented an automated, interruptive alert that fires when clopidogrel is ordered or refilled for biobank participants with structured CYP2C19 intermediate or poor metabolizer genomic indicators in the electronic health record. The implementation began with a narrow cardiovascular indication and setting and was then scaled in 4 primary dimensions: (1) clinical indication; (2) availability across health-system locations; (3) care venue (e.g., inpatient vs outpatient); and (4) provider groups (eg, cardiology and neurology). We iterated our approach over time based on evolving clinical evidence and proactive strategies to optimize CDS maintenance and sustainability. A key facilitator of expansion was socialization of the broader pharmacogenomics initiative among our academic medical center community, accompanied by clinician acceptance of pharmacogenetic alerts in practice. A multidisciplinary collaboration is recommended to facilitate the use of CYP2C19 genotype-guided antiplatelet therapy in patients with cardiovascular and cerebrovascular diseases. Evolving clopidogrel pharmacogenetic evidence necessitates thoughtful iteration of implementation efforts and strategies to optimize long-term maintenance and sustainability.

CYP2C19 genotype prevalence and association with recurrent myocardial infarction in British-South Asians treated with clopidogrel

Abstract Background Pharmacogenomics examines how genes and drugs interact to explain some of the inter-individual variability in response to medications. CYP2C19 is a hepatic enzyme involved in the metabolism of clopidogrel from a prodrug to its active metabolite. Although the European Society of Cardiology and National Institute for Care Excellence recommend ticagrelor (a non CYP2C19 dependent P2Y12 antagonist) as the antiplatelet agent of choice, clopidogrel remains widely prescribed for acute coronary syndrome and myocardial infarction. CYP2C19 poor metabolizers are known to be more common in Asian ancestry but very few studies have looked specifically at South Asian populations or linked metabolizer diplotypes with clinical efficacy data in this population. The outcome studies on which clopidogrel was licensed for efficacy and safety did not include significant South Asian representation. Furthermore, South Asians are known to have a higher prevalence of cardio-metabolic disease compared with European ancestry populations. Methods We studied the Genes &amp; Health cohort of British Bangladeshi and Pakistani ancestry participants to look at prevalence of CYP2C19 metabolizer genotypes and correlate these with recurrent myocardial infarction risk for those who had been prescribed clopidogrel in primary care. Multivariable regression was used to test for association between known CYP2C19 diptotypes and recurrent myocardial infarction in those prescribed clopidogrel, controlling for known CVD risk factors, percutaneous coronary intervention, age, and gender. Results Genes &amp; Health cohort participants (N = 44,396) have a high prevalence (57%) of intermediate or poor CYP2C19 metabolizers, with at least 1 loss of function allele. The prevalence of poor metabolizers carrying 2 CYP2C19 loss of function alleles is 13%, which is higher than in previously studied European (2.4%) and Central/South Asian populations (8.2%). This is primarily due to the *2 LOF allele present in 56% of the population. 69% of the cohort who were diagnosed with an acute MI were prescribed clopidogrel. The presence of the poor metabolizer diplotype is significantly associated with higher risk of recurrent MI, or failed secondary prevention on clopidogrel in this population, OR 3.1 (p = 0.02), with some subsequent ischemic events already described in this young cohort (Acute MI prescribed clopidogrel N = 697, Recurrent MI in this group N=39). Conclusions A pharmacogenomic-driven approach to clopidogrel prescribing has the potential to impact significantly on clinical management and outcomes in individuals of Bangladeshi and Pakistani ancestry. In absence of genotype guided prescribing, maximal adherence to guidelines recommending non CYP2C19 dependent P2Y12 anti-platelet therapy is likely to be disproportionately beneficial in this ethnic cohort.Risk of recurrent MICentral illustration

Interplay among proton pump inhibitors, platelet reactivity and CYP2C19 genotyping in clopidogrel-treated patients after drug-eluting stent implantation

Abstract Background Several published data suggested that concomitant use of clopidogrel and proton pump inhibitors (PPIs) is associated with reduced antiplatelet efficacy of clopidogrel and increased adverse clinical outcomes. We sought to evaluate the interplay between PPI and clopidogrel on platelet reactivity and long-term clinical outcomes in patients after percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation. Methods The PTRG-DES (Platelet function and genoType-Related long-term proGnosis in DES-treated patients) registry is a multi-center, real-world registry of patients who underwent PCI with DES and received dual antiplatelet therapy of aspirin and clopidogrel in South Korea. Patients prescribed with PPI were compared to those without the use of PPI (the control group). The primary outcome was a composite of all-cause death, myocardial infarction, stent thrombosis, and stroke at 5 years. Secondary outcomes included cardiac death, major bleeding, and gastrointestinal bleeding. Adjusted outcomes were compared after 1:2 propensity score (PS) matching analysis. Results Among 13,160 patients, 2235 (17.0%) were prescribed with concomitant PPI at the time of clopidogrel loading. Average age was 64.4 years, 67.2% were men, and 35.1% had diabetes. The PPI group demonstrated a higher on-treatment P2Y12 reaction unit than the control group (p&amp;lt;0.001). The 5-year cumulative incidence of the composite primary outcome was higher in the PPI group (12.1% vs. 9.8%, log-rank p&amp;lt;0.001). After PS matching, the primary outcome was similar between the two groups (12.9% vs. 12.1%, log-rank p=0.24). However, the PPI group with CYP2C19 poor metabolizers showed an increased adjusted risk of the primary outcome (hazard ratio 2.69, p&amp;lt;0.001). Conclusions PPI use in patients with clopidogrel administration after DES implantation was associated with increased platelet reactivity, but similar cardiovascular outcomes in real-world practice. Physicians should be careful when administering PPI with clopidogrel in patients with CYP2C19 poor metabolizers.Distribution of P2Y12 reaction unitCumulative Incidence of outcomes

Escitalopram population pharmacokinetics and remedial strategies based on CYP2C19 phenotype

Background and purposeCYP2C19 is a key factor influencing escitalopram (SCIT) exposure. However, different studies reported various results. This study aims to develop a population pharmacokinetic (popPK) model characterizes the disposition of SCIT in the Chinese population. Based on the popPK model, the study simulates non-adherence scenarios and proposes remedial strategies to facilitate SCIT personalized therapy. MethodsNonlinear mixed-effects modeling using data from two Chinese bioequivalence studies was employed. Monte-Carlo simulation was used to explore non-adherence scenarios and propose remedial strategies based on the proportion of time within the therapeutic window. ResultsResults showed that a one-compartment model with transit absorption and linear elimination described the data well, CYP2C19 phenotypes and weight were identified as significant covariates impacting SCIT exposure. Patients were recommended to take the entire delayed dose immediately if the delay time was no >12 h, followed by the regular regimen at the next scheduled time. When there is one or two doses missed, taking a double dose immediately was recommended to the CYP2C19 intermediate and extensive population, and a 1.5-fold dose was recommended to the CYP2C19 poor metabolizers with the consideration of adverse effects. LimitationAll samples were derived from the homogenized Chinese healthy population for model building, which may pose certain constraints on the ability to identify significant covariates, such as age. ConclusionThe study highlights the importance of considering patient characteristics for personalized medication and offers a unique perspective on utilizing the popPK repository in precision dosing.

Abstract 12412: In Silico Evaluation of Dosing Regimens to Accommodate Coadministration of Mavacamten With Strong Inhibitors of Cytochrome P450 3A4 and Moderate Inhibitors of Cytochrome P450 2C19 in Patients With Obstructive Hypertrophic Cardiomyopathy

Background: Mavacamten is primarily metabolized by cytochrome P450 enzymes CYP2C19 and CYP3A4 and coadministration with strong CYP3A4 or moderate CYP2C19 inhibitors is contraindicated in patients with obstructive hypertrophic cardiomyopathy (HCM) in the US prescribing information (USPI). Aim: To assess the safety and efficacy of accommodating coadministration of mavacamten with strong CYP3A4 and moderate CYP2C19 inhibitors via simulations. Methods: Simulations of 5000 virtual patients with obstructive HCM uniformly distributed by CYP2C19 metabolizer phenotypes were performed using population pharmacokinetic and pharmacodynamic models. The USPI posology and variations were simulated to evaluate if short term (1 week) and long term (chronic) coadministration of CYP3A4 or CYP2C19 inhibitors could be accommodated. Analogous to USPI posology development, comparisons were made by evaluating proportions of patients with left ventricular ejection fraction [LVEF] &lt; 50% (safety) and Valsalva left ventricular outflow tract gradient [VLVOTg] &lt; 30 mmHg (efficacy). Results: When initiating mavacamten with a CYP3A4 inhibitor, a posology using 2.5 mg starting dose, with coadministration stopped if LVEF &lt; 50% at 2.5 mg, resulted in a similar peak proportion of CYP2C19 poor metabolizers with LVEF &lt; 50% (5.7%) and LVEF &lt; 40% (0.9%) compared to the USPI (2.7% and 0.3% respectively; Table ). When initiating mavacamten with a CYP2C19 inhibitor, a 2.5 mg starting dose resulted in a similar peak proportion of LVEF &lt; 50% in CYP2C19 ultrarapid metabolizers to USPI. Optimal efficacy was achieved; in some patients, this was delayed owing to dose reduction. Interruption of mavacamten during short term administration of inhibitors transiently increased VLVOTg for the duration of interruption, with no effect on LVEF. Conclusion: Coadministration of mavacamten with CYP3A4 or CYP2C19 inhibitors could be accommodated within the titration scheme with dose interruption or down titration.

Escitalopram and Sertraline Population Pharmacokinetic Analysis in Pediatric Patients.

Escitalopram and sertraline are commonly prescribed for anxiety and depressive disorders in children and adolescents. The pharmacokinetics (PK) of these medications have been evaluated in adults and demonstrate extensive variability, but studies in pediatric patients are limited. Therefore, we performed a population PK analysis for escitalopram and sertraline in children and adolescents to characterize the effects of demographic, clinical, and pharmacogenetic factors on drug exposure. A PK dataset was generated by extracting data from the electronic health record and opportunistic sampling of escitalopram- and sertraline-treated psychiatrically hospitalized pediatric patients aged 5-18 years. A population PK analysis of escitalopram and sertraline was performed using NONMEM. Concentration-time profiles were simulated using MwPharm++ to evaluate how covariates included in the final models influence medication exposure and compared to adult therapeutic reference ranges. The final escitalopram cohort consisted of 315 samples from 288 patients, and the sertraline cohort consisted of 265 samples from 255 patients. A one-compartment model with a proportional residual error model best described the data for both medications. For escitalopram, CYP2C19 phenotype and concomitant CYP2C19 inhibitors affected apparent clearance (CL/F), and normalizing CL/F and apparent volume of distribution (V/F) to body surface area (BSA) improved estimations. The final escitalopram model estimated CL/F and V/F at 14.2 L/h/1.73 m2 and 428 L/1.73 m2, respectively. For sertraline, CYP2C19 phenotype and concomitant CYP2C19 inhibitors influenced CL/F, and empirical allometric scaling of patient body weight on CL/F and V/F was significant. The final sertraline model estimated CL/F and V/F at 124 L/h/70 kg and 4320 L/70 kg, respectively. Normalized trough concentrations (Ctrough) for CYP2C19 poor metabolizers taking escitalopram were 3.98-fold higher compared to normal metabolizers (151.1 ng/mL vs 38.0 ng/mL, p < 0.0001), and normalized Ctrough for CYP2C19 poor metabolizers taking sertraline were 3.23-fold higher compared to normal, rapid, and ultrarapid metabolizers combined (121.7 ng/mL vs 37.68 ng/mL, p < 0.0001). Escitalopram- and sertraline-treated poor metabolizers may benefit from a dose reduction of 50-75% and 25-50%, respectively, to normalize exposure to other phenotypes. To our knowledge, this is the largest population PK analysis of escitalopram and sertraline in pediatric patients. Significant PK variability for both medications was observed and was largely explained by CYP2C19 phenotype. Slower CYP2C19 metabolizers taking escitalopram or sertraline may benefit from dose reductions given increased exposure.

The Effects of CYP2C19 Genotype on Proxies of SSRI Antidepressant Response in the UK Biobank.

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used psychopharmaceutical treatment for major depressive disorder (MDD), but individual responses to SSRIs vary greatly. CYP2C19 is a key enzyme involved in the metabolism of several drugs, including SSRIs. Variations in the CYP2C19 gene are associated with differential metabolic activity, and thus differential SSRI exposure; accordingly, the CYP2C19 genotype may affect the therapeutic response and clinical outcomes, though existing evidence of this link is not entirely consistent. Therefore, we analysed data from the UK Biobank, a large, deeply phenotyped prospective study, to investigate the effects of CYP2C19 metaboliser phenotypes on several clinical outcomes derived from primary care records, including multiple measures of antidepressant switching, discontinuation, duration, and side effects. In this dataset, 24,729 individuals were prescribed citalopram, 3012 individuals were prescribed escitalopram, and 12,544 individuals were prescribed sertraline. Consistent with pharmacological expectations, CYP2C19 poor metabolisers on escitalopram were more likely to switch antidepressants, have side effects following first prescription, and be on escitalopram for a shorter duration compared to normal metabolisers. CYP2C19 poor and intermediate metabolisers on citalopram also exhibited increased odds of discontinuation and shorter durations relative to normal metabolisers. Generally, no associations were found between metabolic phenotypes and proxies of response to sertraline. Sensitivity analyses in a depression subgroup and metabolic activity scores corroborated results from the primary analysis. In summary, our findings suggest that CYP2C19 genotypes, and thus metabolic phenotypes, may have utility in determining clinical responses to SSRIs, particularly escitalopram and citalopram, though further investigation of such a relationship is warranted.

CYP2C19 genotypes and osteoporotic fractures in long-term users of proton pump inhibitors: A hospital-based study.

Proton pump inhibitors (PPIs) are commonly prescribed medications. The existing data suggest that individuals at a high risk of fractures have been exposed to high doses of PPIs for prolonged durations. CYP2C19 plays a pivotal role in metabolism of PPIs and thereby influences their pharmacokinetic profile. Hence, we hypothesize that CYP2C19 genotypes may be associated with fragility fracture among PPIs users due to PPI exposure. This study aimed to investigate the association between CYP2C19 genotypes, bone mineral density (BMD), and osteoporotic fracture in a hospital-based population. This retrospective cohort study enrolled patients who were prescribed long-term PPIs at Taichung Veterans General Hospital using data extracted from the Taiwan Precision Medicine Initiative between January 2010 and April 2021. Associations between CYP2C19 phenotypes, comorbidities, and fractures in PPI users were analyzed. We enrolled 1518 long-term PPI users; 571 (38%), 727 (48%), and 220 (14%) CYP2C19 normal metabolizers (NMs), intermediate metabolizers (IMs), and poor metabolizers (PMs), respectively. Among them, 49 (3.2%) patients developed fractures within the 1-year follow-up period; 20 (3.5%) fractures in NMs, 24 (3.3%) in IMs, and 5 (2.3%) in PMs, respectively. No significant difference was observed among CYP2C19 genotypes and fracture. Additionally, BMD measurements during the 1-year follow-up period were made available among 75 participants. No significant difference in BMD between CYP2C19 PMs and non-PMs was found. This real-world, hospital-based study concludes that CYP2C19 PMs/IMs are not associated with an increased risk for fractures or reduced BMD in individuals on long-term PPI therapy.

Population Pharmacokinetic Analyses for Belzutifan to Inform Dosing Considerations and Labeling.

Belzutifan (Welireg, Merck & Co, Inc.) is an oral, potent inhibitor of hypoxia-inducible factor (HIF) 2α, approved for the treatment of certain patients with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors (pNET). It is primarily metabolized by the polymorphic uridine 5'-diphospho-glucuronosyltransferase (UGT) 2B17 and cytochrome (CYP) 2C19. A population pharmacokinetic (PK) model was built, using NONMEM® v7.3, based on demographics/PK data from 3 clinical pharmacology (food effect, formulation bridging, genotype/race effect) and 2 clinical (phase 1 dose escalation/expansion in RCC and other solid tumors; phase 2 in VHL patients) studies. Median (range) age for the combined studies was 55 years (19-84) and body weight was 73.6 kg (42.1-165.8). Belzutifan plasma PK was well-characterized by a linear 2-compartment model with first-order absorption and elimination. For VHL patients, the predicted geometric mean (% coefficient of variation [CV]) apparent clearance (CL/F) was 7.3 L/hr (51%), apparent total volume of distribution (Vd/F) was 130 L (35%); and half-life was 12.39 hours (42%). There were no clinically relevant differences in belzutifan PK based on the individual covariates of age, sex, ethnicity, race, body weight, mild/moderate renal impairment, or mild hepatic impairment. In this model dual UGT2B17 and CYP2C19 poor metabolizers (PM) were estimated to have a 3.2-fold higher area under the plasma concentration-time curve (AUC) compared to UGT2B17 extensive metabolizer and CYP2C19 non-PM patients. This population PK analysis enabled an integrated assessment of PK characteristics with covariate effects in overall- and sub-populations for belzutifan labeling.