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Major depressive disorder (MDD) is one of the leading causes of disability worldwide. Polymorphisms in cytochrome P450 genes (CYP450) were demonstrated to play a significant role in antidepressant response and side effects, but their effect in real-world clinical practice is poorly known. We determined the metabolic status of CYP2C19 based on the combination of *1, *2, *3 and *17 alleles extracted from genome-wide data in 1239 patients with MDD, pharmacologically treated in a naturalistic setting. Symptom improvement and side effects were assessed using the Montgomery and Åsberg Depression Rating Scale and the Udvalg for Kliniske Undersøgelse scale, respectively. We tested if symptom improvement, response and side effects were associated with CYP2C19 metabolic status adjusting for potential confounders. We considered patients treated with drugs for depression having CYP2C19 genotyping recommended by guidelines (T1 Drugs); secondarily, with all psychotropic drugs having CYP2C19 as relevant metabolic path (T2 Drugs). In the group treated with T1 drugs (n = 540), poor metabolizers (PMs) showed higher response and higher symptom improvement compared to normal metabolizers (p = 0.023 and p = 0.009, respectively), but also higher risk of autonomic and neurological side effects (p = 0.022 and p = 0.022 respectively). In patients treated with T2 drugs (n = 801), similar results were found. No associations between metabolizer status and other types of side effects were found (psychic and other side effects). Our study suggests potential advantages of CYP2C19 pharmacogenetic testing to guide treatment prescription, that may not be limited to the drugs currently recommended by guidelines.

The aim of this study was to investigate the association between CYP2C19 gene polymorphisms and the risk of cardiovascular events in the early stage and subsequent period after percutaneous coronary intervention (PCI) among patients who received clopidogrel. Between October 2015 and January 2017, CYP2C19 genotyped patients who were treated with clopidogrel after PCI were enrolled in this study. Included patients were categorized as non-loss-of-function metabolizers, intermediate metabolizers, and poor metabolizers based on CYP2C19 genotype. The primary outcome was a composite of any-cause mortality, nonfatal myocardial infarction, nonfatal ischemic stroke, and stent thrombosis occurring during exposure to clopidogrel. The rates of clinical outcome events were compared between CYP2C19 phenotypes. Landmark analyses were processed at 90 days and 1 year post-PCI. Of 1341 patients, 161 (12.0%) had 2 copies of loss-of-function (LOF) alleles, 621(46.3%) had one LOF allele, and 559 (41.7%) had no LOF allele. At the 3-month follow-up, the primary outcome events were more frequent in carriers of 2 LOF alleles (5.6%) than in noncarriers (1.8%) [adjusted hazard ratio (HR) 2.944, 95% confidence interval, 1.184-7.321, P = 0.020). A similar finding was observed among in patients with acute coronary syndrome indications at the index PCI (adjusted HR 3.046, 95% confidence interval, 1.237-7.501, P = 0.015). These differences did not persist within the subsequent 9 months of follow-up, among either all comers or subjects with acute coronary syndrome. In conclusion, these data demonstrate a higher risk for ischemic events in patients with 2 CYP2C19 LOF alleles who are prescribed clopidogrel, seen at 3 months after PCI, that is not sustained for 12 months.

Background Voriconazole, a first-line antifungal drug, exhibits nonlinear pharmacokinetics (PK), together with large interindividual variability but a narrow therapeutic range, and markedly inhibits cytochrome P450 (CYP) 3A4 in vivo. This causes difficulties in selecting appropriate dosing regimens of voriconazole and coadministered CYP3A4 substrates. Objective This study aimed to investigate the metabolism of voriconazole in detail to better understand dose- and time-dependent alterations in the PK of the drug, to provide the model basis for safe and effective use according to CYP2C19 genotype, and to assess the potential of voriconazole to cause drug-drug interactions (DDIs) with CYP3A4 substrates in more detail. Methods In vitro assays were carried out to explore time-dependent inhibition (TDI) of CYP3A4 by voriconazole. These results were combined with 93 published concentration-time datasets of voriconazole from clinical trials in healthy volunteers to develop a whole-body physiologically based PK (PBPK) model in PK-Sim(R). The model was evaluated quantitatively with the predicted/observed ratio of the area under the plasma concentration-time curve (AUC), maximum concentration (C-max), and trough concentrations for multiple dosings (C-trough), the geometric mean fold error, as well as visually with the comparison of predicted with observed concentration-time datasets over the full range of recommended intravenous and oral dosing regimens. Results The result of the half maximal inhibitory concentration (IC50) shift assay indicated that voriconazole causes TDI of CYP3A4. The PBPK model evaluation demonstrated a good performance of the model, with 71% of predicted/observed aggregate AUC ratios and all aggregateC(max)ratios from 28 evaluation datasets being within a 0.5- to 2-fold range. For those studies reporting CYP2C19 genotype, 89% of aggregate AUC ratios and all aggregateC(max)ratios were inside a 0.5- to 2-fold range of 44 test datasets. The results of model-based simulations showed that the standard oral maintenance dose of voriconazole 200 mg twice daily would be sufficient for CYP2C19 intermediate metabolizers (IMs; *1/*2, *1/*3, *2/*17, and *2/*2/*17) to reach the tentative therapeutic range of > 1-2 mg/L to

Indigenous Australians face a disproportionately severe burden of chronic disease relative to other Australians, with elevated rates of morbidity and mortality. While genomics technologies are slowly gaining momentum in personalised treatments for many, a lack of pharmacogenomic research in Indigenous peoples could delay adoption. Appropriately implementing pharmacogenomics in clinical care necessitates an understanding of the frequencies of pharmacologically relevant genetic variants within Indigenous populations. We analysed whole-genome sequence data from 187 individuals from the Tiwi Islands and characterised the pharmacogenomic landscape of this population. Specifically, we compared variant profiles and allelic distributions of previously described pharmacologically significant genes and variants with other population groups. We identified 22 translationally relevant pharmacogenomic variants and 18 clinically actionable guidelines with implications for drug dosing and treatment of conditions including heart disease, diabetes and cancer. We specifically observed increased poor and intermediate metabolizer phenotypes in the CYP2C9 (PM:19%, IM:44%) and CYP2C19 (PM:18%, IM:44%) genes.

Xenobiotics can interact with cytochromes P450 (CYPs), resulting in drug–drug interactions, but CYPs can also contribute to drug–disease interactions, especially in the case of inflammation, which downregulates CYP activities through pretranscriptional and posttranscriptional mechanisms. Interleukin‐6 (IL‐6), a key proinflammatory cytokine, is mainly responsible for this effect. The aim of our study was to develop a physiologically based pharmacokinetic (PBPK) model to foresee the impact of elevated IL‐6 levels in combination with drug interactions with esomeprazole on CYP3A and CYP2C19. Data from a cohort of elective hip surgery patients whose CYP3A and CYP2C19 activities were measured before and after surgery were used to validate the accurate prediction of the developed models. Successive steps were to fit models for IL‐6, esomeprazole, and omeprazole and its metabolite from the literature and to validate them. The models for midazolam and its metabolite were obtained from the literature. When appropriate, a correction factor was applied to convert drug concentrations from whole blood to plasma. Mean ratios between simulated and observed areas under the curve for omeprazole/5‐hydroxy omeprazole, esomeprazole, and IL‐6 were 1.53, 1.06, and 0.69, respectively, indicating an accurate prediction of the developed models. The impact of IL‐6 and esomeprazole on the exposure to CYP3A and CYP2C19 probe substrates and respective metabolites were correctly predicted. Indeed, the ratio between predicted and observed mean concentrations were

Aim: Metamizole (dipyrone) is a prodrug not detectable in serum or urine after oral ingestion. The primary metabolite is 4-methylaminoantipyrine (4-MAA), which can be N-demethylated to 4-aminoantipyrine (4-AA) or oxidized to 4-formylaminoantipyrine (4-FAA) by cytochrome P450 (CYP)-dependent reactions. Our aim was to identify the CYPs involved. Methods: We investigated the metabolism of 4-MAA in vitro using CYP expressing supersomes and the pharmacokinetics of metamizole in the presence of CYP inhibitors in healthy volunteers. Results: The experiments in supersomes revealed CYP1A2 as the major CYP for 4-MAA N-demethylation and 4-FAA formation. CYP2C19 and CYP2D6 contributed to N-demethylation but not to FAA formation. In the subsequent clinical study, we investigated the influence of ciprofloxacin (strong CYP1A2 inhibitor), fluconazole (strong CYP2C19 inhibitor) and the combination ciprofloxacin/fluconazole on the pharmacokinetics of a single dose of metamizole in n=12 healthy volunteers in a randomized, placebo-controlled, double-blind study. Both ciprofloxacin and fluconazole inhibited the metabolism of 4-MAA, confirming the in vitro results. Ciprofloxacin, fluconazole and ciprofloxacin/fluconazole increased the AUC0-12h of 4-MAA by 51%, 17% and 92%, respectively. Ciprofloxacin, fluconazole and ciprofloxacin/fluconazole decreased the AUC0-12h of 4-AA by 27%, 12% and 24%, respectively, and of 4-FAA by 33%, 9% and 51%, respectively. Ciprofloxacin, fluconazole and ciprofloxacin/fluconazole increased the half-life of 4-MAA from 3.22 h (placebo) to 3.91, 3.69 and 6.07 h, respectively. Conclusion: CYP1A2 is the major CYP for the conversion of 4-MAA to 4-AA and 4-FAA. CYP1A2 inhibition increases the 4-MAA exposure by a factor of approximately 1.5, which could be relevant for dose-dependent adverse reactions.

Dietary supplement use has continued to rise. In addition to supplement-drug interactions, it is prudent to consider how dietary supplements may interact with a patient’s specific pharmacogenetics. Variations in genes associated with CYP 450 enzymes have evidence of impacting drug metabolism and adverse effects. This research was performed to evaluate CYP P450 enzyme activity of the top 15 dietary supplements used in the USA in order to initiate pharmacogenetic considerations specific to commonly used dietary supplements. The most common dietary supplements used in the USA were obtained from the National Health and Nutrition Examination Survey (NHANES). Primary literature detailing supplement CYP P450 activity was compiled from PubMed using MeSH search terms: supplement name(s), cytochrome P450 enzymes, metabolism, and pharmacokinetics. Additional resources utilized for documented CYP enzyme genotypes were the pharmacogenetic databases from Clinical Pharmacogenetics Implementation Consortium and The Pharmacogenomic Variation Consortium. Of the 15 most common dietary supplements used in the USA, 53% (cranberry, echinacea, garlic, ginkgo biloba, ginseng, melatonin, milk thistle, and valerian) exhibit CYP P450 metabolism, with some having possible induction activity as well. Melatonin and garlic are substrates of CYP1A2 and CYP2C19, respectively. Additionally, there is evidence of echinacea having possible CYP3A4 induction activity. CYP P450 activity is an important consideration for any patient but becomes increasingly critical if patients have certain CYP P450 phenotypes that impact metabolism. These popular supplements have the potential for changes in supplement exposure, and adverse effects based on pharmacogenetic profiles. Furthermore, these sites of metabolism are shared with many medications, setting the stage for possibly more profound interactions between medications and supplements. This paper highlights the mechanisms in which dietary supplements may constitute a risk for patients with certain CYP P450 phenotypes. Further research is needed in the area of dietary supplements and their pharmacogenomic implications.

This study investigated the impact of polymorphisms of metabolic enzymes on plasma concentrations of cilostazol and its metabolites, and the influence of the plasma concentrations and polymorphisms on the cardiovascular side effects in 30 patients with cerebral infarction. Plasma concentrations of cilostazol and its active metabolites, and CYP3A5*3 and CYP2C19*2 and *3 genotypes were determined. The median plasma concentration/dose ratio of OPC-13213, an active metabolite by CYP3A5 and CYP2C19, was slightly higher and the median plasma concentration rate of cilostazol to OPC-13015, another active metabolite by CYP3A4, was significantly lower in CYP3A5*1 carriers than in *1 non-carriers (p = 0.082 and p = 0.002, respectively). The CYP2C19 genotype did not affect the pharmacokinetics of cilostazol. A correlation was observed between changes in pulse rate from the baseline and plasma concentrations of cilostazol (R = 0.539, p = 0.002), OPC-13015 (R = 0.396, p = 0.030) and OPC-13213 (R = 0.383, p = 0.037). A multiple regression model, consisting of factors of the plasma concentration of OPC-13015, levels of blood urea nitrogen, and pulse rate at the start of the therapy explained 55.5% of the interindividual variability of the changes in pulse rate. These results suggest that plasma concentrations of cilostazol and its metabolites are affected by CYP3A5 genotypes, and plasma concentration of OPC-13015, blood urea nitrogen, and pulse rate at the start of therapy may be predictive markers of cardiovascular side effects of cilostazol in patients with cerebral infarction.

Background: CYP2C19 is an important member of the cytochrome P450 enzyme superfamily. We recently identified 31CYP2C19 alleles in the Han Chinese population; studying the effects of CYP2C19 on drug metabolism can help reduce adverse drug reactions and therapeutic failure. Aim: The aim of this study was to assess the catalytic activities of 31 allelic isoforms and their effects on the metabolism of clomipramine in vitro. Methods: The wild-type and 30 CYP2C19 variants were expressed in insect cells, and each variant was characterized using clomipramine as the substrate. Reactions were performed at 37°C with 5–150 μmol/L substrate for 30 min. By using ultra-high-performance liquid chromatography-mass spectrometry to detect the products, the kinetic parameters Km, Vmax, and intrinsic clearance (Vmax/Km) of N-desmethyl clomipramine were determined. Results: Among the CYP2C19 variants tested, CYP2C19*29, L16F, and T130M showed extremely increased intrinsic clearance of clomipramine, CYP2C19*3C, and N277K showed similar intrinsic clearance (Vmax/Km) values with CYP2C19*1, while the intrinsic clearance values of other variants were significantly decreased (from 0.65% to 63.28%). In addition, CYP2C19*3 and 35FS could not be detected because they have no detectable enzyme activity. Conclusions: As the first report of 31 CYP2C19 alleles for clomipramine metabolism, our study could provide corresponding reference for clomipramine for further studies in vivo and offer valuable information relevant to the personalized medicine for CYP2C19-metabolized drug.

The Pharmacogenomics (PGx) Profile Service was a proof-of-concept project to implement PGx in patient care at Mayo Clinic. Eighty-two healthy individuals aged 18 and older underwent genotyping of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, SLCO1B1, HLA-B*58:01, and VKORC1. A PGx pharmacist was involved in ordering, meeting with patients, interpreting, reviewing, and documenting results. Ninety three percent were CYP1A2 rapid metabolizers, 92% CYP3A4 normal metabolizers, and 88% CYP3A5 poor metabolizers; phenotype frequencies for CYP2C19 and CYP2D6 varied. Seventy-three percent had normal functioning SLCO1B1 transporter, 4% carried the HLA-B*58:01 risk variant, and 35% carried VKORC1 and CYP2C9 variants that increased warfarin sensitivity. Pre-emptive PGx testing offered medication improvement opportunity in 56% of participants for commonly used medications. A collaborative approach involving a PGx pharmacist integrated within a clinical practice with regards to utility of PGx results allowed for implementation of the PGx Profile Service.

Urine drug testing (UDT) is a tool for monitoring drug use, including oxycodone. While variation in cytochrome P450 (CYP) genes is known to alter oxycodone metabolism, its impact on UDT results of oxycodone and its metabolites has not been well-studied. Here, multivariate analysis was performed on retrospective UDT results of 90,379 specimens collected from 14,684 genotyped patients prescribed oxycodone. Genetic variation in CYP2D6 and CYP2C19 had a significant impact on oxymorphone/oxycodone ratios, with a 6.9-fold difference between CYP2D6 ultrarapid metabolizers (UMs) and poor metabolizers (PMs; p < 10-300) and a 1.6-fold difference between CYP2C19 UMs and PMs (p = 1.50 × 10-4). CYP2D6 variation also significantly impacted noroxycodone/oxycodone ratios (p = 6.95 × 10-38). Oxycodone-positive specimens from CYP2D6 PMs were ~5-fold more likely to be oxymorphone-negative compared to normal metabolizers. These findings indicate that multivariate analysis of UDT data may be used to reveal the real-world impact of genetic and non-genetic factors on drug metabolism.

Isoniazid (INH) is prescribed both for the prophylaxis as well as the treatment of tuberculosis. It is primarily metabolized through acetylation by a highly polymorphic enzyme, N-acetyl transferase 2 (NAT2), owing to which significant variable systemic drug levels have been reported among slow and rapid acetylators. Furthermore, many drugs, like phenytoin, diazepam, triazolam, etc., are known to show toxic manifestation when co-administered with INH and it happens prominently among slow acetylators. Additionally, it is revealed in in vitro inhibition studies that INH carries noteworthy potential to inhibit CYP2C19 and CYP3A4 enzymes. However, CYP inhibitory effect of INH gets masked by opposite enzyme-inducing effect of rifampicin, when used in combination. Thus, distinct objective of this study was to fill the knowledge gaps related to gene-drug-drug interactions (DDI) potential of INH when given alone for prophylactic purpose. Whole body-PBPK models of INH were developed and verified for both slow and fast acetylators. The same were then utilized to carry out prospective DDI studies with CYP2C19 and CYP3A4 substrates in both acetylator types. The results highlighted likelihood of significant higher blood levels of CYP2C19 and CYP3A4 substrate drugs in subjects receiving INH pre-treatment. It was also re-established that interaction was more likely in slow acetylators, as compared to rapid acetylators. The novel outcome of the present study is the indication that prescribers should give careful consideration while advising CYP2C19 and CYP3A4 substrate drugs to subjects who are on prophylaxis INH therapy, and are slow to metabolic acetylation.

Cetagliptin is an oral, potent, and newly developed selective inhibitor of dipeptidyl peptidase-4 (DPP-4). We evaluated the in vitro drug-drug interaction (DDI) potential of cetagliptin, as well as the pharmacokinetics of cetagliptin and metformin and the interaction between cetagliptin and metformin.Cetagliptin did not inhibit CYP1A2, CYP2C8, CYP2B6, CYP2C9, CYP2C19, and CYP3A4, only has a moderate inhibitory effect on CYP2D6, and did not induce CYP1A2, CYP2B6, and CYP3A4. Plasma protein binding of cetagliptin didn't have species differences or concentration dependence. Cetagliptin was a substrate for P-glycoprotein (P-gp).The 34 healthy subjects enrolled were randomly divided into two sequences (A and B) with 17 subjects in each sequence. Coadministration with metformin had no effect on cetagliptin AUC0-120 (GMR, 99.25%; 90% CI, 95.96%-102.65%). There was a slightly increase in cetagliptin Cmax (GMR, 117.33%; 90% CI, 102.54%-134.25%). Coadministration with cetagliptin did not affect the metformin's AUC0-24 (GMR, 108.54%; 90% CI, 101.41%-116.17%) or Cmax (GMR, 97.67%; 90% CI, 90.96%-104.89%).Based on in vitro study results, cetagliptin is unlikely to cause CYP-mediated, clinically relevant DDI. Although the possibility of transporter-mediated, clinically relevant DDI cannot be ruled out, there is little or no risk of side effects. Coadministration of cetagliptin and metformin had no clinically meaningful effect on the pharmacokinetics of each drug. There was no drug-drug interaction between cetagliptin and metformin. Both monotherapies and combination therapy were well tolerated. No serious AEs and hypoglycaemia was reported.

Premise: The effects of proton pump inhibitors (PPI) depend on metabolic enzyme CYP2C19 that has different activity due to gene polymorphism. The purpose of this meta-analysis is to determine the potential effects of CYP2C19 polymorphism on the efficiency of PPI-based treatment. Materials & methods: The PubMed, EMBASE, Cochrane Library, etc. were searched for relevant articles published in English or Chinese from inception to 31 May 2020. Finally, 26 randomized controlled trials and 15 cohort studies met the inclusion criteria and used for the meta-analysis via STATA version 15. Results: Poor metabolizer (PM) genotype Helicobacter pylori eradication rates were highest for Asian individuals receiving triple or quadruple first-line therapy based on PPIs (p

Jingyin granules, a marketed antiviral herbal medicine, have been recommended for treating H1N1 influenza A virus infection and Coronavirus disease 2019 (COVID-19) in China. To fight viral diseases in a more efficient way, Jingyin granules are frequently co-administered in clinical settings with a variety of therapeutic agents, including antiviral drugs, anti-inflammatory drugs, and other Western medicines. However, it is unclear whether Jingyin granules modulate the pharmacokinetics of Western drugs or trigger clinically significant herb-drug interactions. This study aims to assess the inhibitory potency of the herbal extract of Jingyin granules (HEJG) against human drug-metabolizing enzymes and to clarify whether HEJG can modulate the pharmacokinetic profiles of Western drug(s) in vivo. The results clearly demonstrated that HEJG dose-dependently inhibited human CES1A, CES2A, CYPs1A, 2A6, 2C8, 2C9, 2D6, and 2E1; this herbal medicine also time- and NADPH-dependently inhibited human CYP2C19 and CYP3A. In vivo tests showed that HEJG significantly increased the plasma exposure of lopinavir (a CYP3A-substrate drug) by 2.43-fold and strongly prolonged its half-life by 1.91-fold when HEJG (3 g/kg) was co-administered with lopinavir to rats. Further investigation revealed licochalcone A, licochalcone B, licochalcone C and echinatin in Radix Glycyrrhizae, as well as quercetin and kaempferol in Folium Llicis Purpureae, to be time-dependent CYP3A inhibitors. Collectively, our findings reveal that HEJG modulates the pharmacokinetics of CYP substrate-drug(s) by inactivating CYP3A, providing key information for both clinicians and patients to use herb-drug combinations for antiviral therapy in a scientific and reasonable way.

Acute coronary syndrome (ACS) carries a high mortality in Uygur populations. Percutaneous coronary intervention (PCI) is a safe treatment for patients with ACS. Clopidogrel reduces the risk for recurrent cardiovascular events after PCI; however, its activity is influenced by cytochrome P450 (CYP450), ATP-binding cassette transporter B1 (ABCB1), and paraoxonase-1 (PON1). To assess the effects of genetic polymorphisms CYP2C19*2, *3, *17, ABCB1 C3435T, and PON1 Q192R along with clinical and demographic factors on variations in responses in Uygur patients following PCI. We enrolled 281 patients with PCI who were treated with clopidogrel and aspirin for at least 12 months and recorded major adverse cardiovascular events (MACE) or bleeding within 1 year. Approximately, 2 mL of peripheral venous blood samples were used for genotype detection. Binary logistic regression with likelihood ratio forward stepwise analysis and redundancy analysis were carried out to identify factors associated with MACE. We analyzed risk factors including age, body mass index, smoking, hypertension, dyslipidemia, gender, alcohol consumption, diabetes mellitus, carriers of ABCB1 C3435T T allele, carriers of PON1 Q192R A allele, metabolizer phenotype of CYP2C19, number of targeted vessels, and number of stents. The CYP2C19 IMs (OR 3.546, 95% CI 1.972–6.375, P = 0.001), CYP2C19 PMs (OR 7.038, 95% CI 1.658–29.880, P = 0.008), and number of targeted vessels (OR 2.033, 95% CI 1.078–3.648, P = 0.026) were significantly associated with MACE. The CYP2C19 IMs, PMs, and the number of targeted vessels are essential factors associated with MACE risk in dual clopidogrel-treated Uygur population with ACS following PCI. These data provide valuable insights into the genetic polymorphisms affecting clopidogrel response among minority groups in China.

Genetic variation in the activation of the prodrug cyclophosphamide (CP) by cytochrome P450 (CYP) enzymes has been shown to influence outcomes. However, CYP are also subject to phenoconversion due to either the effects of comedications or cancer associated down-regulation of expression. The aim of this study was to assess the relationship between CP bioactivation with CYP2B6 and CYP2C19 genotype, as well as CYP2C19 phenotype, in breast cancer patients. CP and the active metabolite levels were assessed in breast cancer patients (n = 34) at cycle 1 and cycle 3 of treatment. Patients were genotyped for a series of SNP known to affect CYP2B6 and CYP2C19 function. The activity of CYP2C19 was also assessed using a probe drug. We found a significant linear gene-dose relationship with CYP2B6 coding SNP and formation of 4-hydroxycyclophosphamide. A possible association with CYP2C19 null genotype at cycle 1 was obscured at cycle 3 due to the substantial intra-individual change in CP bioactivation on subsequent dosing. Comedications may be the cause for this inter-occasion variation in bioactivation of cyclophosphamide and the ensuing phenoconversion may account for the conflicting reports in the literature about the relationship between CYP2C19 genotype and CP bioactivation pharmacokinetics. Trial registration ANZCTR363222 (6/11/2012, retrospectively registered).

Diazepam is one of the most widely prescribed tranquilizers for the therapy of alcohol withdrawal syndrome (AWS). However, diazepam therapy often turns out to be ineffective, and some patients experience dose-dependent adverse drug reactions. Previous studies have shown that the metabolism of diazepam involves the CYP2C19 isoenzyme, whose activity is highly dependent on polymorphism of the encoding gene. The objective of our study was to investigate the effects of CYP2C19*2 genetic polymorphisms on plasma and saliva concentrations of diazepam as well as its impact on the efficacy and safety rates of therapy in patients with AWS. The study was conducted on 100 Russian male patients with AWS who received diazepam in injections at a dosage of 30.0 mg/day for 5 days. Genotyping was performed by real-time polymerase chain reaction. The efficacy and safety assessment was performed using psychometric scales. We revealed differences in the efficacy and safety of therapy in patients with different CYP2C19 681G>A genotypes. Therapeutic drug monitoring (TDM) revealed the statistically significant differences in the levels of diazepam plasma concentration: (GG) 199.83 [82.92; 250.58] vs (GA+AA) 313.47 [288.99; 468.33], p=0.040, and diazepam saliva concentration: (GG) 2.80 [0.73; 3.80] vs (GA+AA) 5.33 [5.14; 6.00], p=0.003).

The effectiveness of antidepressants in the treatment of major depressive disorder varies considerably between patients. With these interindividual differences and a number of antidepressants to choose from, the first choice of treatment often fails to produce improvement in the patient's condition. A substantial part of the variation in response to antidepressants can be explained by genetic factors. Accordingly, variants related to drug metabolism in two pharmacogenes, CYP2D6 and CYP2C19, have already been translated into guidelines for antidepressant prescriptions. The role of variants in other genes that influence antidepressant responses is not yet understood. Furthermore, rare and individual variants account for a substantial part of genetic differences in antidepressant efficacy. Recent years have brought a tremendous increase in the accessibility of genome sequencing in terms of data availability and its clinical use. In this review, we summarize recent developments and current issues in the personalization of major depressive disorder treatment through pharmacogenomics. LINKED ARTICLES: This article is part of a themed issue on New discoveries and perspectives in mental and pain disorders. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.17/issuetoc.

Introduction: Cytochrome P450 (CYP) is a monooxygenase superfamily mediating the elimination of anti-hypertensive drugs. Polymorphisms of CYP would lead to differential drug efficacy. Building relationships between genotype and phenotype will benefit individual medical treatment of hypertension.Areas covered: The review systematically summarizes the polymorphisms of four CYPs (CYP2C9, CYP2C19, CYP2D6, and CYP3A4) concentrated distributed in the Han Chinese population. Moreover, the activity of variants on metabolizing anti-hypertensive drugs are reviewed, especially drugs with adrenoceptor blocking properties, as well as their clinical relevancies.Expert opinion: The polymorphisms of CYP can cause stratification in drug exposure of antihypertensive drugs. Although the clinical relevance has been built partially, the translational medicine still lacks reliable data support. Furthermore, the studies have demonstrated that even the same CYP variant will exhibit different catalytic capability for different drugs, which is another obstacle to hinder its application. With the deepening of multiomics research and structural biology, nucleotide polymorphisms can be combined with transcriptome, proteome, metabolome and molecular structure analyses to study the susceptibility to hypertension and drug efficacy. A complete data chain would be further estabolished by combining studies of pharmacokinetics-pharmacodynamics, which can effectively promote the precise application of anti-hypertensive drugs.

Objectives To demonstrate the successful use of pharmacogenomic testing to specifically tailor antifungal treatment to the phenotype of a patient with human immunodeficiency virus (HIV) and disseminated histoplasmosis who had clinical progression while on itraconazole and subsequently had insufficient therapeutic drug levels of voriconazole. Case summary We present the case of a patient with HIV and disseminated histoplasmosis with a persistently elevated serum Histoplasma capsulatum antigen and subtherapeutic levels of voriconazole. Pharmacogenomic testing revealed he was a CYP2C19 rapid metabolizer, thus explaining his persistent, subtherapeutic levels of voriconazole and prompting a change in therapy. Practice implications Our case illustrates the importance of pharmacogenomic testing as a tool to evaluate subtherapeutic itraconazole or voriconazole levels, especially in patients with failed clinical or Histoplasmosis Ag response despite reporting full adherence to prescribed therapy.

Cardiovascular diseases (CVDs) are the leading cause of disability and mortality worldwide. Increased thrombosis is the trigger point for the development of various CVDs and their complications, and therefore, therapy with P2Y12-receptor inhibitors is always pathogenetically justified and vital. However, according to the various data, 10-25% of patients treated with clopidogrel have “resistance” to antiplatelet therapy. The causes for the formation of resistance are still not clear. There is no generally accepted, standard methodology for determining resistance to antiplatelet agents. In addition, there are no methodological approaches to identify the patients with resistance to antiplatelet drugs, and standardized schemes for correcting a low sensitivity to these drugs.The aim of this review was to summarize the available results of foreign and domestic studies devoted to the investigation of the effectiveness and safety problems of antiplatelet drugs administration from the point of view of the genetic predisposition to changes in their metabolism.Materials and methods. For the review, the following information from scientific literature represented in open and accessible sources for the period of 1996-2020, was used: pharmgkb.org, PubMed, Scopus, Web of Science Core Collection, Elibrary. Search queries – “Genetic features+antiplatelet therapy+ethnic groups”, “CYP2C19+clopidogrel+antiplatelet therapy effectiveness”; “Stent retrombosis+CYP2C19 polymorphism+ residual platelet reactivity” and “CYP2C19 polymorphism+ethnic groups+clopidogrel resistance” in both Russian and English equivalents. All these data are placed in electronic databases.Results. Currently, the problem of the resistance formation to antiplatelet drugs is studied insufficiently. The best thought-out issue is the research of the effect of the polymorphic alleles carriage of the CYP2C19 gene on the residual platelet reactivity in the patients administrated with dual antiplatelet treatment, including clopidogrel. In general, the analysis of open literature sources indicates the presence of a statistically significant association between the carrier of slow alleles of the CYP2C19 gene and the residual platelet reactivity, clinically manifested by thrombosis and adverse cardiovascular events. The occurrence frequency of polymorphic carriage of the CYP2C19 gene varies in different ethnic groups, so it cannot be extrapolated to individual subjects, peculiar in the ethnic diversity.Conclusion. To develop preventive and predictive measures aimed at overcoming resistance to antiplatelet agents, as well as working out methodological approaches to personalized prescribtion of this group drugs, a further investigation with the expansion of the search for causes and the study of the other genes participation of the cytochrome P450 system, is required.

GLPG1205 is a novel agent being investigated for the treatment of idiopathic pulmonary fibrosis. GLPG1205 may be concomitantly administered with pirfenidone in future clinical development; therefore, the potential for GLPG1205 to interact with enzymes involved in the metabolism of pirfenidone (cytochrome P450 [CYP] 1A2, CYP2C9, 2C19) was evaluated. In vitro experiments indicated weak inhibition of CYP1A2 and moderate but reversible inhibition of CYP2C9 and CYP2C19 by GLPG1205. A phase 1 randomized, double‐blind crossover study in 14 healthy males (NCT02623296) evaluated the effect of GLPG1205 100 mg or placebo (once daily for 12 days) on the single‐dose pharmacokinetics of a cocktail of CYP1A2, CYP2C9, and CYP2C19 substrates (coadministered on day 13). GLPG1205 had no effect on the exposure of CYP2C9 and CYP1A2 substrates or metabolites; however, a trend toward increased omeprazole (CYP2C19 substrate) exposure was observed. Although considered not clinically relevant, GLPG1205 increased the elimination rate of 5‐hydroxyomeprazole (CYP2C19 metabolite) 1.16‐fold versus placebo. GLPG1205 had no effect on the elimination of all other substrates or metabolites. GLPG1205 had a favorable safety and tolerability profile. In conclusion, GLPG1205 100 mg once daily does not interact with CYP2C9, CYP2C19, or CYP1A2 to a clinically relevant extent and may be administered concomitantly with drugs metabolized by these enzymes.

The Pharmacogene Variation Consortium (PharmVar) catalogues star (*) allele nomenclature for the polymorphic human CYP2B6 gene. Genetic variation within the CYP2B6 gene locus impacts the metabolism or bioactivation of clinically important drugs. Of particular importance are efficacy and safety concerns regarding: efavirenz, which is used for the treatment of HIV type-1 infection; methadone, a mainstay in the treatment of opioid use disorder and as an analgesic; ketamine, used as an antidepressant and analgesic; and bupropion, which is prescribed to treat depression and for smoking cessation. This GeneFocus provides a comprehensive overview and summary of CYP2B6 and describes how haplotype information catalogued by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).

Reduced clopidogrel effectiveness in preventing recurrent myocardial ischemia following percutaneous coronary intervention has been demonstrated in CYP2C19 loss-of-function carriers. Less is known about the effect of CYP2C19 genotype on the effectiveness of clopidogrel for stroke prevention, particularly in Caucasians. This is a retrospective cohort study, in which we used the Clalit clinical database to follow genotyped clopidogrel initiators, for up to 3 years. Endpoint was a new primary discharge diagnosis of ischemic stroke; secondary endpoints were new primary discharge diagnoses of coronary angioplasty, myocardial infarction (MI), or a composite endpoint of: stroke, MI, or coronary angioplasty. After 3 years of follow up over 628 clopidogrel initiators, 2 out of 12 (16.7%) poor metabolizers, 9 out of 144 intermediate metabolizers (6.3%), and 29 out of 472 (6.1%) normal/rapid/ultrarapid metabolizers have been newly diagnosed with ischemic stroke. Poor metabolizer status was associated with higher risk for ischemic stroke, marginally significant in univariate analysis and in multivariable models; and higher risk for the composite outcome of stroke, myocardial infarction and coronary angioplasty, HR = 3.32 (1.35-8.17) p = 0.009, 2.86 (1.16-7.06) p = 0.02 (univariate and multivariate analyses, respectively). Poor metabolizer status was associated with higher risk for stroke HR = 5.80 (1.33-25.24) p = 0.019, HR = 4.13 (0.94-18.13) p = 0.06 (univariate and multivariate analyses, respectively) in patients who "survived" the first year, and were in the cohort 1-3 years. Caucasian treated with clopidogrel who are homozygote for the CYP2C19 loss-of function allele might be at increased risk for ischemic stroke, and for the composite outcome of ischemic stroke, myocardial infarction and coronary angioplasty.

Pharmacogenotyping is applied to determine the hereditable component of a patient's susceptibility to experience therapy failure and/or adverse drug reactions (ADRs). We present the case of a female patient diagnosed with breast cancer and treated with tamoxifen as recurrence therapy who experienced various ADRs. Pharmacogenotyping revealed variants in the cytochrome P450 (CYP) enzymes CYP2D6, CYP2C9, and CYP2C19. The observed genotype was associated with a risk for lower tamoxifen efficacy. Aside from the tamoxifen therapy, the comedication was reviewed for the influence of the patient’s pharmacogenetic profile. As a result of this pharmacist-led medication review with pharmacogenetic analyses, concrete genotype-driven recommendations for the treating gynecologist were compiled. This case revealed the added value of a large pharmacogenetic panel and the complexity of integrating a pharmacogenetic profile into a recommendation.

Aim This study aims to assess the potential effects of zanubrutinib on the activity of cytochrome P450 (CYP) enzymes and drug transporter proteins using a cocktail probe approach. Methods Patients received single oral doses of probe drugs alone and after at least 8 days of treatment with zanubrutinib 160 mg twice daily in a single-sequence study in 18 healthy male volunteers. Simultaneous doses of 10 mg warfarin (CYP2C9) and 2 mg midazolam (CYP3A) were administered on Day 1 and Day 14, 0.25 mg digoxin (P-glycoprotein [P-gp]) and 10 mg rosuvastatin (breast cancer resistance protein [BCRP]) on Day 3 and Day 16, and 20 mg omeprazole (CYP2C19) on Day 5 and Day 18. Pharmacokinetic (PK) parameters were estimated from samples obtained up to 12 h post dose for zanubrutinib; 24 h for digoxin, omeprazole and midazolam; 48 h for rosuvastatin; and 144 h for warfarin. Results The ratios (%) of geometric least squares means (90% confidence intervals) for the area under the concentration-time curve from time zero to the last quantifiable concentration in the presence/absence of zanubrutinib were 99.80% (97.41-102.2%) for S-warfarin; 52.52% (48.49-56.88%) for midazolam; 111.3% (103.8-119.3%) for digoxin; 89.45% (78.73-101.6%) for rosuvastatin; and 63.52% (57.40-70.30%) for omeprazole. Similar effects were observed for maximum plasma concentrations. Conclusions Zanubrutinib 320 mg total daily dose had minimal or no effect on the activity of CYP2C9, BCRP and P-gp, but decreased the systemic exposure of CYP3A and CYP2C19 substrates (mean reduction

Background: Cytochrome P450 (CYP450) enzymes play an important role in the metabolism of 70-80% of the currently used medications, including proton pump inhibitors. There are some data analyzing the impact of gene polymorphisms of CYP450 enzymes on most widely used PPIs, such as omeprazole, however, the data on pantoprazole are highly lacking. Objective: To summarize the most recent publications and studies on the role of polymorphisms of the genes encoding CYP450 enzyme 2C19 in the metabolism of pantoprazole and pantoprazole based Helicobacter pylori eradication regimens. Methods: We performed a non-systematic search of the available literature on the selected topic. Results and conclusion: The data on cytochrome P450 gene polymorphisms and their role in pantoprazole metabolism and pantoprazole based Helicobacter pylori eradication remain conflicting. Individual differences in pantoprazole metabolism might be partly related to genetic polymorphisms of CYP450 enzymes. Most of the studies support the observation that cytochrome 2C19 polymorphisms have an impact on the pharmacokinetics of pantoprazole and its therapeutic effects: poor metabolizers of PPIs are more likely to have a better response to pantoprazole therapy and achieve better H. pylori eradication rates compared to rapid metabolizers. The determination of alleles that are associated with decreased (e.g., *2, *3 alleles) or increased (e.g., *17 allele) cytochrome 2C19 enzyme activity might be used as predictive factors for the potential of acid suppression and the success of Helicobacter pylori eradication. Overall, currently available data do not provide robust evidence, therefore, the application of genetic polymorphisms of cytochrome enzymes in clinical practice still cannot be recommended as routine practice for personalized pantoprazole prescription strategies.

AIMS Cytochrome 2C19 genotype-directed dosing of voriconazole (VRC) reduces the incidence of insufficient VRC trough concentrations (Cmin ) but does not account for CYP3A polymorphisms, also involved in VRC metabolism. This prospective observational study aimed to evaluate the utility of a genetic score combining CYP2C19 and CYP3A genotypes to predict insufficient initial VRC Cmin (

Background:: Cytochrome P450s (CYPs) are drug-metabolizing enzymes catalyzing the metabolism of about 75% of drug in clinical use. CYP2C9 represents 20% CYP proteins in liver cells and is a crucial member of CYPs superfamily. CYP2C19 metabolizes very important drugs such as antiulcer drug omeprazole, the antiplatelet drug clopidogrel and anticonvulsant mephenytoin. Single nucleotide polymorphisms (SNPs) of CYP genes have been associated with unexpected drug reactions and diseases in different populations. Objective:: We examined the associations of CYP2C9*3 (rs1057910) and CYP2C19*3 (rs4986893) with T2D in Saudi population. Methods:: We used the allele-specific PCR (AS-PCR) and DNA sequencing in 111 cases and 104 controls for rs1057910, and in 119 cases and 110 controls for rs4986893. Results:: It is indicated that the genotype distribution of rs1057910 in cases and controls were not significantly different (P=0.0001). The genotypes of rs1057910 were not associated with type 2 diabetes (T2D) (P>0.05). Whereas the genotype distribution of rs4986893 in cases and controls was significantly different (P=0.049). The AA genotype of rs4986893 may be associated in increased risk to T2D with OR=17.25 (2.06-143.8), RR=6.14(0.96-39.20), P=0.008. Conclusion:: The CYP2C9*3 (rs1057910) may not be associated with T2D, while CYP2C19*3 (rs4986893) is probably associated with T2D. These findings need to be validated in follow-up studies with larger sample sizes and different populations.

Variations in clinical response to tamoxifen (TAM) may be related to polymorphic cytochromes P450 (CYPs) involved in forming its active metabolite endoxifen (ENDO). We developed a population pharmacokinetic (PopPK) model for tamoxifen and six metabolites to determine clinically relevant factors of ENDO exposure. Concentration-time data for TAM and 6 metabolites come from a prospective, multicenter, 3-year follow-up study of adjuvant TAM (20 mg/day) in patients with breast cancer, with plasma samples drawn every 6 months, and genotypes for 63 genetic polymorphisms (PHACS study, NCT01127295). Concentration data for TAM and 6 metabolites from 928 patients (n = 27,433 concentrations) were analyzed simultaneously with a 7-compartment PopPK model. CYP2D6 phenotype (poor metabolizer (PM), intermediate metabolizer (IM), normal metabolizer (NM), and ultra-rapid metabolizer (UM)), CYP3A4*22, CYP2C19*2, and CYP2B6*6 genotypes, concomitant CYP2D6 inhibitors, age, and body weight had a significant impact on TAM metabolism. Formation of ENDO from N-desmethyltamoxifen was decreased by 84% (relative standard error (RSE) = 14%) in PM patients and by 47% (RSE = 9%) in IM patients and increased in UM patients by 27% (RSE = 12%) compared with NM patients. Dose-adjustment simulations support an increase from 20 mg/day to 40 and 80 mg/day in IM patients and PM patients, respectively, to reach ENDO levels similar to those in NM patients. However, when considering Antiestrogenic Activity Score (AAS), a dose increase to 60 mg/day in PM patients seems sufficient. This PopPK model can be used as a tool to predict ENDO levels or AAS according to the patient's CYP2D6 phenotype for TAM dose adaptation.

Rivoceranib (known in China as apatinib) is a selective vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor which inhibits angiogenesis in solid tumors. The aim of study was to evaluate potential pharmacokinetic (PK) differences between the Caucasian, Japanese, and Chinese populations. An open-label, single-dose, parallel-design PK study of rivoceranib was conducted in Caucasian, Japanese, and Chinese subjects. A total of 18 healthy males were recruited to each group (54 total), and 201 mg rivoceranib tablets (as 250 mg rivoceranib mesylate) were administered orally to subjects. Plasma samples were collected, and rivoceranib plasma concentration was determined using LC-MS/MS. For PK analysis, non-compartmental and compartmental analyses were performed. Intrinsic factors (CYP2C19 and CYP3A4 genotype) were also examined. Non-compartmental analysis showed no significant difference in AUC0-t , AUC0-∞ , Cmax , tmax , and t1⁄2 . Apparent clearance and volume of distribution were different across the three populations; however, the extent of this difference does not require dose modification. For compartmental modeling, a two-compartment model was used to fit the plasma concentrations. No significant difference was observed in absorption, elimination, and intercompartmental transfer rate constants among the three groups. The present study shows no major ethnic PK differences between Caucasian, Japanese, and Chinese populations.

We report the case of a patient with major depression treated with high-dose bupropion due to prior detected subtherapeutic blood concentrations at standard dosing. Pharmacogenetic panel testing identified the patient as a carrier of the CYP2B6*6 allele, which has been associated with reduced bupropion metabolism and decreased concentrations of the pharmacologically active metabolite hydroxybupropion. Interestingly, we also found the patient to be homozygous for the CYP2C19*17 allele, predicting an ultra rapid metabolizer phenotype. We propose a combined effect of the detected CYP2C19 and CYP2B6 genetic variants on bupropion metabolism. This case underlines the potential benefit of pre-emptive pharmacogenotyping but also the yet still fragmentary evidence making precise pharmacogenotype guided antidepressant selection and dosing challenging.

Background There have been few studies on CYP2C19 genotypes and clopidogrel response associated with ischemic stroke (IS), especially IS complicated by type 2 diabetes mellitus (T2DM). This study aimed to investigate the possible association between CYP2C19 polymorphisms and high on-treatment platelet reactivity (HTPR) in IS patients with T2DM in China. Patients and Methods A total of 426 consecutive IS patients with T2DM were enrolled in this case-control study and they were divided into HTPR group and non-HTPR group according to the ADP-induced platelet inhibition (PIADP) assessed by thromboelastography (TEG). Genotypes were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Various clinical and demographic data were also recorded. The association between CYP2C19 genetic variants and platelet function was assessed. Results Carriers of CYP2C19*2 heterozygous and mutant homozygous genotypes showed significantly lower PIADP than non-carriers (27.2% vs 38.3%, p < 0.001; 27.41% vs 38.3%, p = 0.012, respectively). Compared with the control group, the CYP2C19*2 A allele was more frequent in the HTPR group (34.51% vs 25.82%, p = 0.002). The carriage of CYP2C19*2 mutant allele was significantly associated with increased risk of HTPR (odds ratio (OR) = 1.94, 95% confidence interval (CI) = 1.32-2.85). There was no significant correlation between CYP2C19*3 or *17 genotypes and HTPR risk. Conclusion CYP2C19*2 mutant allele was associated with attenuated platelet response to clopidogrel and increased risk of HTPR in IS patients with T2DM, suggesting that CYP2C19*2 polymorphism might be an important predictor of HTPR in this high-risk population.

This review aimed to evaluate the clinical success of clopidogrel dosing based on CYP2C19 genotype and to identify the relevant additional factors that may be useful for consideration by the clinician when dosing individuals with clopidogrel. The results indicated that genotype-guided dosing in individuals with acute coronary syndrome undergoing percutaneous coronary intervention is frequently practiced, although the advantages remain controversial. Demographic factors, such as age, ethnicity, and some comorbidities, such as diabetes mellitus, can potentially contribute to further refinement of clopidogrel dosage but additional clinical studies to guide these practices are required. Drugs that are CYP2C19 or CYP3A4 inhibitors may reduce the effectiveness of clopidogrel and should be carefully considered during co-administration. In particular, as stated in the clopidogrel label, concomitant use with strong or moderate CYP2C19 inhibitors, such as omeprazole, should be avoided. Increased exposure and response to clopidogrel has been observed in smokers. Noteworthy, a very recent study has shown that smoking cessation in clopidogrel patients may result in reduced response and carries the risk of high on-clopidogrel platelet reactivity. Recent studies have shown clinically significant increases in exposure to CYP2C8 substrates (repaglinide, dasabuvir, and desloratadine) and a CYP2B6 substrate (s-sibutramine) following co-administration with clopidogrel, indicating that therapeutic strategies with clopidogrel should avoid these drugs.

Dual antiplatelet therapy with aspirin and clopidogrel is commonly used for coronary artery disease (CAD) patients undergoing percutaneous coronary intervention to prevent stent thrombosis and ischemic events. However, some patients show high on-treatment platelet reactivity (HTPR) during clopidogrel therapy. Genetic factors such as loss-of-function variants of CYP2C19 are validated to increase the risk of HTPR. Flavin-containing monooxygenase 3 (FMO3) is reported to be associated with potency of platelet responsiveness and thrombosis. This study aimed to explore the association between FMO3 rs1736557 polymorphism and clopidogrel response. Five hundred twenty-two Chinese CAD patients treated with dual antiplatelet therapy were recruited from Xiangya Hospital. After oral administration of 300 mg loading dose (LD) clopidogrel for 12–24 h or 75 mg daily maintenance dose (MD) clopidogrel for at least 5 days, the platelet reaction index (PRI) was determined by vasodilator-stimulated phosphoprotein-phosphorylation assay. FMO3 rs1736557, CYP2C19*2, and CYP2C19*3 polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Mean PRI value was significantly higher in CYP2C19 poor metabolizers (PMs) and intermediate metabolizers (IMs) than the extensive metabolizers (EMs) (p

Genetic variability of CYP2C19 may affect safety or efficacy of many clinically important medications as outlined in the clinical pharmacogenetics implementation consortium (CPIC) dosing guidelines. To determine the predictive prevalence of high-risk phenotypes due to CYP2C19 genetic variants collectively in the world population and to establish a correlation how the identified high-risk phenotypes may affect safety or effectiveness of drugs, this study was conducted. Frequency of CYP2C19*2, *3 and *17 alleles were obtained from 1000 Genomes project Phase III in line with Fort Lauderdale principles. Phenotypes were assigned using international standardized consensus terms based on the carrier of characteristics alleles. Association of predicted high-risk phenotypes with the safety or effectiveness of medications was gained from CPIC dosing guidelines. Ultrarapid and poor metabolizers were considered as being as high-risk phenotypes for at least ten clinically important medications. Meta-analysis of the prevalence of high-risk phenotypes showed that it was statistically significant (p

Genotyping for CYP2C19 no function alleles to guide antiplatelet therapy after percutaneous coronary intervention (PCI) improves clinical outcomes. Although results for the increased function CYP2C19*17 allele are also reported, its clinical relevance in this setting remains unclear. A collaboration across nine sites examined antiplatelet therapy prescribing and clinical outcomes in 3,342 patients after implementation of CYP2C19-guided antiplatelet therapy. Risk of major atherothrombotic and bleeding events over 12 months after PCI were compared across cytochrome P450 2C19 isozyme (CYP2C19) metabolizer phenotype and antiplatelet therapy groups by proportional hazards regression. Clopidogrel was prescribed to a similar proportion of CYP2C19 normal (84.5%), rapid (82.9%), and ultrarapid metabolizers (80.6%) (P = 0.360). Clopidogrel-treated normal metabolizers (20.4 events/100 patient-years; adjusted hazard ratio (HR) 1.00, 95% confidence interval (CI), 0.75-1.33, P = 0.993) and clopidogrel-treated rapid or ultrarapid metabolizers (19.1 events/100 patient-years; adjusted HR 0.95, 95% CI, 0.69-1.30, P = 0.734) exhibited no difference in major atherothrombotic events compared with patients treated with prasugrel or ticagrelor (17.6 events/100 patient-years). In contrast, clopidogrel-treated intermediate and poor metabolizers exhibited significantly higher atherothrombotic event risk compared with prasugrel/ticagrelor-treated patients (adjusted HR 1.56, 95% CI, 1.12-2.16, P = 0.008). When comparing clopidogrel-treated rapid or ultrarapid metabolizers to normal metabolizers, no difference in atherothrombotic (adjusted HR 0.97, 95% CI, 0.73-1.29, P = 0.808) or bleeding events (adjusted HR 1.34, 95% CI, 0.83-2.17, P = 0.224) were observed. In a real-world setting of genotype-guided antiplatelet therapy, the CYP2C19*17 allele did not significantly impact post-PCI prescribing decisions or clinical outcomes. These results suggest the CYP2C19 *1/*17 and *17/*17 genotypes have limited clinical utility to guide antiplatelet therapy after PCI.

Pexidartinib is approved for treatment of adults with symptomatic tenosynovial giant cell tumor. In vitro data showed pexidartinib's potential to inhibit and induce cytochrome P450 (CYP) 3A, inhibit CYP2C9, CYP2C19 and P‐glycoprotein (P‐gp). Herein, 2 open‐label, single‐sequence, crossover studies evaluated the drug‐drug interaction potential of pexidartinib on CYP enzymes (CYP2C9, CYP2C19, and CYP3A) and P‐gp. Thirty‐two subjects received single oral doses of midazolam (CYP3A substrate) and tolbutamide (CYP2C9 substrate) alone and after single and multiple oral doses of pexidartinib. Twenty subjects received single oral doses of omeprazole (CYP2C19 substrate) and digoxin (P‐gp substrate) alone or with pexidartinib. Analysis of variance was conducted to determine the effect of pexidartinib on various substrates’ pharmacokinetics. No drug‐drug interaction was concluded if the 90% confidence interval of the ratio of test to reference was within the range 80% to 125%. Coadministration of single and multiple doses of pexidartinib resulted in 21% and 52% decreases, respectively, in the area under the plasma concentration–time curve from time zero to the last measurable time point (AUClast) of midazolam, whereas AUClast values of tolbutamide increased 15% and 36%, respectively. Omeprazole exposure decreased on concurrent administration with pexidartinib, the metabolite‐to‐parent ratio was similar following omeprazole administration alone vs coadministration with pexidartinib; pexidartinib did not affect CYP2C19‐mediated metabolism. Maximum plasma concentrations of digoxin slightly increased (32%) with pexidartinib coadministration; no significant effect on digoxin AUClast. These results indicate that pexidartinib is a moderate inducer of CYP3A and a weak inhibitor of CYP2C9 and does not significantly affect CYP2C19‐mediated metabolism or P‐gp transport.

Lopinavir-ritonavir combination is being used for the treatment of SARS-CoV-2 infection. A low dose of ritonavir is added to other protease inhibitors to take advantage of potent inhibition of cytochrome (CYP) P450 3A4, thereby significantly increasing the plasma concentration of coadministered lopinavir. Ritonavir also inhibits CYP2D6 and induces CYP2B6, CYP2C19, CYP2C9, and CYP1A2. This potent, time-dependent interference of major hepatic drug-metabolizing enzymes by ritonavir leads to several clinically important drug-drug interactions. A number of patients presenting with acute coronary syndrome and acute heart failure may have SARS-CoV-2 infection simultaneously. Lopinavir-ritonavir is added to their prescription of multiple cardiac medications leading to potential drug-drug interactions. Many cardiology, pulmonology, and intensivist physicians have never been exposed to clinical scenarios requiring co-prescription of cardiac and antiviral therapies. Therefore, it is essential to enumerate these drug-drug interactions, to avoid any serious drug toxicity, to consider alternate and safer drugs, and to ensure better patient care.

Background Acute coronary syndrome (ACS) is a highly thrombotic state, and a sustained antiplatelet effect is vital to the prevention of thrombotic complications. Clopidogrel, the most widely used oral P2Y12 receptor antagonist in ACS, has attracted considerable attention because of significant variability in antiplatelet effect depending on the presence of CYP2C19 allele. Other P2Y12 receptor antagonists offer sustained and more predictable antiplatelet effects than clopidogrel albeit at an increased cost. Several studies have demonstrated the promising application of pharmacogenetics in choosing personalized antiplatelet therapy using the point-of-care genotype assays. Areas of uncertainty Guidelines regarding the genotype-guided approach to the selection of antiplatelet therapy have been conflicting, and studies evaluating the effect of pharmacogenetic-guided selection of antiplatelet therapy on the outcomes have demonstrated mixed results. Data sources A literature search was conducted using MEDLINE and EMBASE for studies reporting the association of pharmacogenetic-guided selection of antiplatelet therapy and the outcomes in patients with ACS until December 2018. Results Presence of specific CYP2C19 allele significantly influences clopidogrel metabolism and associated outcomes in patients with ACS. Thrombotic and bleeding complications are more common in patients with loss-of-function (LOF) and gain-of-function (GOF) alleles, respectively. Although the pharmacogenetic-guided approach to the selection of antiplatelet therapy appears promising in ACS, studies have shown conflicting results, and direct randomized evidence linking this approach with the better outcomes is lacking. Conclusions Genotype-guided selection of antiplatelet therapy is expected to be useful in patients undergoing percutaneous coronary intervention (PCI) with a high risk of adverse outcomes. The patient-physician discussion should be an essential part of this decision-making process. Large-scale multicenter randomized controlled trials using the point-of-care genotype assay are needed to investigate this approach further before its use can be recommended in all comers.

Highly purified cannabidiol (CBD) has demonstrated efficacy with an acceptable safety profile in patients with Lennox‐Gastaut syndrome or Dravet syndrome in randomized, double‐blind, add‐on, controlled phase 3 trials. It is important to consider the possibility of drug‐drug interactions (DDIs). Here, we review six trials of CBD (Epidiolex/Epidyolex; 100 mg/mL oral solution) in healthy volunteers or patients with epilepsy, which investigated potential interactions between CBD and enzymes involved in drug metabolism of common antiseizure drugs (ASDs). CBD did not affect CYP3A4 activity. Induction of CYP3A4 and CYP2C19 led to small reductions in exposure to CBD and its major metabolites. Inhibition of CYP3A4 activity did not affect CBD exposure and caused small increases in exposure to CBD metabolites. Inhibition of CYP2C19 activity led to a small increase in exposure to CBD and small decreases in exposure to CBD metabolites. One potentially clinically important DDI was identified: combination of CBD and clobazam (CLB) did not affect CBD or CLB exposure, but increased exposure to major metabolites of both compounds. Reduction of CLB dose may be considered if adverse reactions known to occur with CLB are experienced when it is coadministered with CBD. There was a small increase of exposure to stiripentol (STP) when coadministered with CBD. STP had no effect on CBD exposure but led to minor decreases in exposure to CBD metabolites. Combination of CBD and valproate (VPA) did not cause clinically important changes in the pharmacokinetics of either drug, or 2‐propyl‐4‐pentenoic acid. Concomitant VPA caused small increases in exposure to CBD metabolites. Dose adjustments are not likely to be necessary when CBD is combined with STP or VPA. The safety results from these trials were consistent with the known safety profile of CBD. These trials indicate an overall low potential for DDIs between CBD and other ASDs, except for CLB.

Objectives To examine current knowledge on the clinical utility of therapeutic drug monitoring (TDM) in voriconazole therapy, the impact of CYP2C19 genotype on voriconazole plasma concentrations, and the role of CYP2C19 genotyping in voriconazole therapy. Data Sources Three literature searches were conducted for original reports on (1) TDM and voriconazole outcomes and (2) voriconazole and CYP2C19 polymorphisms. Searches were conducted through EMBASE, MEDLINE/PubMed, Scopus, and Cochrane Central Register of Controlled Trials from inception to June 2020. Study Selection and Data Extraction Randomized controlled trials, cohort studies, and case series with ≥10 patients were included. Only full-text references in English were eligible. Data Synthesis A total of 63 studies were reviewed. TDM was recommended because of established concentration and efficacy/toxicity relationships. Voriconazole trough concentrations ≥1.0 mg/L were associated with treatment success; supratherapeutic concentrations were associated with increased neurotoxicity; and hepatotoxicity associations were more prevalent in Asian populations. CYP2C19 polymorphisms significantly affect voriconazole metabolism, but no relationship with efficacy/safety were found. Genotype-guided dosing with TDM was reported to increase chances of achieving therapeutic range. Relevance to Patient Care and Clinical Practice Genotype-guided dosing with TDM is a potential solution to optimizing voriconazole efficacy while avoiding treatment failures and common toxicities. Conclusions Voriconazole plasma concentrations and TDM are treatment outcome predictors, but research is needed to form a consensus target therapeutic range and dosage adjustment guidelines based on plasma concentrations. CYP2C19 polymorphisms are a predictor of voriconazole concentrations and metabolism, but clinical implications are not established. Large-scale, high-methodological-quality trials are required to investigate the role for prospective genotyping and establish CYP2C19-guided voriconazole dosing recommendations.

Pharmacogenetic variants can alter the mechanism of action (pharmacodynamic gene variants) or kinetic processes such as absorption, distribution, metabolism and elimination (pharmacokinetic gene variants). Many initial successes in precision medicine occurred in the context of genes encoding the cytochromes P450 (CYP enzymes). CYP2C19 activates the antiplatelet drug clopidogrel, and polymorphisms in the CYP2C19 gene are known to alter the outcome for patients taking clopidogrel in the context of cardiovascular disease. CYP2C19 loss-of-function alleles are specifically associated with increased risk for coronary stent thrombosis and major adverse cardiovascular events in patients taking clopidogrel following percutaneous coronary intervention. We explore successes and challenges encountered as the clinical and scientific communities advance CYP2C19 genotyping in the context of routine patient care.

While the impact of genetic polymorphisms on the metabolism of various pharmaceuticals is well known, more data are needed to better understand the specific influence of pharmacogenetics on the metabolism of delta 9-tetrahydocannabinol (Δ9-THC). Therefore, the aim of the study was to analyze the potential impact of variations in genes coding for phase I enzymes of the Δ9-THC metabolism. First, a multiplex assay for genotyping different variants of genes coding for phase I enzymes was developed and applied to 66 Δ9-THC-positive blood samples obtained in cases of driving under the influence of drugs (DUID). Genetic and demographic data as well as plasma concentrations of Δ9-THC, 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-Δ9-THC), and 11-nor-9-carboxy-Δ9-THC (Δ9-THC-COOH) were combined and statistically investigated. For cytochrome P450 2C19 (CYP2C19) variants, no differences in analyzed cannabinoid concentrations were found. There were also no differences in the concentrations of Δ9-THC and 11-OH-Δ9-THC for the different allelic CPY2C9 status. We recognized significantly lower Δ9-THC-COOH concentrations for CYP2C9*3 (p = 0.001) and a trend of lower Δ9-THC-COOH concentrations for CYP2C9*2 which did not reach statistical significance (p = 0.068). In addition, this study showed significantly higher values in the ratio of Δ9-THC/Δ9-THC-COOH for the carriers of the CYP2C9 variants CYP2C9*2 and CYP2C9*3 compared with the carriers of the corresponding wild-type alleles. Therefore, an impact of variations of the CYP2C9 gene on the interpretation of cannabinoid plasma concentrations in DUID cases should be considered.

This study focuses on Quantitative structure–activity relationship (QSAR) and in silico pharmacokinetics/ADMET predictions to investigate the structural features and pharmacokinetic/ADMET properties that influenced the antipsychotic activity of some arylpiperazine derivatives as inhibitors of Serotonin Transporter (SERT) for antidepressant agents. Density Functional Theory approach (DFT/B3LYP/6-31G*) via Spartan 14 V1.1.4 software was used for the geometry optimization of the compounds while the Genetic Function Algorithm (GFA) and Multiple Linear Regression Analysis (MLRA) in Material studio software were used for variable selection and development of QSAR models. The statistical analysis and validation parameters of the best model (RTrain2 = 0.944, RTest2 = 0.637, Qcv2 = 0.895, cRp2 = 0.845 and RMSE = 0.100) shows that the model was predictive, reliable, robust and very stable. More so, molecular descriptors; SpMax6_Bhm, VP-3, geomDiameter, RDF35i and E1e were significantly contributed to the observed antipsychotic activities of the compounds with SpMax6_Bhm (37.5%) played a predominant role and positively correlated to the observed antipsychotic property of the compounds. Similarly, the in silico pharmacokinetics/ADMET investigations revealed that the selected compounds portend to be orally bioavailable, highly absorbed by the gastrointestinal system and could permeate into the brain with low ADMET risk. Likewise, all the selected compounds were inhibitors of CYP2C19 and CYP2D6 cytochromes P450 (CYP) enzymes and none of the selected compounds exhibit human ether-a-go-go-related gene (hERG) cardiovascular toxicity. Hence, the model possessed good quality assurance and satisfied OECD Principles for model development. In consequence, the physicochemical and pharmacokinetic parameters/properties derived from this study could be considered when developing other arylpiperazine derivatives with improved activity as antidepressant agents.