UNASSIGNED: Precise estimation of a patient\'s drug metabolism capacity is important for antiseizure dose personalization.
UNASSIGNED: To quantify the differences in plasma concentrations for antiseizure drugs associated with variants of genes encoding drug metabolizing enzymes.
UNASSIGNED: PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to September 30, 2023, without language restrictions.
UNASSIGNED: Two reviewers performed independent study screening and assessed the following inclusion criteria: appropriate genotyping was performed, genotype-based categorization into subgroups was possible, and each subgroup contained at least 3 participants.
UNASSIGNED: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for data extraction and subsequent quality, validity, and risk-of-bias assessments. The results from the included studies were pooled with random-effect meta-analysis.
UNASSIGNED: Plasma concentrations of antiseizure drugs were quantified with the dose-normalized area under the concentration-time curve, the dose-normalized steady state concentration, or the concentrations after a single dose at standardized dose and sampling time. The ratio of the means was calculated by dividing the mean drug plasma concentrations of carriers and noncarriers of the pharmacogenetic variant.
UNASSIGNED: Data from 98 studies involving 12 543 adult participants treated with phenytoin, valproate, lamotrigine, or carbamazepine were analyzed. Studies were mainly conducted within East Asian (69 studies) or White or European (15 studies) cohorts. Significant increases of plasma concentrations compared with the reference subgroup were observed for phenytoin, by 46% (95% CI, 33%-61%) in CYP2C9 intermediate metabolizers, 20% (95% CI, 17%-30%) in CYP2C19 intermediate metabolizers, and 39% (95% CI, 24%-56%) in CYP2C19 poor metabolizers; for valproate, by 12% (95% CI, 4%-20%) in CYP2C9 intermediate metabolizers, 12% (95% CI, 2%-24%) in CYP2C19 intermediate metabolizers, and 20% (95% CI, 2%-41%) in CYP2C19 poor metabolizers; and for carbamazepine, by 12% (95% CI, 3%-22%) in CYP3A5 poor metabolizers.
UNASSIGNED: This systematic review and meta-analysis found that CYP2C9 and CYP2C19 genotypes encoding low enzymatic capacity were associated with a clinically relevant increase in phenytoin plasma concentrations, several pharmacogenetic variants were associated with statistically significant but only marginally clinically relevant changes in valproate and carbamazepine plasma concentrations, and numerous pharmacogenetic variants were not associated with statistically significant differences in plasma concentrations of antiseizure drugs.

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

BACKGROUND: Clopidogrel is a P2Y12 inhibitor that has become a mainstay treatment following percutaneous intervention with drug-eluting stent placement to decrease restenosis and its potential complications, including sudden cardiac death and ischaemic strokes in patients with significant vascular disease.
METHODS: As a prodrug, the metabolism and efficacy of clopidogrel are contingent on the presence of wild-type CYP450 (CYP2C19) alleles. Genetic polymorphisms and variants are well known to impair its ability to prevent major adverse cardiovascular events in these patients, with inadequate response rates as high as 30% in previous publications. Patterns of allelic frequencies are expected to exhibit similarities between individuals of the same ancestry, ethnic group or geographic region. Accordingly, we seek to further elucidate worldwide prevalence rates for genetic polymorphisms in the CYP2C19-dependent metabolism of clopidogrel and review the potential of personalised CYP2C19 genotyping in clinical practice to mitigate this high treatment resistance and its associated burden on patients.
UNASSIGNED: Our findings support the consideration of genotyping before initiation of therapy to guide adequate dosage or substitutions of other P2Y12 inhibitors to promote personalised, precision medicine and to prevent adverse events when these therapies may inevitably fail in patients with variants of the CYP450 (CYP2C19) system.

Tacrolimus is a calcineurin inhibitor used to prevent rejection in allogenic solid organ transplant recipients, which is metabolized in the liver with cytochrome P450 isoforms 3A4 and 3A5 (CYP3A4, CYP3A5). In turn, proton pump inhibitors (PPIs), such as Omeprazole - a substrate and inhibitor of CYP2C19 and CYP3A4 enzymes - are administered to kidney transplant patients in order to prevent duodenal and gastric ulcer disease, associated with the glucocorticoid treatment. Simultaneous administration of both drugs in renal patients has the potential to trigger drug interactions. In fact, there are several mechanisms which may impact the pharmacokinetics of tacrolimus. Inhibition of the CYP2C19 isoform may suppress the metabolism of omeprazole, subsequently altering its metabolic pathway to be metabolized by the CYP3A4 enzyme in order to maintain adequate biotransformation. Therefore, the competition for CYP3A4 may affect the metabolism of tacrolimus and result in its increased plasma concentrations, as well as in adverse reactions. Another mechanism has been related to the genetic polymorphism of the CYP2C19 isoform. Since all these interactions may lead to dysfunctions of the transplanted kidney, it seems significant to eliminate their consequences, for instance via the administration of drugs which are neither substrates, nor inhibitors of the CYP3A4 enzyme. Finally, the nephrotoxic effect of omeprazole should also be accounted for. Bearing in mind the aforementioned observations, the aim of the presented paper was to review the available studies addressing the effect of omeprazole on the pharmacokinetics of tacrolimus.

Major depressive disorders are prevalent conditions with limited treatment response and remission. Pharmacogenomics tests including CYP2D6 and CYP2C19 genomic variants provide the most reliable actionable approach to guide choice and dosing of antidepressants in major depression to improve outcomes. We carried out a meta-analysis and meta-regression analyses of randomised controlled trials evaluating pharmacogenomic tests with CYP2D6 and CYP2C19 polymorphisms in major depression. A systematic review was conducted according to PRISMA and Cochrane guidelines to search several electronic databases. Logarithmically transformed odds ratios (OR) and confidence intervals (CI) for improvement, response and remission were calculated. A random-effects meta-analysis and meta-regression analyses were subsequently carried out. Twelve randomised controlled trials were included. Pharmacogenomic tests in the treatment of depression were more effective than treatment as usual for improvement (OR:1.63, CI: 1.19-2.24), response (OR: 1.46; CI: 1.16-1.85) and remission (OR: 1.85; CI: 1.23-2.76) with no evidence of publication bias. Remission was less favourable in recent studies. The results are promising but cautious use of pharmacogenomics in major depression is advisable. PROSPERO registration ID: CRD42021261143.

Background: Various genetic factors influence warfarin maintenance dose. Methods: A literature search was performed on PubMed, Embase and the Cochrane Library, and a meta-analysis to analyze the impact of CYP2C19 polymorphisms on warfarin maintenance dose was conducted. Results: From nine studies encompassing 1393 patients, three CYP2C19 SNPs were identified: rs4244285, rs4986893 and rs3814637. Warfarin maintenance dose was significantly reduced by 10% in individuals with the rs4986893 A allele compared with the GG carriers and was 34%, 16% and 18% lower in patients with rs3814637 TT and CT genotypes and T allele, respectively, than that in CC carriers. No significant dose difference was observed among the rs4244285 genotypes. Conclusion: CYP2C19 rs4986893 and rs3814637 are associated with significantly reduced warfarin dose requirements.

To assess the impact of cytochrome P450 (CYP) 2C19 polymorphisms on the clinical efficacy and safety of voriconazole.
We systematically searched PubMed, EMBASE, CENTRAL, ClinicalTrials.gov, and three Chinese databases from their inception to 18 March 2021 using a predefined search algorithm to identify relevant studies. Studies that reported voriconazole-treated patients and information on CYP2C19 polymorphisms were included. The efficacy outcome was success rate. The safety outcomes included overall adverse events, hepatotoxicity, and neurotoxicity.
A total of 20 studies were included. Intermediate metabolizers (IMs) and poor metabolizers (PMs) were associated with increased success rates compared with normal metabolizers (NMs) [risk ratio (RR), 1.18; 95% confidence interval (CI), 1.03-1.34; I2 = 0%; P = 0.02; RR, 1.28; 95% CI, 1.06-1.54; I2 = 0%; P = 0.01]. PMs were at increased risk of overall adverse events in comparison with NMs and IMs (RR, 2.18; 95% CI, 1.35-3.53; I2 = 0%; P = 0.001; RR, 1.80; 95% CI, 1.23-2.64; I2 = 0%; P = 0.003). PMs demonstrated a trend towards an increased incidence of hepatotoxicity when compared with NMs (RR, 1.60; 95% CI, 0.94-2.74; I2 = 27%; P = 0.08), although there was no statistically significant difference. In addition, there was no significant association between CYP2C19 polymorphisms and neurotoxicity.
IMs and PMs were at a significant higher success rate in comparison with NMs. PMs were significantly associated with an increased incidence of all adverse events compared with NMs and IMs. Researches are expected to further confirm these findings. Additionally, the relationship between hepatotoxicity and CYP2C19 polymorphisms deserves clinical attention.

OBJECTIVE: To conduct a systematic review to identify studies that assessed the association between CYP2C19 polymorphisms and clinical outcomes in peripheral artery disease (PAD) patients who took clopidogrel.
METHODS: We systematically searched Ovid EMBASE, PubMed, and Web of Science from November 1997 (inception) to September 2020. We included observational studies evaluating how CYP2C19 polymorphism is associated with clopidogrel\'s effectiveness and safety among patients with PAD. We extracted relevant information details from eligible studies (e.g., study type, patient population, study outcomes). We used the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) Tool to assess the risk of bias for included observational studies.
RESULTS: The outcomes of interest were the effectiveness and safety of clopidogrel. The effectiveness outcomes included clinical ineffectiveness (e.g., restenosis). The safety outcomes included bleeding and death related to the use of clopidogrel. We identified four observational studies with a sample size ranging from 50 to 278. Outcomes and comparison groups of the studies varied. Three studies (75%) had an overall low risk of bias. All included studies demonstrated that carrying CYP2C19 loss of function (LOF) alleles was significantly associated with reduced clinical effectiveness and safety of clopidogrel.
CONCLUSIONS: Our systematic review showed an association between CYP2C19 LOF alleles and reduced functions of clopidogrel. The use of CYP2C19 testing in PAD patients prescribed clopidogrel may help improve the clinical outcomes. However, based on the limited evidence, there is a need for randomized clinical trials in PAD patients to test both the effectiveness and safety outcomes of clopidogrel.

Studies show inconsistent results regarding the impact of CYP2C19 genotype on the pharmacodynamics (PD) and clinical outcomes of ticagrelor. With the implementation of genotype-guided individualized antiplatelet therapy, the association between CYP2C19 polymorphism and the efficacy and safety of ticagrelor for patients is still worthy of exploring and studying.
This systematic review protocol has been registered in the PROSPERO network (No. CRD 42020158920). Electronic databases of PubMed, EmBase, and the Cochrane Library were systematically searched from inception to January 6th, 2022 to select studies investigating the impact of CYP2C19 genotype on PD and clinical outcomes of ticagrelor. The results were presented as odds ratio (OR) or weight mean difference with its 95% confidence interval (CI) by using the random-effects model. Trial sequential analysis (TSA) was used to control risk of random errors and detect the robustness of outcomes.
Eight studies recruited a total of 6405 patients treated with ticagrelor. Mostly trials reported no significant effect of any or no CYP2C19 loss-of-function (LOF) allele (*2 or *3) on all the endpoints. Compared with no LOF allele carriers, subgroup analysis suggested any LOF allele in Asian patients was associated with a significant decreased risk of bleeding events (OR: 0.41; 95% CI: 0.22-0.75; P = 0.004). Furthermore, any LOF allele carriers didn\'t yield any impact on the risk of MACEs (OR: 1.11; 95% CI: 0.76-1.64; P = 0.586), stroke (OR: 1.71; 95% CI: 0.99-2.96; P = 0.054), definite stent thrombosis (OR: 0.88; 95% CI: 0.17-4.60; P = 0.882), bleeding (OR: 0.63; 95% CI: 0.27-1.46; P = 0.281), myocardial infarction (OR: 0.81; 95% CI: 0.30-2.20; P = 0.682), and revascularization (OR: 0.81; 95% CI: 0.33-2.00; P = 0.649) in all patients. The results of TSA were indicated that more further trials would be required.
This qualitative and quantitative study suggested Asian patients carrying any CYP2C19 LOF allele might have a lower risk of bleeding events comparing with no LOF allele carriers when treated with ticagrelor. However, we did not prove an important role of CYP2C19 genotype on the risk of PD and clinical endpoints in the whole cohort. In future, more large-scale prospective studies and more different ethnic populations should be included.

Previous studies on the efficacy and safety of genotype-guided antiplatelet therapy in patients with coronary artery disease (CAD) or undergoing percutaneous coronary intervention (PCI) have been inconclusive.
We conducted a meta-analysis to evaluate if the genotype-guided antiplatelet strategy is superior to the standard therapy in patients with CAD or undergoing PCI.
PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials databases were searched up to October 1st, 2021. Studies reporting efficacy and safety outcomes in the genotype-guided treatment and standard treatment groups were included. The two groups were statistically compared.
Eleven randomized controlled trials (RCTs) involving 11740 patients were included in this meta-analysis. Compared with the standard treatment group, the genotype-guided group had significant lower risks of all efficacy outcomes, including major adverse cardiovascular events (MACEs) (RR 0.60, 95%, CI 0.44-0.82, P=0.001), all-cause death (RR 0.70, 95% CI 0.51-0.95, P=0.02), cardiovascular death (RR 0.71, 95% CI 0.53-0.95, P=0.02), myocardial infarction (RR 0.53, 95% CI 0.42-0.67, P<0.0001), stroke (RR 0.64, 95% CI 0.41-0.98, P=0.04), stent thrombosis (RR 0.63, 95% CI 0.43-0.91, P=0.01) and targeted vessel revascularization (RR 0.79, 95% CI 0.67-0.92, P=0.003). There was no significant difference in any bleeding events between the two groups. As a result of the subgroup analyses, the genotype-guided treatment was more likely to reduce the incidence of MACEs in the subgroup where the proportion of patients with ACS was ≥ 90%, and subgroup of the Chinese population.
Genotype-guided antiplatelet treatment could reduce the risk of MACEs without increasing the risk of bleeding events as compared with the standard treatment in patients with CAD or those undergoing PCI. In addition, Genotype-guided antiplatelet treatment might benefit Chinese population or patients with ACS.