CYP2C19 Genotype Research Articles

Factors Influencing Pharmacokinetics of Tamoxifen in Breast Cancer Patients: A Systematic Review of Population Pharmacokinetic Models.

Tamoxifen is useful in managing breast cancer and it is reported to have significant variability in its pharmacokinetics. This review aimed to summarize reported population pharmacokinetics studies of tamoxifen and to identify the factors affecting the pharmacokinetics of tamoxifen in adult breast cancer patients. A systematic search was undertaken in Scopus, Web of Science, and PubMed for papers published in the English language from inception to 20 August 2022. Studies were included in the review if the population pharmacokinetic modeling was based on non-linear mixed-effects modeling with a parametric approach for tamoxifen in breast cancer patients. After initial selection, 671 records were taken for screening. A total of five studies were selected from Scopus, Web of Science, PubMed, and by manual searching. The majority of the studies were two-compartment models with first-order absorption and elimination to describe tamoxifen and its metabolites' disposition. The CYP2D6 phenotype and CYP3A4 genotype were the main covariates that affected the metabolism of tamoxifen and its metabolites. Other factors influencing the drug's pharmacokinetics included age, co-medication, BMI, medication adherence, CYP2B6, and CYP2C19 genotype. The disposition of tamoxifen and its metabolites varies primarily due to the CYP2D6 phenotype and CYP3A4 genotype. However, other factors, such as anthropometric characteristics and menopausal status, should also be addressed when accounting for this variability. All these studies should be externally evaluated to assess their applicability in different populations and to use model-informed dosing in the clinical setting.

Effect of evidence-based care in continuous renal replacement therapy for severe pancreatitis and the effect on serum PCT, CRP levels, and CYP2C19 genotyping

This paper presents an in-depth study and analysis of evidence-based care in continuous renal replacement therapy for severe pancreatitis and examines the effects of serum procalcitonin (PCT), C-reactive protein (CRP) levels, and CYP2C19 genotyping. Eighty patients with severe pancreatitis who met the inclusion criteria were randomly assigned to the medium metabolic group and the slow metabolic group according to their CYP2C19 gene test results, and then the two groups were randomly divided into the control group and the observation group according to the different treatment regimens. Group 1 was CYP2C19 gene intermediate metabolism and was given to the control group; group 2 was CYP2C19 gene intermediate metabolism and was given to the observation group; group 3 was CYP2C19 gene slow metabolism and was given to the control group; group 4 was CYP2C19 gene slow metabolism and was given to the observation group. The number of cases in each group was 20, and follow-up was taken, but enteral nutrition also has some complications, such as feeding intolerance, if clinicians and nursing staff actively give effective care, it can significantly reduce the incidence of complications, and improve the value of enteral nutrition, shorten the hospitalization time, and improve the clinical prognosis. The relationship between serum CRP and PCT levels and Spatially Oriented Format for Acoustics (SOFA) score and the type of Virtual Access Point (VAP) pathogens and prognosis was investigated by Spearman correlation analysis. Finally, Pearson correlation analysis was used to investigate the relationship between serum CRP and PCT levels and SOFA scores in VAP patients. Based on the above analysis, the clinical value of CRP, PCT levels, and SOFA scores in VAP was evaluated. Several evidence-based guidelines were developed to provide clear recommendations and guidance for the preventive management of enteral nutrition feeding intolerance, but there is a gap between clinical care practice and the best evidence, so the best evidence was introduced. We compare the analysis of the test results with previously reported similar tests, and our results show good accuracy and higher efficiency.

Effects of CYP2C19 genetic polymorphism on the pharmacokinetics of tolperisone in healthy subjects

Tolperisone hydrochloride is a centrally-acting muscle relaxant used for relieving spasticities of neurological origin and muscle spasms associated with painful locomotor diseases. It is metabolized to the inactive metabolite mainly by CYP2D6 and, to a lesser extent, by CYP2C19 and CYP1A2. In our previous study, the pharmacokinetics of tolperisone was significantly affected by the genetic polymorphism of CYP2D6, but the wide interindividual variation of tolperisone pharmacokinetics was not explained by genetic polymorphism of CYP2D6 alone. Thus, we studied the effects of CYP2C19 genetic polymorphism on tolperisone pharmacokinetics. Eighty-one subjects with different CYP2C19 genotypes received a single oral dose of 150mg tolperisone with 240mL ofwater, and blood samples were collected up to 12h after dosing. The plasma concentration of tolperisone was measured by a liquid chromatography-tandem mass spectrometry system. The CYP2C19PM group had significantly higher Cmax and lower CL/F values than the CYP2C19EM and CYP2C19IM groups. The AUCinf of the CYP2C19PM group was 2.86-fold and 3.00-fold higher than the CYP2C19EM and CYP2C19IM groups, respectively. In conclusion, the genetic polymorphism of CYP2C19 significantly affected tolperisone pharmacokinetics.

Ticagrelor Aspirin vs Clopidogrel Aspirin in CYP2C19 Loss-of-Function Carriers With Minor Stroke or TIA Stratified by Risk Profile.

Genotype data of the Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) trial showed that efficacy of clopidogrel aspirin depended on CYP2C19 genotype and risk profile. A stratification of patients who carried CYP2C19 loss-of-function (LOF) alleles according to the risk of recurrent stroke may be important for selecting optimal antiplatelet therapy. We aimed to compare the efficacy and safety of ticagrelor aspirin with clopidogrel aspirin in CYP2C19 LOF carriers with minor stroke or transient ischemic attack (TIA) stratified by risk profile. Data were obtained from Ticagrelor or Clopidogrel with Aspirin in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II (CHANCE-2) trial. Low-risk and high-risk profiles were defined by Essen Stroke Risk Score (ESRS) (<3 [low risk] and ≥3 [high risk], respectively). A total of 6,412 CYP2C19 LOF carriers were enrolled; ticagrelor aspirin was associated with a reduced risk of primary outcome (new stroke within 90-day follow-up) in patients at low risk (hazard ratio [HR], 0.65; 95% CI, 0.48-0.82), but not in those at high risk (HR, 0.97; 95% CI, 0.73-1.29), compared with clopidogrel aspirin (p = 0.02 for interaction). Secondary outcomes generally went in the same direction as the primary outcome. The primary safety outcome of severe or moderate bleeding did not differ based on risk profile (p = 0.24 for interaction), although the incidence of total bleeding was greater with ticagrelor aspirin than with clopidogrel aspirin among patients at low risk (p < 0.01 for interaction). Analysis in the per-protocol population yielded similar results. This post hoc analysis of CHANCE-2 trial showed that CYP2C19 LOF carriers with minor stroke or TIA at low risk of recurrent stroke received a greater benefit from ticagrelor aspirin than from clopidogrel aspirin. This study provides Class II evidence that CYP2C19 LOF carriers with minor stroke or TIA at low risk, but not at high risk, of recurrent stroke (by the ESRS) received a greater benefit from ticagrelor aspirin than from clopidogrel aspirin. URL: www. gov. Unique identifier: NCT04078737.

Pharmacogenetic Testing and Therapeutic Drug Monitoring Of Sertraline at a Residential Treatment Center for Children and Adolescents: A Pilot Study.

Background: Sertraline is commonly prescribed to children for the treatment of anxiety and major depressive disorder and is metabolized in part by CYP2C19. While dosing recommendations based on CYP2C19 genotype exist, there is sparse data in children on the relationship between sertraline concentrations and CYP2C19 genotype. Additionally, although rarely utilized in the United States, therapeutic drug monitoring can also help to guide dosing. The primary objective of this pilot study was to compare sertraline concentrations with CYP2C19 genotype. Secondary objectives included exploring the feasibility of using pharmacogenetic testing and therapeutic drug monitoring in a residential treatment center for children and adolescents. Methods: This study was a prospective, open-label study of children prescribed sertraline being treated at a residential treatment center for children and adolescents. Individuals were included if they were < 18 years of age, taking sertraline for at least 2 weeks allowing them to reach steady-state concentrations, being treated through the residential treatment program, and able to understand and speak English. Results: A total of 20 participants (80% female) completed all study procedures, including pharmacogenetic testing and therapeutic drug monitoring, with an average age of 15.4 years (range: 9-17 years). Forty percent (n=8) of participants had a diagnosis of Generalized Anxiety Disorder, while 30% (n=6) had a diagnosis of Major Depressive Disorder. Overall, average sertraline and desmethylsertraline concentrations were 21.1 ng/ml (range: 1-78 ng/ml) and 52.4 ng/ml (range: 1-258 n/ml). Based on CYP2C19 genotypes, 60% (n=12) were normal metabolizers, 10% (n=2) were intermediate metabolizers, and 30% (n=6) were rapid metabolizers. Daily sertraline dose (mg/day) accounted for a significant amount of the observed variability in sertraline (p<0.0001; r2=0.62) and desmethylsertraline concentrations (p<0.001; r2=0.45). When comparing weight-based dosing by sertraline and desmethylsertraline concentrations, sertraline daily dose by weight (mg/kg/day) also accounted for a significant amount of the observed variability in sertraline (p<0.0001; r2=0.60) and desmethylsertraline (p<0.0001; r2=0.59) concentrations. Average daily and weight-based doses for CYP2C19 intermediate, normal, and rapid metabolizers were 75mg/day, 87.5mg/day, and 79.2mg/day and 1.5mg/kg/day, 1.3mg/kg/day, and 1.1mg/kg/day, though these were not significantly different. Conclusion: This small, pilot study showed sertraline dose to be significantly associated with sertraline and desmethylsertraline concentrations. No differences were noted between CYP2C19 metabolizer groups, likely due to the limited sample size. These results also suggest that ordering pharmacogenetic testing and therapeutic drug monitoring in the setting of a child and adolescent residential treatment center is feasible.

The Effect of Voriconazole on Tacrolimus in Kidney Transplantation Recipients: A Real-World Study.

Tacrolimus is an immunosuppressant with a narrow therapeutic window. Tacrolimus exposure increased significantly during voriconazole co-therapy. The magnitude of this interaction is highly variable, but it is hard to predict quantitatively. We conducted a study on 91 kidney transplantation recipients with voriconazole co-therapy. Furthermore, 1701 tacrolimus concentration data were collected. Standard concentration adjusted by tacrolimus daily dose (C/D) and weight-adjusted standard concentration (CDW) increased to 6 times higher during voriconazole co-therapy. C/D and CDW increased with voriconazole concentration. Patients with the genotype of CYP3A5 *3/*3 and CYP2C19 *2/*2 or *2/*3 were more variable at the same voriconazole concentration level. The final prediction model could explain 54.27% of the variation in C/D and 51.11% of the variation in CDW. In conclusion, voriconazole was the main factor causing C/D and CDW variation, and the effect intensity should be quantitative by its concentration. Kidney transplant recipients with CYP3A5 genotype of *3/*3 and CYP2C19 genotype of *2/*2 and *2/*3 should be given more attention during voriconazole co-therapy. The prediction model established in this study may help to reduce the occurrence of rejection.

CYP2C19 genotype and platelet aggregation test-guided dual antiplatelet therapy after off-pump coronary artery bypass grafting: A retrospective cohort study.

Dual antiplatelet therapy (DAPT) is recommended in patients undergoing off-pump coronary artery bypass graft surgery (OPCAB). Clopidogrel is less effective among patients with loss-of-function (LoF) of CYP2C19 alleles, while ticagrelor has direct effects on P2Y12 receptor. Whether a CYP2C19 genotype plus platelet aggregation test (PAgT)-guided DAPT after CABG could improve clinical outcomes remain uncertain. From August 2019 to December 2020, 1,134 consecutive patients who underwent OPCAB received DAPT for 1 year after surgery in Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. According to the actual treatment they received in real-world, 382 (33.7%) of them received a traditional DAPT: aspirin 100 mg qd + clopidogrel 75 mg qd, no matter the CYP2C19 genotype and response in platelet aggregation test (PAgT). The other 752 (66.3%) patients received an individual DAPT based on CYP2C19 genotype and PAgT: aspirin 100 mg qd + clopidogrel 75 mg qd if CYP2C19 was extensive metabolizer, or moderate metabolizer but normal response in PAgT; aspirin 100 mg qd + ticagrelor 90 mg bid if CYP2C19 was poor metabolizer, or moderate metabolizer but no or low response in PAgT. One-year follow-up was achieved for all patients. The primary outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke. The safety outcome was thrombolysis in myocardial infarction (TIMI) criteria major bleeding. Compared with the traditional DAPT group, the risk of MACE in the individual DAPT group was significantly lower (5.5 vs. 9.2%, HR 0.583; 95% CI, 0.371-0.915; P = 0.019), mainly due to the decreased risk of MI (1.7 vs. 4.2%, HR 0.407; 95% CI, 0.196-0.846; P = 0.016). The risk of TIMI major bleeding events was similar between the two groups (5.3 vs. 6.0%, RR 0.883; 95% CI, 0.537-1.453; P = 0.626). For patients who underwent OPCAB, individual DAPT (CYP2C19 genotype plus PAgT-guided strategy) was associated with a lower risk of MACE and a similar risk of major bleeding.

Evaluation of Potential Racial Disparities in CYP2C19-Guided P2Y12 Inhibitor Prescribing After Percutaneous Coronary Intervention.

Black patients suffer worse outcomes after percutaneous coronary intervention (PCI) than White patients. Inequities in antiplatelet prescribing may contribute to this health disparity. We compared P2Y12 inhibitor prescribing by race following CYP2C19 genotyping to guide antiplatelet therapy selection after PCI. Patients from 9 sites that performed clinical CYP2C19 genotyping after PCI were included. Alternative therapy (e.g., prasugrel or ticagrelor) was recommended for CYP2C19 no-function allele carriers, in whom clopidogrel is predicted to be less effective. The primary outcome was choice of P2Y12 inhibitor (clopidogrel vs. alternative therapy) based on genotype. Of 3,342 patients included, 2,448 (73%) were White, and 659 (20%) were Black. More Black than White patients had a no-function allele (34.3% vs. 29.7%, P= 0.024). At hospital discharge following PCI, 44.2% of Black and 44.0% of White no-function allele carriers were prescribed alternative therapy. At the time of the last follow-up within 12 months, numerically fewer Black (51.8%) than White (56.7%) no-function allele carriers were prescribed alternative therapy (P=0.190). However, the difference was not significant after accounting for other factors associated with P2Y12 inhibitor selection (odds ratio 0.79, 95% confidence interval 0.58-1.08). Alternative therapy use did not differ between Black (14.3%) and White (16.7%) patients without a no-function allele (P=0.232). Among real-world patients who received CYP2C19 testing after PCI, P2Y12 inhibitor prescribing rates did not differ between Black and White patients. Our data suggest an absence of racial disparity in genotype-guided antiplatelet prescribing among patients receiving CYP2C19 testing.

A Physiological-Based Pharmacokinetic Model Embedded with a Target-Mediated Drug Disposition Mechanism Can Characterize Single-Dose Warfarin Pharmacokinetic Profiles in Subjects with Various CYP2C9 Genotypes under Different Cotreatments.

Warfarin, a commonly prescribed oral anticoagulant medication, is highly effective in treating deep vein thrombosis and pulmonary embolism. However, the clinical dosing of warfarin is complicated by high interindividual variability in drug exposure and response and its narrow therapeutic index. CYP2C9 genetic polymorphism and drug-drug interactions (DDIs) are substantial contributors to this high variability of warfarin pharmacokinetics (PK), among numerous factors. Building a physiology-based pharmacokinetic (PBPK) model for warfarin is not only critical for a mechanistic characterization of warfarin PK but also useful for investigating the complicated dose-exposure relationship of warfarin. Thus, the objective of this study was to develop a PBPK model for warfarin that integrates information regarding CYP2C9 genetic polymorphisms and their impact on DDIs. Generic PBPK models for both S- and R-warfarin, the two enantiomers of warfarin, were constructed in R with the mrgsolve package. As expected, a generic PBPK model structure did not adequately characterize the warfarin PK profile collected up to 15 days following the administration of a single oral dose of warfarin, especially for S-warfarin. However, following the integration of an empirical target-mediated drug disposition (TMDD) component, the PBPK-TMDD model well characterized the PK profiles collected for both S- and R-warfarin in subjects with different CYP2C9 genotypes. Following the integration of enzyme inhibition and induction effects, the PBPK-TMDD model also characterized the PK profiles of both S- and R-warfarin in various DDI settings. The developed mathematic framework may be useful in building algorithms to better inform the clinical dosing of warfarin. SIGNIFICANCE STATEMENT: The present study found that a traditional physiology-based pharmacokinetic (PBPK) model cannot sufficiently characterize the pharmacokinetic profiles of warfarin enantiomers when warfarin is administered as a single dose, but a PBPK model with a target-mediated drug disposition mechanism can. After incorporating CYP2C9 genotypes and drug-drug interaction information, the developed model is anticipated to facilitate the understanding of warfarin disposition in subjects with different CYP2C9 genotypes in the absence and presence of both cytochrome P450 inhibitors and cytochrome P450 inducers.

Dosage optimization of voriconazole in children with haematological malignancies based on population pharmacokinetics.

Voriconazole has a complex pharmacokinetic profile and exhibits different pharmacokinetic characteristics in adults and children. Nevertheless, few studies have been conducted on the population pharmacokinetics (PPK) of voriconazole in children with haematological malignancies. This study aims to build a PPK model and propose a suitable voriconazole treatment scheme for children with haematological malignancies. We retrospectively collected 146 samples from 67 children aged from 1.08 to 17.92 years. The PPK model was established using nonlinear mixed effects modelling (NONMEM). Dosage simulations were conducted on the basis of the final model's covariates. Data were fully characterized by a one-compartment model with first-order absorption and elimination. The weight (WT), CYP2C19 phenotype, and Albumin (ALB) were notable covariates for clearance (CL). The typical values of CL, the volume of distribution (V), and oral bioavailability (F) were 2.29 L/h, 76 L, and 0.902, respectively. The proposed doses for different CYP2C19 genotypes were presented in this ranking: EM (extensive metabolizer) > IM (intermediate metabolizer) > PM (poor metabolizer). Furthermore, higher dosages for light WT patients were recommended while lower ALB levels required lower doses. The probability of achieving the target (PTA) for the recommended doses ranged from 72.2% to 99%. We successfully built a voriconazole PPK model for children with hematologic malignancies. Dosing regimens were developed for different patients based on the final model, which could enhance the rational use of voriconazole in children with haematological malignancies.

Derivation of a Novel Scoring System Predicting High Platelet Reactivity on Prasugrel in Patients with Coronary Artery Disease.

High platelet reactivity (HPR) has been associated with an increased risk of thrombotic events in patients undergoing percutaneous coronary intervention. HPR has been well examined in patients treated with clopidogrel; however, HPR on prasugrel is poorly investigated. Four prospective studies were pooled, in which platelet reactivity on prasugrel was measured using VerifyNow assay; genotyping of CYP2C19 was also performed. Factors associated with HPR on prasugrel were identified using multivariable analysis to develop a risk prediction model. In total, 180 patients were examined in this study, of whom 51 (28%) had HPR on prasugrel. The multivariable analysis indicated that hypertension, diabetes, hemodialysis, and the number of CYP2C19 loss-of-function (LOF) alleles are significant factors for HPR on prasugrel. These four factors were then incorporated to develop the HHD-GENE score. The receiver operating characteristic curve analysis showed that the HHD-GENE score predicted HPR on prasugrel (area under the curve (AUC) 0.74, best cutoff value 5, p＜0.001). With the best cutoff value, patients with the HHD-GENE score ≥ 5 had a significantly increased risk of HPR on prasugrel than their counterpart (50% vs. 18%, p＜0.001). The HHD-GENE score consisting of hypertension, diabetes, hemodialysis, and CYP2C19 LOF alleles may be useful in identifying patients on prasugrel who are at high risk for HPR. External validation is needed to define the clinical utility of this novel scoring system.

Evaluation of supervised machine learning algorithms in predicting the poor anticoagulation control and stable weekly doses of warfarin.

Machine learning algorithms (MLAs) carry a huge potential in identifying predicting factors and are being explored for their utility in the field of personalized medicine. We aimed to investigate MLAs for identifying predictors (clinical and genetic) of poor anticoagulation status (ACS) and stable weekly warfarin dose (SWWD). Clinical factors, in addition to the CYP2C9, VKORC1, and CYP4F2 genotypes, were obtained for patients receiving warfarin for at least the previous six months. The C5.0 decision tree classification algorithm was used to predict poor ACS while classification and regression tree analysis (CART), in addition to the Chi-square automatic interaction detector (CHAID), was used to predict SWWD. The percentage of patients within 20% of the actual dose, root mean squared error (RMSE), and area under the receiver-operating characteristics curve (AUROC) were identified as performance indicators of the models. In the C5.0 classification decision tree, the CYP4F2 genotype was the strongest predictor of ACS (AUROC = 0.53). In the CART analysis of SWWD, VKORC1 polymorphisms were the most significant predictor, followed by the CYP2C9 genotype (percentage of patients within 20% of the actual dose = 38.2%, RMSE = 13.6). For the CHAID algorithm, the percentage of patients within 20% of the actual dose was 49%, while the RMSE was found to be 13.4. Genetic and non-genetic predictive factors were identified by the MLAs for ACS and SWWD. Further, the need to externally validate the MLAs in a prospective study was highlighted.

Genetic abnormality of cytochrome-P2C9*3 allele predisposes to epilepsy and phenytoin-induced adverse drug reactions: genotyping findings of cytochrome-alleles in the North Indian population

BackgroundThis research aims to study the association of genetic polymorphism in genes coding for CYP2C9 and CYP2C19 in phenytoin-induced dose-related toxicity and to assess if the presence of allele CYP2C9*3 plays a role in phenytoin-induced idiosyncratic adverse effects. Current observational case control study included 142 patients with phenytoin-induced adverse drug reactions (ADRs) and 100 controls. All these patients underwent genotyping to determine the type of CYP2C9 allele [CYP2C9*1, CYP2C9*2 or CYP2C9*3) and CYP2C19 allele (CYP2C19*1, CYP2C19*2 or CYP2C19*3] by real-time polymerase chain reaction (RT-PCR) using Applied Biosystems (ABI) 7500 Real-Time PCR System (USA).ResultsPresence of homozygous status for allele CYP2C9*3 was associated with significantly higher risk of phenytoin-induced dose-dependent ADRs, dose-independent ADRs, gum hyperplasia, and skin rash. Presence of heterozygous status for allele CYP2C9*3 was associated with significantly higher risk of phyenytoin-induced dose-dependent ADRs and dose-independent ADRs. Presence of either heterozygous or homozygous status for CYP2C9*2 and CYP2C19*2 did not have any bearing on dose-related side effects. None of the patients showed CYP2C19*3 allele.ConclusionVariant alleles of CYP2C9*3 are significantly overexpressed among patients with phenytoin-induced ADRs, thereby suggesting the role for CYP2C9 genotype testing to predict risk of phenytoin-related ADRs.

Microdialysis of Voriconazole and its N-Oxide Metabolite: Amalgamating Knowledge of Distribution and Metabolism Processes in Humans

PurposeVoriconazole is an essential antifungal drug whose complex pharmacokinetics with high interindividual variability impedes effective and safe therapy. By application of the minimally-invasive sampling technique microdialysis, interstitial space fluid (ISF) concentrations of VRC and its potentially toxic N-oxide metabolite (NO) were assessed to evaluate target-site exposure for further elucidating VRC pharmacokinetics.MethodsPlasma and ISF samples of a clinical trial with an approved VRC dosing regimen were analyzed for VRC and NO concentrations. Concentration-time profiles, exposure assessed as area-under-the-curve (AUC) and metabolic ratios of four healthy adults in plasma and ISF were evaluated regarding the impact of multiple dosing and CYP2C19 genotype.ResultsVRC and NO revealed distribution into ISF with AUC values being ≤2.82- and 17.7-fold lower compared to plasma, respectively. Intraindividual variability of metabolic ratios was largest after the first VRC dose administration while interindividual variability increased with multiple dosing. The CYP2C19 genotype influenced interindividual differences with a maximum 6- and 24-fold larger AUCNO/AUCVRC ratio between the intermediate and rapid metabolizer in plasma and ISF, respectively. VRC metabolism was saturated/auto-inhibited indicated by substantially decreasing metabolic concentration ratios with increasing VRC concentrations and after multiple dosing.ConclusionThe feasibility of the simultaneous microdialysis of VRC and NO in vivo was demonstrated and provided new quantitative insights by leveraging distribution and metabolism processes of VRC in humans. The exploratory analysis suggested substantial dissimilarities of VRC and NO pharmacokinetics in plasma and ISF. Ultimately, a thorough understanding of target-site pharmacokinetics might contribute to the optimization of personalized VRC dosing regimens.

A one-year follow-up study of treatment-compliant suicide attempt survivors: relationship of CYP2D6-CYP2C19 and polypharmacy with suicide reattempts

This study of a cohort of 1-year treatment-compliant survivors of a suicide attempt examined for the first time whether a high CYP2D6-CYP2C19 metabolic capacity (pharmacogenes related to psychopathology, suicide, and attempt severity) and/or polypharmacy treatments predicted repeat suicide attempts, adjusting for sociodemographic and clinical factors as confounders. Of the 461 (63% women) consecutively hospitalized patients who attempted suicide and were evaluated and treated after an index attempt, 191 (67.5% women) attended their 6- and 12-month follow-up sessions. Clinicians were blinded to the activity scores (AS) of their genotypes, which were calculated as the sum of the values assigned to each allele (CYP2C19 *2, *17; CYP2D6 *3, *4, *4xN, *5, *6, *10, wtxN). No differences were found in polypharmacy prescription patterns and the variability of CYP2D6 and CYP2C19 genotypes between adherents and dropouts, but the formers were older, with a higher frequency of anxiety and bipolar disorders and fewer alcohol and substance use disorders. The risk of reattempts was higher for CYP2D6 ultrarapid (AS > 2) metabolizers (β = 0.561, p = 0.005) and violent suicide survivors (β = −0.219, p = 0.042) if the attempt occurred during the first 6-month period, individuals with an increased number of MINI DSM-IV Axis I mental disorders (β = 0.092, p = 0.032) during the second 6-month period and individuals with a combined high CYP2D6-CYP2C19 metabolic capacity (AS > 4) (β = 0.345, p = 0.024) and an increased use of drugs other than antidepressants, anxiolytics-depressants and antipsychotics-lithium (β = 0.088, p = 0.005) in multiple repeaters during both periods. CYP2D6 and CYP2C19 rapid metabolism and polypharmacy treatment for somatic comorbidities must be considered to prevent the severe side effects of short-term multiple suicide reattempts after a previous attempt.

Machine learning advances the integration of covariates in population pharmacokinetic models: Valproic acid as an example.

Background and Aim: Many studies associated with the combination of machine learning (ML) and pharmacometrics have appeared in recent years. ML can be used as an initial step for fast screening of covariates in population pharmacokinetic (popPK) models. The present study aimed to integrate covariates derived from different popPK models using ML. Methods: Two published popPK models of valproic acid (VPA) in Chinese epileptic patients were used, where the population parameters were influenced by some covariates. Based on the covariates and a one-compartment model that describes the pharmacokinetics of VPA, a dataset was constructed using Monte Carlo simulation, to develop an XGBoost model to estimate the steady-state concentrations ( ) of VPA. We utilized SHapley Additive exPlanation (SHAP) values to interpret the prediction model, and calculated estimates of VPA exposure in four assumed scenarios involving different combinations of CYP2C19 genotypes and co-administered antiepileptic drugs. To develop an easy-to-use model in the clinic, we built a simplified model by using CYP2C19 genotypes and some noninvasive clinical parameters, and omitting several features that were infrequently measured or whose clinically available values were inaccurate, and verified it on our independent external dataset. Results: After data preprocessing, the finally generated combined dataset was divided into a derivation cohort and a validation cohort (8:2). The XGBoost model was developed in the derivation cohort and yielded excellent performance in the validation cohort with a mean absolute error of 2.4mg/L, root-mean-squared error of 3.3mg/L, mean relative error of 0%, and percentages within 20% of actual values of 98.85%. The SHAP analysis revealed that daily dose, time, CYP2C19*2 and/or *3 variants, albumin, body weight, single dose, and CYP2C19*1*1 genotype were the top seven confounding factors influencing the of VPA. Under the simulated dosage regimen of 500 mg/bid, the VPA exposure in patients who had CYP2C19*2 and/or *3 variants and no carbamazepine, phenytoin, or phenobarbital treatment, was approximately 1.74-fold compared to those with CYP2C19*1/*1 genotype and co-administered carbamazepine + phenytoin + phenobarbital. The feasibility of the simplified model was fully illustrated by its performance in our external dataset. Conclusion: This study highlighted the bridging role of ML in big data and pharmacometrics, by integrating covariates derived from different popPK models.

Is the CYP2D6 Genotype Associated with Antipsychotic-Induced Weight Gain?

Antipsychotic-induced weight gain (AIWG) is a serious adverse effect. Studies have linked genetically-predicted CYP2D6 metabolic capacity to AIWG. The evidence, however, is ambiguous. We performed multiple regression analyses examining the association between genetic-predicted CYP2D6 metabolic capacity and AIWG. Analyses were based on previously unpublished data from an RCT investigating the clinical utility of routine genotyping of CYP2D6 and CYP2C19 in patients with schizophrenia. A total of 211 patients, corresponding to 71% of the original study population, were included. Our analyses indicated an effect of genetically predicted CYP2D6 metabolic capacity on AIWG with significant weight gain in both CYP2D6 poor metabolizers (PMs) (4.00 kg (95% CI: 0.80; 7.21)) and ultrarapid metabolizers (UMs) (6.50 kg (95% CI: 1.03; 12.0)). This finding remained stable after adjustment for covariates (PMs: 4.26 kg (0.88; 7.64), UMs: 7.26 kg (1.24; 13.3)). In addition to the CYP2D6 metabolic capacity, both baseline body mass index (−0.24 (95% CI: −0.44; −0.03)) and chlorpromazine equivalents per day (0.0041 (95% CI: 0.0005; 0.0077)) were statistically significantly associated with weight change in the adjusted analysis. Our results support that the genetically predicted CYP2D6 metabolic capacity matters for AIWG.

The effect of polymorphic alleles carriage of the VKORC1 gene on clinical and laboratory ­parameters in patients with acute coronary syndrome

Background. The role of the VKORC1 (1639GA, rs9923231) gene polymorphism in hypersensitivity to warfarin and hypocoagulation is known. It has been proven that polymorphisms in the VKORC1 gene can lead to the progression of atherosclerosis and hypercoagulability, and, therefore, can be factors contributing to the development of acute coronary syndrome.&#x0D; Aim. To study the effect of polymorphic genotypes carriage of the VKORC1 gene on the clinical and laboratory parameters of patients with acute coronary syndrome.&#x0D; Material and methods. The pilot observational cross-sectional study involved 77 patients who were under observation in the conditions of the Federal Center for Cardiovascular Surgery in Astrakhan and the vascular center of Kirov City Hospital No. 3 (Astrakhan), from October 2020 to May 2021. Genotyping for CYP2C9, VKORC1, CYP4F2 on a PCR analyzer was performed. For statistical processing, the HardyWeinberg and Student criteria; 95% confidence interval were determined using Statistica Trial 13 and IBM SPSS Statistics 26.0. Differences were considered statistically significant at p 0.05.&#x0D; Results. Significant differences related to the frequency of hemodynamically significant stenosis in homozygous carriers of the GG gene for VKORC1 compared with the group of carriers of the GA genotype 3 (8.8%) versus 7 (22.5%); p=0.0058. Carriers of the GA and GG genotypes were most often diagnosed with myocardial infarction (Q- and non-Q-forming). Carriers of the AA genotype were more likely to have new or progressive angina pectoris. The level of hyperglycemia and triglyceridemia was the highest in the group of patients with the AA genotype, VKORC1 gene.&#x0D; Conclusion. Statistically significant differences were established in the clinical and laboratory parameters of patients with acute coronary syndrome, carriers of different genotypes of the VKORC1 gene.

Approaches to de-escalation of antiplatelet treatment in stabilized post-myocardial infarction patients with high ischemic risk

ABSTRACT Introduction In patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI), dual antiplatelet therapy (DAPT) with a potent P2Y12 inhibitor is normally recommended for 12 months. However, the greatest anti-ischemic benefit of DAPT occurs early, while most excess bleeding events occur during chronic treatment. De-escalation of DAPT is an emerging treatment strategy for ACS patients. Areas covered This review critically evaluates the evidence for de-escalation based on clinical judgment (i.e. unguided) or guided by either platelet function testing or CYP2C19 genotyping. Ongoing trials and research directions are also discussed. Expert opinion De-escalation of antiplatelet therapy represents a viable therapeutic alternative to standard DAPT for patients after an ACS, aimed at providing a good balance between the risks of thrombosis and bleeding. It is not clear if this approach is better with or without guidance by platelet function testing or genotyping. Also, the benefit versus short DAPT is uncertain. Current guidelines support the de-escalation of DAPT for selected patients who are unsuitable for potent platelet inhibition, a cohort of patients that was not specifically represented in landmark trials of de-escalation. More studies are needed to define the optimal candidates for this strategy.

Genotyping of patients treated with selective serotonin reuptake inhibitors.

Selective serotonin reuptake inhibitors (SSRIs) are used by over 180,000 people in Norway. The enzymes CYP2D6 and CYP2C19 are key in the metabolism of SSRI antidepressants. The serotonin transporter coded by SLC6A4 may be significant for the efficacy of the drugs. All patients who had undergone genotyping for CYP2D6, CYP2C19 and SLC6A4 at the Centre for Psychopharmacology in 2020 were included, irrespective of indication. For those patients where data were available, CYP2C19 genotype was linked to serum concentration measurement of escitalopram, which is the most commonly used SSRI drug. Out of 3,492 patients, 432 (12.4%) had a combination of genotypes of CYP2D6, CYP2C19 and SLC6A4 considered to lead to the most favourable metabolism and efficacy of SSRI antidepressants. The dose requirement in patients with poor CYP2C19 metabolism was more than halved to achieve the same concentration of escitalopram compared to patients with normal metabolism. Our findings demonstrate the low prevalence of the most favourable genotype combination for response to SSRIs. Genotype combinations probably contribute to the wide variation between individuals in the efficacy of these drugs and the fact that treatment does not produce the desired outcome in many patients.