Genomic Ancestry, CYP2D6, CYP2C9, and CYP2C19 Among Latin Americans.

We present the distribution of CYP2D6, CYP2C9, and CYP2C19 variants and predicted phenotypes in 33 native and admixed populations from Ibero-America (n > 6,000) in the context of genetic ancestry (n = 3,387). Continental ancestries are the major determinants of frequencies of the increased-activity allele CYP2C19*17 and CYP2C19 gUMs (negatively associated with Native American ancestry), decreased-activity alleles CYP2D6*41 and CYP2C9*2 (positively associated with European ancestry), and decreased-activity alleles CYP2D6*17 and CYP2D6*29 (positively associated with African ancestry). For the rare alleles, CYP2C9*2 and CYPC19*17, European admixture accounts for their presence in Native American populations, but rare alleles CYP2D6*5 (null-activity), CYP2D6-multiplication alleles (increased activity), and CYP2C9*3 (decreased-activity) were present in the pre-Columbian Americas. The study of a broad spectrum of Native American populations from different ethno-linguistic groups show how autochthonous diversity shaped the distribution of pharmaco-alleles and give insights on the prevalence of clinically relevant phenotypes associated with drugs, such as paroxetine, tamoxifen, warfarin, and clopidogrel.

Interethnic Variability in CYP2D6, CYP2C9, and CYP2C19 Genes and Predicted Drug Metabolism Phenotypes Among 6060 Ibero- and Native Americans: RIBEF-CEIBA Consortium Report on Population Pharmacogenomics.

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 < 0.05). Native Americans also showed less CYP2C19 gUMs than the rest of the population sample. In addition, differences within Native Americans (mostly North vs. South) were also found. The interethnic differences described supports the need for population-specific personalized and precision medicine programs for Native Americans. To the best of our knowledge, this is the largest study carried out in Native Americans and other Ibero-American populations analyzing CYP2D6, CYP2C9, and CYP2C19 genetic polymorphisms. Population pharmacogenomics is a nascent field of global health and warrants further research and education.

MDR-1 genotypes and quetiapine pharmacokinetics in healthy volunteers.

BACKGROUND: P-glycoprotein is an efflux transporter encoded by the multidrug-resistance MDR-1 gene, which influences the absorption and excretion of a variety of drugs. The relation between quetiapine pharmacokinetics and MDR-1 genetic polymorphisms remains controversial. Therefore, the aim of the present study was to analyze the association between quetiapine plasma concentrations and MDR-1 genetic polymorphisms in a bioequivalence trial. METHODS: Quetiapine bioequivalence was studied in 24 unrelated healthy Caucasian adults with an open-label, randomized, cross-over, two-sequence and two-period design. Subjects were genotyped for 3435C>T and 1236C>T single-nucleotide polymorphisms. A linear mixed model was performed to compare pharmacokinetic parameters. RESULTS: Subjects with 3435T/T genotype vs. C carriers showed a higher area under the concentration-time curve from 0 to 36 h (p=0.01). Subjects classified according to 1236C>T SNP and haplotypes showed no statistically significant differences. CONCLUSIONS: These results suggest that the polymorphic MDR-1, in particular the 3435C>T allelic variant, might influence plasma levels of quetiapine.

Single-dose relative bioavailability of a new quetiapine fumarate extended-release formulation: a postprandial, randomized, open-label, two-period crossover study in healthy Uruguayan volunteers.

BACKGROUND: Quetiapine is a dibenzothiazepine derivative that has been established as an effective therapy for schizophrenia and bipolar disorder. A new extended-release (XR) solid formulation of quetiapine was developed in the United Kingdom and a Uruguayan company has developed a branded generic version of the innovator. OBJECTIVE: The goal of the present study was to assess the relative bioavailability of a new XR formulation of quetiapine 300 mg versus the XR reference product after the administration of a high-fat breakfast as required to assume bioequivalence according to the Uruguayan regulatory authority. METHODS: This was a randomized-sequence, open-label, 2-period crossover study performed in healthy Uruguayan volunteers with a washout period of 7 days. One tablet of quetiapine XR 300 mg (test and reference formulations) was administered as a single oral dose, and blood samples were collected over 36 hours. Plasma quetiapine concentration was measured by using HPLC. Plasma concentration-time curves were plotted for each volunteer, and AUC from 0 to 36 hours (AUC(0-36)), AUC(0-∞), C(max), and T(max) were calculated. A priori bioequivalence requirements were set to require a 90% CI of the test/reference ratios for AUC and C(max) values that were between 0.80 and 1.25. Adverse events were determined using clinical assessment, laboratory test results, and monitoring of vital signs throughout the study. Study subjects were asked to report any adverse events at any time during the study. RESULTS: Twenty-four healthy volunteers (12 men, 12 women) were enrolled and completed the study (mean [SD] age, 31 [6.5] years; weight, 68 [12] kg; height, 1.69 [0.09] m; body mass index, 23.7 [3.2] kg/m(2)). Arithmetic mean (SD) of AUC(0-36), AUC(0-∞), C(max), and T(max) were 3279 (1169) ng/mL/h, 3731 (1332) ng/mL/h, 341.5 (108.3) ng/mL, and (median [range]) 5.0 (1.5-12.0) hours, respectively, for the test formulation and 3528 (1308) ng/mL/h, 3546 (1350) ng/mL/h, 365.9 (136.4) ng/mL, and (median [range]) 5.0 (2.5-10.0) hours, respectively, for the reference formulation. The geometric mean (90% CI) for the test/reference ratio of the log-transformed AUC(0-36), AUC(0-∞), and C(max) values were: 0.99 (0.91-1.07), 1.06 (0.95-1.18), and 0.94 (0.84-1.05), respectively. The frequency of reported adverse events was: hypotension (27%), dry mouth (27%), dizziness (10%), headache (7%), and nausea (7%). The difference between formulations was not statistically significant (P > 0.05). CONCLUSIONS: This single-dose study found that the test and reference formulations of quetiapine met the regulatory criteria for bioequivalence among healthy male and female volunteers who took the medicines after a high-fat breakfast. Both products were generally well tolerated.

Bioequivalence of two film-coated tablets of imatinib mesylate 400 mg: a randomized, open-label, single-dose, fasting, two-period, two-sequence crossover comparison in healthy male South American volunteers.

BACKGROUND: Imatinib is a tyrosine kinase inhibitor that has been established as a highly effective therapy for chronic myelogenous leukemia and gastrointestinal stromal tumors. A new generic, once-daily 400-mg tablet of imatinib has been developed by a pharmaceutical company in Argentina, where the regulatory standard for marketing authorization of an imatinib generic is in vitro dissolution testing. OBJECTIVE: The aim of this study was to assess the bioequivalence of a new generic film-coated test tablet formulation versus a film-coated reference tablet formulation of imatinib 400 mg. The local manufacturer seeks to validate the in vitro performance of this new formulation with a bioequivalence study. METHODS: A randomized, open-label, single-dose, fasting, 2-period, 2-sequence crossover design with a 2-week washout period was used in this study. The study population consisted of healthy male South American (Uruguayan) volunteers, who were assigned in a 1:1 ratio to a randomized sequence (test-reference or reference-test). In each period, the test or reference formulation was administered after an overnight fast. During the 72-hour follow-up period, participants were monitored for vital signs and symptoms. Blood samples were collected at 15 time points, including baseline, until 72 hours. Physical examination and laboratory tests (blood, urine) were repeated 1 week after study completion. A noncompartmental model was used to determine the pharmacokinetic parameters of imatinib. The 90% CIs of the test/reference ratios for AUC(0-infinity) and C(max) were determined; the test and reference formulations were considered bioequivalent if the 90% CIs were between 0.80 and 1.25. Adverse events were assessed by a nurse who administered a questionnaire while the healthy volunteers were admitted in the unit. RESULTS: The bioequivalence study was conducted in 30 Uruguayan male volunteers. Demographic characteristics (mean [SD]) included age, 27.8 (6.5) years; weight, 71.2 (9.8) kg; height, 1.71 (0.09) m; and body mass index, 24.3 (3.0) kg/m2. The mean (SD) of AUC(0-infinity) was 38,179 (15,504) ng/mL x h(-1) for the test formulation and 40,554 (17,027) ng/mL x h(-1) for the reference formulation. The mean of Cmax for the test formulation was 2472 (933) ng/mL, and the mean Tmax was 3.28 (0.93) hours. The mean of Cmax for the reference formulation was 2566 (963) ng/mL, and the mean T(max) was 3.63 (1.20) hours. The point estimates (90% CIs) for the test/reference ratios of the log-transformed AUC- and C(max) mean values were 0.95 (0.87-1.03) and 0.97 (0.89-1.05), respectively, which met the regulatory criteria for bioequivalence. Thirty-four mild to moderate adverse events were reported (13 with the test formulation and 21 with the reference formulation), and no serious or unexpected adverse events were observed during the study. The adverse events included 16 cases of headache, 13 cases of nausea, 4 cases of vomiting, and 1 episode of diarrhea. CONCLUSIONS: The results of this study suggest that the test formulation of imatinib met the regulatory criteria for bioequivalence to the reference formulation in these healthy fasting male volunteers. Both formulations were generally well tolerated and appeared to have a similar adverse-event profile.

Estudio de bioequivalencia: enfoque metodológico y aplicaciones prácticas en la evaluación de medicamentos genéricos / Bioequivalence studies: methodological approach and practical applications for the assessment of generic drugs

Un problema que el médico enfrenta a diario en nuestro país es la sustitución de medicamentos similares (genéricos). A efectos de llevar a cabo esta sustitución debe disponer de la evidencia científica que le permita contestar la siguiente pregunta: ¿Cuál es el desempeño farmacocinético y, especialmente, la biodisponibilidad de este medicamento sustitutivo en relación al original?. Los estudios de bioequivalencia dan la respuesta a esta pregunta al aportar la evidencia para decidir la sustitución. La premisa de la cual se parte es la siguiente: Si demostramos que el principio activo tiene el mismo desempeño farmacocinético en el medicamento genérico que en el innovador, entonces podemos considerarlos intercambiables y la evidencia de eficacia clínica y seguridad del innovador se aplica al genérico. En este artículo se analizarán la metodología para diseñar, realizar y evaluar los estudios de bioequivalencia. La exposición se ilustrará con ejemplos prácticos que muestran algunas fallas en la bioequivalencia que el autor ha encontrado a lo largo de 20 años de experiencia. Por otra parte se enfatiza la coordinación de recursos humanos y metodológicos que permite llevar a cabo la evaluación de medicamentos genéricos

Monitoreo terapéutico de la clomipramina y sus desmetil y oximetabolitos en pacientes deprimidos: análisis farmacogenéticos y correlación con la respuesta clínica / Therapeutic monitoring of clomipramine and its demethil and oxi-metabolites in depressed patients: pharmacogenetic analysis and correlation with clinical response

Los antidepresivos tricíclicos se utilizan en la práctica clínica desde hace más de cuatro décadas. En los últimos años ha habido un gran desarrollo de la química analítica que permite la medición de estos agentes terapéuticos y sus metabolitos con gran precisón. Esto ha posibilitado el estudio de la relación entre los niveles en plasma y la respuesta clínica. En el presente estudio se evalúa esta correlación y se introduce el concepto de cociente metabólico como una nueva herramienta para racionalizar el monitoreo farmacoterapéutico. Se estudiaron 28 pacientes con trastornos del humor tratados con clomipramina a los cuales se les midió la concentración plasmática del antidepresivo y sus metabolitos desmetilado y oxidados a lo largo de 42 días de tratamiento. Se encontró una correlación estadísticamente significativa entre la concentración de clomipramina y sus metabolitos y la respuesta clínica medida mediante una escala de Autoevaluación Análogo-Visual y la escala Hamilton para depresión. El cociente metabólico que refleja el carácter hidrocilador mostró una correlación significativa con el efecto. Sin embargo no se constató la misma correlación con el cociente metabólico que refleja la N demetilación de la clomipramina. Se constató un subgrupo de pacientes que se comportan como "metabolizadores lentos" para la N-desmetilación. Se especula sobre la posibilidad de encontrarnos ante un polimorfismo del citocromo CYP2C8

Variabilidad del metabolismo oxidativo de fármacos en la población uruguaya: polimorfismo genético del citocromo P-450 2D6 / Variability of the oxidative metabolism of drugs in the uruguayan population: genetic polymorphism of cytochrome P450 2D6

El estudio de los factores genéticos que determinan la respuesta a los medicamentos se denomina farmacogenética. En la década del 70 se describió el polimorfismo genético de la debrisoquina-hidroxilasa, un hallazgo de gran relevancia dado que muchos fármacos utilizados en terapéutica se oxidan por la misma vía metabólica. Esto explica gran parte de la variabilidad individual que se observa en las concentraciones plasmáticas de estos agentes terapéuticos lo cual determina tanto la falta de efecto como las reacciones adversas, tóxicas o ambas. El dextrometorfano es un derivado opiáceo sintético que se metaboliza por la misma vía que la debrisoquina siendo su uso más seguro, por lo cual se lo utilizó como sonda farmacogenética para explorar la vía metabólica oxidativa del citocromo P-450 2D6 mediante su metabolito O-demetilado, el dextrorfano. En el presente artículo se estudia la distribución fenotípica de la O-demetilación del dextrometorfano en la población uruguaya mediante el cociente metabólico (CM). Este se calcula dividiendo la concentración urinaria el dextrometorfano sobre la concentración urinaria del dextrofano (metabolito O-demetilado). Se caracterizaron fenotípicamente 302 voluntarios en condiciones casi basales y se encontró una variabilidad interindividual diez veces superior a la intraindividual. El examen del fenotipo muestra una distribución trimodal con 13,9 por ciento de metabolizadores rápidos, 78,8 por ciento de metabolizadores intermedios y 7,3 por ciento de metabolizadores lentos. El histograma de frecuencias del CM maestra algunas peculiaridades que se discuten en el texto

Farmacología clínica: desarrollo histórico y estado actual de la investigación y la enseñanza en Uruguay / Clinical pharmacology: historical development and current status of research and teaching in Uruguay

El presente artículo se propone: a) describir la evolución de los hechos que impulsaron el desarrollo de la farmacología clínica en el mundo, b) pergeñar un diagnóstico de la situación actual de la investigación y la enseñanza de la disciplina y c) definir el rol del farmacólogo clínico en la racionalización del uso de los medicamentos. Se aborda también la organización y el desarrollo de la disciplina en aquellos países en que se ha establecido, con particular referencia a la experiencia sueca, y se analiza la inserción de su enseñanza en el curriculum médico de las universidades de ese país así como de otras escuelas médicas europeas. Se enfatiza la necesidad del desarrollo de la farmacología clínica en Uruguay como un todo docente-científico-asistencial. Por último, se hace referencia a la trayectoria individual de destacados farmacólogos de nuestra Facultad de Medicina, priorizando el establecimiento institucional de la disciplina

Estudio del polimorfismo genético de la O-demetilación del dextrometorfano (CYP2D6) en la población uruguaya / Study of genetic polymorphism in O-demethylation of dextromethorphan (CYP2D6) in Uruguayan population

Es de interés para el farmacólogo clínico general el estudio de los factores genéticos que determinan la respuesta a los medicamentos. El polimorfismo genético de la debrisoquina/sparteína ha sido descrito en la década del 70 y ha tomado gran relevancia dado que un número significativo de fármacos utilizados en terapéutica clínica se oxidan por la misma vía metabólica que éstos. El dextrometorfan es un antitusígeno que cosegrega con la debrisoquina y su uso es más seguro. En el presente estudio se caracterizó la distribución de la O-demetilación del dextrometorfan en la población uruguaya (fenotipificación) mediante el cociente metabólico (CM). El objetivo del estudio fue conocer el comportamiento farmacogenético de nuestra población para esta vía metabólica. Se fenotipificaron 165 voluntarios en condiciones basales y se encontró un 6,3 por ciento de metabolizadores lentos. El histograma de frecuencia del CM muestra algunas peculiaridades que se discuten en el texto