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Aim: We evaluated the potential influence of genetic ( CYP3A5, EPHX1, NR1I2, HNF4A, ABCC2, RALBP1, SCN1A, SCN2A and GABRA1) and nongenetic factors on carbamazepine (CBZ) response, adverse drug reactions and CBZ plasma concentrations in 126 Mexican Mestizos (MM) with epilepsy. Subjects & methods: Patients were genotyped for 27 variants using TaqMan® assays. Results: CBZ response was associated with NR1I2 variants and lamotrigine cotreatment. CBZ-induced adverse drug reactions were related to antiepileptic polytherapy and SCN1A rs2298771/rs3812718 haplotype. CBZ plasma concentrations were influenced by NR1I2-rs2276707 and -rs3814058, and by phenytoin cotreatment. CBZ daily dose was also influenced by NR1I2-rs3814055 and EPHX1-rs1051740. Conclusion: Interindividual variability in CBZ treatment was partly explained by NR1I2, EPHX1 and SCN1A variants, as well as antiepileptic cotreatment in MM with epilepsy.

This work aimed to describe and characterize the GnG-PK/PD-AD study and the population of subjects diagnosed with depression and treated with fluoxetine, paroxetine, and venlafaxine recruited in the scope of this project, particularly in terms of antidepressant pharmacokinetics and clinical outcomes and relevant genetic and nongenetic individual factors. 182 subjects diagnosed with depression and treated with these drugs were clinically and therapeutically characterized and submitted to the quantification of drug/metabolite plasma concentrations and genotyping of ABCB1, CYP2C9, CYP2C19, and CYP2D6 genes. Clinical outcomes, including remission and antidepressant adverse effects, were assessed by means of the Hamilton Depression Rating Scale and Antidepressant Side-Effect Checklist, respectively. Most subjects were women (81.9%), suffered from chronic depression (73.6%) and displayed a high prevalence of comorbidities (76.9%), polytherapy (88.5%), and genetic polymorphisms/non-wild-type genotype-predicted phenotypes at the level of CYP2C9, CYP2C19, CYP2D6, and ABCB1 genes (39-78.6%). Noteworthy, most of them were under risk of presenting P-gp, CYP2C9, CYP2C19, and CYP2D6 inhibited due to drug-induced phenoconversion (64.3-98.4%) and 80.8% were at risk of occurrence of at least one antidepressant-drug interaction. Around 40% presented drug plasma concentrations outside of the recommended therapeutic range, 66.5% did not achieve remission of the depressive symptoms and 67.6% presented at least one relevant antidepressant adverse effect. Pharmacokinetics and clinical outcomes with fluoxetine, paroxetine, and venlafaxine were found to be suboptimal and highly variable between subjects. Several genetic and nongenetic factors were identified as potential sources of interindividual variability in the antidepressant outcomes, which deserve to be further investigated. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Aim: Pharmacogenomics (PGx) is a rising scientific area in many countries, such as Brazil. Objectives: To identify biomarkers, therapeutic areas, probe drugs and regions/ethnicities most studied in the country in order to guide future studies. Materials & methods: Systematic review of 1060 studies (from 1968 to 2020) comprising 80 genes, six probe drugs and 3,819,233 individuals. Results: MTHFR and HLA-A/B were the most studied genes and metoprolol and dextromethorphan the most studied probe drugs. Oncology was the most studied therapeutic area considering PGx biomarkers. The country’s regions and ethnic groups were studied unevenly, with south/southeast and White people over-represented in respect to their demographic relevance, in detriment of the center-west/northeast/north and Black/mixed individuals. Conclusion: Many of the gaps and possible paths to be covered to reach even PGx data are pointed out by this review.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300–600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75–150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175–300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100–200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250–400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150–300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300–600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Aim: The need for pharmacogenomic education is becoming more and more urgent. Our aim was to evaluate the progress in pharmacogenomics education since then, and to put forward further recommendations. Methods: A survey was sent to 248 schools of medicine, pharmacy, nursing and health professions around the world. Results: The majority of the study programs (87%) include pharmacogenomics education, which is generally taught as part of the pharmacology curriculum. On average, educators and teachers have selected appropriate and highly relevant pharmacogenomics biomarkers to include in their teaching programs. Conclusions: Based on the results, we can conclude that the state of pharmacogenomics education at the surveyed universities has improved substantially since 2005. ispartof: PHARMACOGENOMICS vol:20 issue:9 pages:643-657 ispartof: location:England status: published

There is a growing demand for the clinical implementation of pharmacogenetics (PGx), personalized and precision medicine (PPM) for drug prescription to reduce adverse drug reactions (ADRs), drug failure, and ultimately health care costs. However, it is convenient to clarify the concept of clinical implementation to realize its benefits. Advances on PGx clinical implementation depend on the integration of genetic along with other relevant biomarkers and clinical information influencing variability in drug response for being interpreted and translated into clinical decisionmaking to optimize drug treatment choice during routine clinical practice.

Testicular cancer is an aggressive malignancy with a rising incidence rate across the globe. Testicular germ cell tumors are the most commonly diagnosed cancers, and surgical removal of the testes is often a radical necessity along with chemotherapy and radiotherapy. While seminomas are receptive to radiotherapy as well as chemotherapy, non-seminomatous germ cell tumors respond to chemotherapy only. Due to the singular nature of testicular cancers with associated orchiectomy and mortality, it is important to study the molecular basis and genetic underpinnings of this group of cancers across male populations globally. In this review, we shed light on the population pharmacogenetics of testicular cancer, pediatric and adult tumors, current clinical trials, genetic determinants of chemotherapy-induced toxicity in testicular cancer, as well as the molecular signal transduction pathways operating in this malignancy. Taken together, our discussions will help in enhancing our understanding of genetic factors in testicular carcinogenesis and chemotherapy-induced toxicity, augment our knowledge of this aggressive cancer at the cellular and molecular level, as well as improve precision medicine approaches to combat this disease.

Resumen: Introducción: Las reacciones adversas a medicamentos (RAM) son un problema de salud pública y una importante causa de morbimortalidad a nivel mundial. En el caso de los fármacos antiepilépticos (FAE), la presencia de RAM puede ser un impedimento para lograr el éxito terapéutico al dificultar la adherencia al tratamiento e impactar la calidad de vida del paciente. La farmacogenética busca la identificación de variantes genéticas asociadas a la seguridad de los fármacos. En este artículo se revisan los genes que codifican para enzimas metabolizadoras y transportadores de fármacos, así como en el sistema HLA asociados a RAM inducidas por FAE. Desarrollo: A la fecha, se ha reportado la asociación de los alelos CYP2C9*2 y *3, que codifican para enzimas de actividad reducida, con efectos neurotóxicos por fenitoína (PHT); alelos nulos de GSTM1 asociados con hepatotoxicidad inducida por carbamazepina (CBZ) y ácido valproico (VPA); polimorfismos genéticos de EPHX1 en la teratogénesis inducida por PHT; variantes genéticas de ABCC2 asociadas con RAM neurológicas por CBZ y VPA, y también diversos alelos de HLA (p. ej., HLA-B*15:02, -A*31:01, -B*15:11, -C*08:01) asociados con RAM de tipo cutáneas. Conclusiones: Los hallazgos publicados muestran que existen RAM con base farmacogenética con una alta variabilidad interétnica, lo que refleja la necesidad de que se realicen estudios en distintas poblaciones para poder obtener resultados que sean de utilidad a un número mayor de pacientes. La búsqueda de biomarcadores que permitan la predicción de RAM a FAE podría mejorar la farmacoterapia en la epilepsia. Abstract: Introduction: Adverse drug reactions (ADRs) are a major public health concern and a leading cause of morbidity and mortality in the world. In the case of antiepileptic drugs (AEDs), ADRs constitute a barrier to successful treatment since they decrease treatment adherence and impact patients’ quality of life of patients. Pharmacogenetics aims to identify genetic polymorphisms associated with drug safety. This article presents a review of genes coding for drug metabolising enzymes and drug transporters, and HLA system genes that have been linked to AED-induced ADRs. Development: To date, several genetic variations associated with drug safety have been reported: CYP2C9*2 and *3 alleles, which code for enzymes with decreased activity, have been linked to phenytoin (PHT)-induced neurotoxicity; GSTM1 null alleles with hepatotoxicity induced by carbamazepine (CBZ) and valproic acid (VPA); EPHX1 polymorphisms with teratogenesis; ABCC2 genetic variations with CBZ- and VPA-induced neurological ADRs; and HLA alleles (e.g. HLA-B*15:02, -A*31:01, -B*15:11, -C*08:01) with cutaneous ADRs. Conclusions: Published findings show that there are ADRs with a pharmacogenetic basis and a high interethnic variability, which indicates a need for future studies in different populations to gather more useful results for larger number of patients. The search for biomarkers that would allow predicting ADRs to AEDs could improve pharmacotherapy for epilepsy. Palabras clave: Farmacogenética, Reacciones adversas a medicamentos, Fármacos antiepilépticos, CYP2C9, ABCC2, Antígeno leucocitario humano (HLA), Keywords: Pharmacogenetics, Adverse drug reactions, Antiepileptic drugs, CYP2C9, ABCC2, Human leukocyte antigen (HLA)

The present article reports the first liquid chromatography (LC) assay for the simultaneous quantification of fluoxetine (FLU), its metabolite norfluoxetine (NFLU) and paroxetine (PAR) in human plasma, applying the microextraction by packed sorbent (MEPS) technology in sample preparation. Chromatographic analysis of FLU, NFLU and PAR was achieved in

A long-standing question and dilemma in precision medicine is whether and to what extent genotyping or phenotyping drug metabolizing enzymes such as CYP2D6 can be used in real-life global clinical and societal settings. Although in an ideal world using both genotype and phenotype biomarkers are desirable, this is not always feasible for economic and practical reasons. Moreover, an additional barrier for clinical implementation of precision medicine is the lack of correlation between genotype and phenotype, considering that most of the current methods include only genotyping. Thus, the present study evaluated, using dextromethorphan as a phenotyping probe, the relationship between CYP2D6 phenotype and CYP2D6 genotype, especially for the ultrarapid metabolizer (UM) phenotype. We report in this study, to the best of our knowledge, the first comparative clinical pharmacogenomics study in a Cuban population sample (N = 174 healthy volunteers) and show that the CYP2D6 genotype is not a robust predictor of the CYP2D6 ultrarapid metabolizer (mUM) status in Cubans. Importantly, the ultrarapid CYP2D6 phenotype can result in a host of health outcomes, such as drug resistance associated with subtherapeutic drug concentrations, overexposure to active drug metabolites, and altered sensitivity to certain human diseases by virtue of altered metabolism of endogenous substrates of CYP2D6. Hence, phenotyping tests for CYP2D6 UMs appear to be a particular necessity for precision medicine in the Cuban population. Finally, in consideration of ethical and inclusive representation in global science, we recommend further precision medicine biomarker research and funding in support of neglected or understudied populations worldwide.

Amfepramone (AFP) is an appetite-suppressant drug used in the treatment of obesity. Nonetheless, studies on interindividual pharmacokinetic variability and its association with genetic variants are limited. We employed a pharmacokinetic and pharmacogenetic approach to determine possible metabolic phenotypes of AFP and identify genetic markers that could affect the pharmacokinetic variability in a Mexican population. A controlled, randomized, crossover, single-blind, two-treatment, two-period, and two sequence clinical study of AFP (a single 75 mg dose) was conducted in 36 healthy Mexican volunteers who fulfilled the study requirements. Amfepramone plasma levels were measured using high-performance liquid chromatography mass spectrometry. Genotyping was performed using real-time PCR with TaqMan probes. Four AFP metabolizer phenotypes were found in our population: slow, normal, intermediate, and fast. Additionally, two gene polymorphisms, ABCB1-rs1045642 and CYP3A4-rs2242480, had a significant effect on AFP pharmacokinetics (P ABCB1 and CYP3A4 gene polymorphisms were associated with a fast metabolizer phenotype. These results suggest that metabolism of AFP in the Mexican population is variable. In addition, the genetic variants ABCB1-rs1045642 and CYP3A4-rs2242480 may partially explain the AFP pharmacokinetic variability.

This work presents the GnG-PK/PD-AD study-a pharmacokinetics/pharmacodynamics (PK/PD) analysis of the impact of genetic and nongenetic factors on the treatment with the antidepressant fluoxetine (FLU)-with a focus on potential biomarkers. Seventy-nine depressed patients treated with FLU were recruited and clinically characterized in the scope of the study. Clinical outcomes, including remission and antidepressant adverse effects were assessed by means of the Hamilton Depression Rating Scale and the Antidepressant Side-Effect Checklist, respectively. Patients were submitted to therapeutic drug monitoring of FLU and norfluoxetine and genotyping of the CYP2C9, CYP2C19, CYP2D6, and ABCB1 genes. A multivariate analysis was used to evaluate the impact of genetic and nongenetic factors on the drug plasma concentrations and clinical outcomes and to identify potential biomarkers. Genetically determined CYP2D6 activity was found to be a predictor of FLU and norfluoxetine concentrations (p < .05). In turn, genetic and nongenetic factors related to CYP2D6 and P-glycoprotein were found as potential biomarkers of the clinical outcomes of FLU (p < .05). Specifically, the potential of the CYP2D6 to be inhibited by drug-induced phenoconversion was associated with a higher severity of depression (p < .05). Moreover, ABCB1 TTT-haplotype was favorable to better clinical outcomes with FLU (higher likelihood of remission and lower severity of adverse effects; p < .05). The potential of the P-glycoprotein to be inhibited by drug-induced phenoconversion was also related to a worse tolerability profile (higher severity and number of adverse effects; p < .05). Lastly, the presence of nervous system comorbidities was associated with a higher severity of adverse effects and aging and the female gender with a higher severity of depression and lower probability of remission (p < .05). (PsycInfo Database Record (c) 2020 APA, all rights reserved).

The Fourth European Society of Pharmacogenomics and Personalized Therapy biennial conference was organized in collaboration with the Italian Society of Personalized Medicine (SIMeP) and was held at Benedictine Monastery of San Nicolò l’Arena in Catania, Sicily (Italy) on 4–7 October 2017. The congress addressed the research progress and clinical implementation in pharmacogenomics and personalized medicine. The Fourth European Society of Pharmacogenomics and Personalized Therapy congress brought together leading international scientists and healthcare professionals actively working in the fields of pharmacogenomics and personalized therapy. Altogether, 25 speakers in 15 session comprehensively covered broad spectrum of pharmacogenetics and pharmacogenomics research, clinical applications in different clinical disciplines attended by 270 delegates.

Interethnic variability in the drug-metabolizing capacity of CYP450 enzymes may lead to discrepancies in the relationship between genotypes and phenotypes worldwide. The present study was aimed to analyze for the first time whether there is a relationship between clinically relevant CYP450 genetic polymorphisms and their drug oxidation capacity (metabolic phenotype) in a population of healthy Nicaraguan volunteers. Two hundred and twelve participants were genotyped for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and their actual metabolic phenotype (evaluated by the Metabolic Ratio, MR) was analyzed by using the CEIBA cocktail approach. The results showed the wide interindividual variability in all the studied enzymes and a significant difference (p

Genetic and nongenetic factors may contribute to lamotrigine (LTG) plasma concentration variability among patients. We simultaneously investigated the association of UGT1A1, UGT1A4, UGT2B7, ABCB1, ABCG2, and SLC22A1 variants, as well as antiepileptic drug co-treatment, on LTG plasma concentration in 97 Mexican Mestizo (MM) patients with epilepsy. UGT1A4*1b was associated with lower LTG dose-corrected concentrations. Patients with the UGT2B7-161T allele were treated with 21.22% higher LTG daily dose than those with CC genotype. Two novel UGT1A4 variants (c.526A>T; p.Thr185= and c.496T>C; p.Ser166Leu) were identified in one patient. Patients treated with LTG + valproic acid (VPA) showed higher LTG plasma concentration than patients did on LTG monotherapy or LTG + inducer. Despite the numerous drug-metabolizing enzymes and transporter genetic variants analyzed, our results revealed that co-treatment with VPA was the most significant factor influencing LTG plasma concentration, followed by UGT1A4*1b, and that patients carrying UGT2B7 c.-161T required higher LTG daily doses. These data provide valuable information for the clinical use of LTG in MM patients with epilepsy.

In September 2018, the European Society of Pharmacogenomics and Personalised Therapy (ESPT), with the support of the Swiss Personalized Health Network (SPHN), organized its 4th biennial summer school, entitled ‘Precision Medicine and Personalised Health’ (Campus Biotech, Geneva, Switzerland; www.esptsummerschool.eu/ ). The school’s comprehensive and innovative educational program aimed to address the fundamentals of pharmacogenomics, the latest knowledge on established and new concepts in the field of precision medicine, as well as its advanced clinical applications in personalized health. The school consisted of 31 lectures, eight interactive workshops, visits to genome center and poster presentations, involving 40 speakers from distinguished international faculties. The meeting was a resounding success by generating informal environments between more than 80 participants from 26 different countries.

The majority of Mexican patients with diabetes mellitus type 2 (DMT2) (67.9-85.0%) are prescribed sulpho nylureas (SUs), which are metabolized by cytochrome P450 2C9 (abbreviated as CYP2C9). SUs are a type of oral anti-diabetic compound which inhibit ATP-sensitive potas sium channels, thus inducing glucose-independent insulin release by the β-pancreatic cells. The wide variability reported in SU responses has been attributed to the polymorphisms of CYP2C9. The present study aimed to describe CYP2C9 polymorphisms (*2, *3 and IVS8‑109T) within a sample of Mexican patients with DMT2, while suggesting the potential clinical implications in terms of glibenclamide response vari ability. From a sample of 248 patients with DMT2 who initially consented to be studied, those ultimately included in the study were treated with glibenclamide (n=11), glibenclamide combined with metformin (n=112) or metformin (n=76), and were subsequently genotyped using a reverse transcrip tion-quantitative polymerase chain reaction (PCR), end-point allelic discrimination and PCR amplifying enzymatic restric tion fragment long polymorphism. Clinical data were gathered through medical record revision. The frequencies revealed were as follows: CYP2C9*1/*1, 87.5%; *1/*2, 6.5%; *1/*3, 5.2%; and CYP2C9, IVS8‑109A>T, 16.1%. Glibenclamide significantly reduced the level of pre‑prandial glucose (PT compared with combined glibenclamide and metformin treatment. Concerning the various treatments with respect to the different genotypes, the percentages obtained were as follows: Glibenclamide A/A, HbA1c

Genetic variations within the cytochrome P450 (CYP450) superfamily of drug metabolizing enzymes confer substantial person-to-person and between-population differences in pharmacokinetics, and by extension, highly variable clinical effects of medicines. In this context, "personalized medicine," "precision medicine," and "stratified medicine" are related concepts attributed to what is essentially targeted therapeutics and companion diagnostics, aimed at improving safety and effectiveness of health interventions. We report here, to the best of our knowledge, the first comparative clinical pharmacogenomics study, in an Ecuadorian population sample, of five key CYP450s involved in drug metabolism: CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. In 139 unrelated, medication-free, and healthy Ecuadorian subjects, we measured the phenotypic activity of these drug metabolism pathways using the CEIBA multiplexed phenotyping cocktail. The subjects were genotyped for each CYP450 enzyme gene as well. Notably, based on the CYP450 metabolic phenotypes estimated by the genotype data, 0.75% and 3.10% of the subjects were genotypic poor metabolizers (gPMs) for CYP2C19 and CYP2D6, respectively. Additionally, on the other extreme, genotype-estimated ultrarapid metabolizer (gUMs) phenotype was represented by 15.79% of CYP2C19, and 5.43% of CYP2D6. There was, however, considerable discordance between directly measured phenotypes (mPMs and mUMs) and the above genotype-estimated enzyme phenotypes. For example, among individuals genotypically carrying enhanced activity alleles (gUMs), many showed a lower actual drug metabolism capacity than expected by their genotypes, even lower than individuals with reduced or no activity alleles. In conclusion, for personalized medicine in the Ecuadorian population, we recommend CYP450 multiplexed phenotyping, or genotyping and phenotyping in tandem, rather than CYP450 genotypic tests alone. Additionally, we recommend, in consideration of equity, ethical, and inclusive representation in global science, further precision medicine research and funding in support of neglected or understudied populations worldwide.

Aim: CYP2C9 is one of the major drug metabolizing enzymes, however, little is known about polymorphisms in CYP2C9 gene and pharmacological implications in Mexican indigenous populations. Thus, frequencies of CYP2C9*2 and CYP2C9*3 alleles were evaluated in indigenous groups located in northwest (Cora), center (Mazahua and Teenek), south (Chatino and Mixteco) and southeast (Chontal and Maya) regions Mexico. Materials & methods: Allelic discrimination was performed by real-time PCR. Results: CYP2C9*2 allele was found only in Chontal and Maya groups, despite the low contribution of Caucasian component in these populations. CYP2C9*3 allele was present in all populations except in Mazahua, showing a wide genetic variability in the studied populations. Interestingly, we found significant differences between indigenous groups in CYP2C9*3 allele, even in groups located at the same region and belonging to the same linguistic family. Conclusion: These results contribute to laying the pharmacogenetic bases in Mexico, in addition to improving treatment, taking into account the genetic interethnic differences.

Aim: The present review was aimed at analyzing the pharmacogenetic scientific activity in Central America and the Caribbean. Materials & methods: A literature search for pharmacogenetic studies in each country of the region was conducted on three databases using a list of the most relevant pharmacogenetic biomarkers including ‘phenotyping probe drugs’ for major drug metabolizing enzymes. The review included 132 papers involving 47 biomarkers and 35,079 subjects (11,129 healthy volunteers and 23,950 patients). Results: The country with the most intensive pharmacogenetic research was Costa Rica. The most studied medical therapeutic area was oncology, and the most investigated biomarkers were CYP2D6 and HLA-A/B. Conclusion: Research activity on pharmacogenetics in Central American and the Caribbean populations is limited or absent. Therefore, strategies to promote effective collaborations, and foster interregional initiatives and research efforts among countries from the region could help for the rational clinical implementation of pharmacogenetics and personalized medicine.

This study investigated whether the risk of presenting antipsychotic (AP)-induced extrapyramidal symptoms (EPS) could be related to single-nucleotide polymorphisms (SNPs) in a naturalistic cohort of first episode psychosis (FEP) patients. Two hundred and two SNPs in 31 candidate genes (involved in dopamine, serotonin and glutamate pathways) were analyzed in the present study. One hundred and thirteen FEP patients (43 presenting EPS and 70 non-presenting EPS) treated with high-potency AP (amisulpride, paliperidone, risperidone and ziprasidone) were included in the analysis. The statistical analysis was adjusted by age, gender, AP dosage, AP combinations and concomitant treatments as covariates. Four SNPs in different genes (DRD2, SLC18A2, HTR2A and GRIK3) contributed significantly to the risk of EPS after correction for multiple testing (P

A high frequency (7-10%) of CYP2D6 ultrarapid metabolizers estimated from the genotype (gUMs) has been claimed to exist among Spaniards and Southern Europeans. However, methodological aspects such as the inclusion of individuals carrying non-active multiplied alleles as gUMs may have led to an overestimation. Thus, this study aimed to analyze the gUM frequency (considering only those carrying more than two active genes) in 805 Spanish healthy volunteers studied for CYP2D6*2, *3, *4, *5, *6, *10, *17, *35, *41, and multiplications. Second, all worldwide studies reporting gUM frequencies were reviewed in order to evaluate potential misclassifications. The gUM frequency in this Spanish population was 5.34%, but increased to 8.3% if all individuals with CYP2D6 multiplications were classified as gUMs without considering the activity of the multiplied alleles. Moreover, among all reviewed worldwide studies only 55.6% precisely determined whether the multiplied alleles were active. Present results suggest that the evaluation of CYP2D6 ultrarapid metabolism should be standarized, and that the frequency of gUMs should be reconsidered in Spaniards and globally.

A twofold higher frequency of CYP2D6 ultrarapid metabolizers (estimated from genotype: gUMs) was reported among Ashkenazi Jews (AJ) living in New York (USA) than in other North American Caucasians, which might be important to guide the prescription for CYP2D6 substrates in AJ communities around the world. This study was aimed to determine whether the high frequency of CYP2D6 gUMs described in AJ from USA was replicated in AJ from Argentina when compared with other multiethnic admixture Argentines (GA). The frequency of the most common allelic variants and of CYP2D6 gUMs (>2 active genes) and poor metabolizers (0 active genes, gPMs) was also compared among the studied Argentine populations. CYP2D6 genotyping was performed in 173 AJ and 246 GA DNA samples of unrelated donors from the metropolitan area of Buenos Aires. CYP2D6 alleles (*2, *3, *4, *5, *6, *10, *17, *35, *41 and multiple copies), genotypes and functional phenotype frequencies were determined. The frequencies of gUMs and gPMs in AJ from Argentina were 11.5% and 5.2%, respectively, whereas in GA, the frequencies of gUM and gPMs were 6.5% and 4.9%, respectively. Comparisons between AJ and GA showed that gUMs frequencies were twofold higher (P

WOS: 000374760800008, 27093110

Despite strong pharmacological support, association studies using genotype-predicted phenotype as a variable have yielded conflicting or inconclusive evidence to promote personalized pharmacotherapy. Unless the patient is a genotypic poor metabolizer, imputation of patient's metabolic capacity (or metabolic phenotype), a major factor in drug exposure-related clinical response, is a complex and highly challenging task because of limited number of alleles interrogated, population-specific differences in allele frequencies, allele-specific substrate-selectivity and importantly, phenoconversion mediated by co-medications and inflammatory co-morbidities that modulate the functional activity of drug metabolizing enzymes. Furthermore, metabolic phenotype and clinical outcomes are not binary functions; there is large intragenotypic and intraindividual variability. Therefore, the ability of association studies to identify relationships between genotype and clinical outcomes can be greatly enhanced by determining phenotype measures of study participants and/or by therapeutic drug monitoring to correlate drug concentrations with genotype and actual metabolic phenotype. To facilitate improved analysis and reporting of association studies, we propose acronyms with the prefixes ‘g’ (genotype-predicted phenotype) and ‘m’ (measured metabolic phenotype) to better describe this important variable of the study subjects. Inclusion of actually measured metabolic phenotype, and when appropriate therapeutic drug monitoring, promises to reveal relationships that may not be detected by using genotype alone as the variable.

Phenotyping of the CYP450 enzyme activities contributes to personalized medicine, but the past phenotyping approaches have followed a piecemeal strategy measuring single enzyme activities in vivo. A barrier to phenotyping of populations in rural and remote areas is the limited time and resources for sample collection. The CEIBA cocktail approach allows metabolic capacity estimation of multiple CYP450 enzymes in a single sample analysis, but the attendant sample collection schemes for applications in diverse global settings are yet to be optimized. The present study aimed to select an optimal matrix to simultaneously analyze CYP450 enzyme activities so as to simplify the sampling schemes in the phenotyping protocol to enhance its throughput and feasibility in native populations or in remote and underserviced geographies and social contexts. We evaluated 13 Ecuadorian healthy volunteers for CYP1A2, CYP2C9, CYP2C19, and CYP2D6 genotypes and their metabolic phenotypes, including CYP3A4, in plasma and urine after administering one reduced dose of caffeine, losartan, omeprazole, and dextromethorphan. Pharmacokinetic analyses were performed, and the correlation between AUC parent/AUC metabolite and the ratio between concentrations of probe drugs and their corresponding metabolites at timepoints ranging from 0 to 12 hours post-dose were analyzed. A single sampling timepoint, 4 hours post-dose in plasma, was identified as optimal to reflect the metabolic activity of the attendant CYP450 enzymes. This study optimizes the CEIBA multiplexed phenotyping approach and offers new ways forward for integrated drug metabolism analyses, in the pursuit of global personalized medicine applications in resource-limited regions, be they in developed or developing countries.

Purpose The symposium Health and Medicines in Indigenous Populations of America was organized by the Council for International Organizations of Medical Sciences (CIOMS) Working Group on Clinical Research in Resource-Limited Settings (RLSs) and the Ibero-American Network of Pharmacogenetics and Pharmacogenomics (RIBEF). It was aimed to share and evaluate investigators' experiences on challenges and opportunities on clinical research and pharmacogenetics. Methods A total of 33 members from 22 countries participated in 2 sessions: RIBEF studies on population pharmacogenetics about the relationship between ancestry with relevant drug-related genetic polymorphisms and the relationship between genotype and phenotype in Native Americans (session 1) and case examples of clinical studies in RLSs from Asia (cancer), America (diabetes and women health), and Africa (malaria) in which the participants were asked to answer in free text their experiences on challenges and opportunities to solve the problems (session 2). Later, a discourse analysis grouping common themes by affinity was conducted. Findings The main result of session 1 was that the pharmacogenetics-related ancestry of the population should be considered when designing clinical studies in RLSs. In session 2, 21 challenges and 20 opportunities were identified. The social aspects represent the largest proportion of the challenges (43%) and opportunities (55%), and some of them seem to be common. Implications The main discussion points were gathered in the Declaration of Merida/T'Ho and announced on the Parliament of Extremadura during the CIOMS-RIBEF meeting in 4 of the major Latin American autochthonous languages (Nahualth, Mayan, Miskito, and Kichwa). The declaration highlighted the following: (1) the relevance of population pharmacogenetics, (2) the sociocultural contexts (interaction with traditional medicine), and (3) the education needs of research teams for clinical research in vulnerable and autochthonous populations.

Fil: Naranjo, María Eugenia G. RIBEF Ibero-American Network of Pharmacogenetics and Pharmacogenomics; España Fil: Naranjo, María Eugenia G. Universidad de Extremadura; España Fil: Rodrigues Soares, Fernanda. RIBEF Ibero-American Network of Pharmacogenetics and Pharmacogenomics; España Fil: Rodrigues Soares, Fernanda. Universidade Federal de Minas Gerais; Brasil Fil: Rodrigues Soares, Fernanda. Faculdade Uninassau; Brasil Fil: Peñas Lledó, Eva M. RIBEF Ibero-American Network of Pharmacogenetics and Pharmacogenomics; España Fil: Peñas Lledó, Eva M. Universidad de Extremadura; España Fil: Tarazona Santos, Eduardo. RIBEF Ibero-American Network of Pharmacogenetics and Pharmacogenomics; España Fil: Tarazona Santos, Eduardo. Universidade Federal de Minas Gerais; Brasil Fil: Tarazona Santos, Eduardo. Prisma; Perú Fil: Fariñas, Humberto. RIBEF Ibero-American Network of Pharmacogenetics and Pharmacogenomics; España Fil: Fariñas, Humberto. Universidad de Extremadura; España Fil: Rodeiro, Idania. RIBEF Ibero-American Network of Pharmacogenetics and Pharmacogenomics; España Fil: Rodeiro, Idania. Instituto de Ciencias del Mar; Cuba Fil: Terán, Enrique. RIBEF Ibero-American Network of Pharmacogenetics and Pharmacogenomics; España Fil: Terán, Enrique. Universidad San Francisco de Quito; Ecuadro Fil: Grazina, Manuela. RIBEF Ibero-American Network of Pharmacogenetics and Pharmacogenomics; España Fil: Grazina, Manuela. University of Coimbra; Portugal Fil: Moya, Graciela E. RIBEF Ibero-American Network of Pharmacogenetics and Pharmacogenomics; España Fil: Moya, Graciela E. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: López López, Marisol. RIBEF Ibero-American Network of Pharmacogenetics and Pharmacogenomics; España Fil: López López, Marisol. Universidad Autónoma Metropolitana; México Fil: Sarmiento, Alba P. Pontifica Universidad Javeriana; Colombia Fil: Calzadilla, Luis R. Centro Comunitario de Salud Mental de la Habana Vieja; Cuba Fil: Calzadilla, Luis R. RIBEF Ibero-American Network of Pharmacogenetics and Pharmacogenomics; España Fil: Ramírez Roa, Ronald. Universidad Nacional Autónoma de Nicaragua; Nicaragua Fil: Ramírez Roa, Ronald. RIBEF Ibero-American Network of Pharmacogenetics and Pharmacogenomics; España Fil: Ortiz López, Rocío. RIBEF Ibero-American Network of Pharmacogenetics and Pharmacogenomics; España Fil: Ortiz López, Rocío. Tecnológico de Monterrey; México Fil: Estévez Carrizo, Francisco E. RIBEF Ibero-American Network of Pharmacogenetics and Pharmacogenomics; España Fil: Estévez Carrizo, Francisco E. Universidad de Montevideo; Uruguay Fil: Sosa Macías, Martha. RIBEF Ibero-American Network of Pharmacogenetics and Pharmacogenomics; España Fil: Sosa Macías, Martha. Instituto Politécnico Nacional; México Fil: Barrantes, Ramiro. Universidad de Costa Rica Fil: Barrantes, Ramiro. RIBEF Ibero-American Network of Pharmacogenetics and Pharmacogenomics; España Fil: Llerena Adrián. RIBEF Ibero-American Network of Pharmacogenetics and Pharmacogenomics; España Fil: Llerena Adrián. Universidad de Extremadura; España Abstarct Pharmacogenetic variation in Latin Americans is understudied, which sets a barrier for the goal of global precision medicine. The RIBEF-CEIBA Network Consortium was established to characterize interindividual and between population variations in CYP2D6, CYP2C9, and CYP2C19 drug metabolizing enzyme genotypes, which were subsequently utilized to catalog their "predicted drug metabolism phenotypes" across Native American and Ibero American populations. Importantly, we report in this study, a total of 6060 healthy individuals from Ibero-America who were classified according to their self-reported ancestry: 1395 Native Americans, 2571 Admixed Latin Americans, 96 Afro-Latin Americans, 287 white Latin Americans (from Cuba), 1537 Iberians, and 174 Argentinean Ashkenazi Jews. Moreover, Native Americans were grouped into North-, Central-, and South Amerindians (from Mexico, Costa Rica, and Peru, respectively). All subjects were studied for the most common and functional CYP2D6, CYP2C9, and CYP2C19 allelic variants, and grouped as genotype-predicted poor or ultrarapid metabolizer phenotypes (gPMs and gUMs, respectively). Native Americans showed differences from each ethnic group in at least two alleles of CYP2D6, CYP2C9, and CYP2C19. Native Americans had higher frequencies of wild-type alleles for all genes, and lower frequency of CYP2D6*41, CYP2C9*2, and CYP2C19*17 (p

Carbamazepine (CBZ) is used for the treatment of epilepsy and other neurological and psychiatric disorders. The occurrence of adverse reactions (ADRs) to CBZ can negatively impact the quality of life of patients, as well as increase health-care costs. Thus, knowledge of CBZ-induced ADRs is important to achieve safer treatment outcomes. Areas covered: This review describes the clinical features, known mechanisms, and clinical management of the main CBZ-induced ADRs. In addition, pharmacogenetic studies focused on ADRs induced by CBZ are cited. Expert commentary: CBZ-induced ADRs are well known in the literature. The metabolite CBZ-10,11-epoxide plays an important role in the mechanism that underlies the ADRs induced by CBZ. Several factors should be considered for a safer use of CBZ, such as monotherapy prescription when possible, an adequate dose titration, knowledge of previous ADRs in the patient, and routine monitoring of CBZ plasma concentrations in symptomatic patients. Pharmacogenetics is a potential tool for CBZ therapy improvement, and the design of multicenter studies focused on the identification of biomarkers for CBZ-induced ADRs could provide useful information for a safer CBZ therapy.