Monitorización terapéutica de los fármacos biológicos en la enfermedad inflamatoria intestinal. Documento de Posicionamiento del Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU) / Therapeutic drug monitoring in inflammatory bowel diseases. Position statement of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis

El tratamiento de la enfermedad inflamatoria intestinal (EII) ha sufrido una gran transformación tras la introducción de los fármacos biológicos. Gracias a ellos, los objetivos del tratamiento han evolucionado desde la respuesta y remisión clínica a objetivos más ambiciosos, como la remisión endoscópica o radiológica. Sin embargo, aunque los biológicos son muy eficaces, un porcentaje importante de pacientes no obtendrá una respuesta inicial o la perderá a lo largo del tiempo. Sabemos que existe una relación directa entre las concentraciones valle del biológico y su eficacia terapéutica, que cuanto más exigente sea el objetivo terapéutico serán necesarios niveles superiores del fármaco y que es frecuente la exposición insuficiente al mismo. La monitorización terapéutica de medicamentos biológicos, así como los modelos farmacocinéticos, nos brindan la posibilidad de ofrecer un enfoque personalizado del abordaje en pacientes con EII. Durante los últimos años se ha acumulado información relevante respecto a su utilidad durante o después de la inducción, así como en el mantenimiento del tratamiento biológico, en estrategias reactivas o proactivas y antes de la retirada o desintensificación del esquema.El objetivo de este documento es establecer recomendaciones sobre la utilidad de la monitorización terapéutica de biológicos en pacientes con EII, en los diferentes escenarios de la práctica clínica e identificar las áreas donde su utilidad es evidente, prometedora o controvertida. (AU)

The treatment of inflammatory bowel disease has undergone a significant transformation following the introduction of biologic drugs. Thanks to these drugs, treatment goals have evolved from clinical response and remission to more ambitious objectives, such as endoscopic or radiologic remission. However, even though biologics are highly effective, a significant percentage of patients will not achieve an initial response or may lose it over time. We know that there is a direct relationship between the trough concentrations of the biologic and its therapeutic efficacy, with more demanding therapeutic goals requiring higher drug levels, and inadequate exposure being common.Therapeutic drug monitoring of biologic medications, along with pharmacokinetic models, provides us with the possibility of offering a personalized approach to treatment for patients with IBD. Over the past few years, relevant information has accumulated regarding its utility during or after induction, as well as in the maintenance of biologic treatment, in reactive or proactive strategies, and prior to withdrawal or treatment de-escalation.The aim of this document is to establish recommendations regarding the utility of therapeutic drug monitoring of biologics in patients with inflammatory bowel disease, in different clinical practice scenarios, and to identify areas where its utility is evident, promising, or controversial. (AU)

Tools for a personalized tacrolimus dose adjustment in the follow-up of renal transplant recipients. Metabolizing phenotype according to CYP3A genetic polymorphisms versus concentration-dose ratio.

BACKGROUND AND JUSTIFICATION: The strategy of the concentration-dose (C/D) approach and the different profiles of tacrolimus (Tac) according to the cytochrome P450 polymorphisms (CYPs) focus on the metabolism of Tac and are proposed as tools for the follow-up of transplant patients. The objective of this study is to analyse both strategies to confirm whether the stratification of patients according to the pharmacokinetic behaviour of C/D corresponds to the classification according to their CYP3A4/5 cluster metabolizer profile. MATERIALS AND METHODS: 425 kidney transplant patients who received Tac as immunosuppressive treatment have been included. The concentration/dose ratio (C/D) was used to divide patients in terciles and classify them according to their Tac metabolism rate (fast, intermediate, and slow). Based on CYP3A4 and A5 polymorphisms, patients were classified into 3 metabolizer groups: fast (CYP3A5*1 carriers and CYP34A*1/*1), intermediate (CYP3A5*3/3 and CYP3A4*1/*1) and slow (CYP3A5*3/*3 and CYP3A4*22 carriers). RESULTS: When comparing patients included in each metabolizer group according to C/D ratio, 47% (65/139) of the fast metabolizers, 85% (125/146) of the intermediate and only 12% (17/140) of the slow also fitted in the homonym genotype group. Statistically lower Tac concentrations were observed in the fast metabolizers group and higher Tac concentrations in the slow metabolizers when compared with the intermediate group both in C/D ratio and polymorphisms criteria. High metabolizers required approximately 60% more Tac doses than intermediates throughout follow-up, while poor metabolizers required approximately 20% fewer doses than intermediates. Fast metabolizers classified by both criteria presented a higher percentage of times with sub-therapeutic blood Tac concentration values. CONCLUSION: Determination of the metabolizer phenotype according to CYP polymorphisms or the C/D ratio allows patients to be distinguished according to their exposure to Tac. Probably the combination of both classification criteria would be a good tool for managing Tac dosage for transplant patients.

Herramientas para un ajuste de dosis de tacrolimus más personalizado en el seguimiento de los pacientes con transplante renal. Fenotipo metabolizador según polimorfismos genéticos del CYP3A vs. el cociente concentración-dosis / Tools for a personalized tacrolimus dose adjustment in the follow-up of renal transplant recipients: Metabolizing phenotype according to CYP3A genetic polymorphisms versus concentration–dose ratio

Antecedentes y justificación: La estrategia de la aproximación concentración-dosis (C/D) y los distintos perfiles del tacrolimus (Tac), según los polimorfismos del citocromo P450 (CYPs) se centran en el metabolismo de Tac y se plantean como herramientas para el seguimiento de los pacientes trasplantados. El objetivo de este estudio es comparar la exposición al Tac analizado según ambas estrategias. Materiales y métodos: Se han incluido 425 pacientes trasplantados renales. El cálculo del cociente concentración Tac/dosis (C/D) permitió dividir la población en terciles y clasificar los pacientes según su tasa de metabolismo del Tac en tres grupos (rápida, intermedia y lenta). Con base en los polimorfismos del CYP3A4 y A5, los pacientes se agruparon en metabolizadores rápidos (portadores del CYP3A5*1 y CYP34A *1/*1), intermedios (CYP3A5*3/3 y CYP3A4*1/*1) y lentos (CYP3A5 *3/*3 y portadores del CYP3A4*22). Resultados: Al comparar los pacientes de cada grupo metabolizador según los dos criterios, coincidieron 47% (65/139) de los metabolizadores rápidos, 85% (125/146) de los intermedios y solo 12% (17/140) de los lentos. Se observaron concentraciones de Tac estadísticamente menores en los metabolizadores rápidos y concentraciones mayores en los lentos, comparándolos con el grupo intermedio según el cociente C/D o según polimorfismos. Los metabolizadores rápidos requirieron alrededor de 60% más de dosis de Tac que los intermedios a lo largo del seguimiento, mientras que los lentos aproximadamente 20% menos de dosis que los intermedios. Los metabolizadores rápidos clasificados por ambos criterios presentan un porcentaje mayor de veces con valores de concentración de Tac en sangre infraterapéuticos... (AU)

Background and justification: The strategy of the concentration–dose (C/D) approach and the different profiles of tacrolimus (Tac) according to the cytochrome P450 polymorphisms (CYPs) focus on the metabolism of Tac and are proposed as tools for the follow-up of transplant patients. The objective of this study is to analyse both strategies to confirm whether the stratification of patients according to the pharmacokinetic behaviour of C/D corresponds to the classification according to their CYP3A4/5 cluster metabolizer profile. Materials and methods: Four hundred and twenty-five kidney transplant patients who received Tac as immunosuppressive treatment have been included. The concentration/dose ratio (C/D) was used to divided patients in terciles and classify them according to their Tac metabolism rate (fast, intermediate, and slow). Based on CYP3A4 and A5 polymorphisms, patients were classified into three metabolizer groups: fast (CYP3A5*1 and CYP34A*1/*1 carriers), intermediate (CYP3A5*3/3 and CYP3A4*1/*1) and slow (CYP3A5*3/*3 and CYP3A4*22 carriers). Results: When comparing patients included in each metabolizer group according to C/D ratio, 47% (65/139) of the fast metabolizers, 85% (125/146) of the intermediate and only 12% (17/140) of the slow also fitted in the homonym genotype group. Statistically lower Tac concentrations were observed in the fast metabolizers group and higher Tac concentrations in the slow metabolizers when compared with the intermediate group both in C/D ratio and polymorphisms criteria. High metabolizers required approximately 60% more Tac doses than intermediates throughout follow-up, while poor metabolizers required approximately 20% fewer doses than intermediates. Fast metabolizers classified by both criteria presented a higher percentage of times with sub-therapeutic blood Tac concentration values... (AU)

Therapeutic drug monitoring in inflammatory bowel diseases. Position statement of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis. / Monitorización terapéutica de los fármacos biológicos en la enfermedad inflamatoria intestinal. Documento de Posicionamiento del Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU).

The treatment of inflammatory bowel disease has undergone a significant transformation following the introduction of biologic drugs. Thanks to these drugs, treatment goals have evolved from clinical response and remission to more ambitious objectives, such as endoscopic or radiologic remission. However, even though biologics are highly effective, a significant percentage of patients will not achieve an initial response or may lose it over time. We know that there is a direct relationship between the trough concentrations of the biologic and its therapeutic efficacy, with more demanding therapeutic goals requiring higher drug levels, and inadequate exposure being common. Therapeutic drug monitoring of biologic medications, along with pharmacokinetic models, provides us with the possibility of offering a personalized approach to treatment for patients with IBD. Over the past few years, relevant information has accumulated regarding its utility during or after induction, as well as in the maintenance of biologic treatment, in reactive or proactive strategies, and prior to withdrawal or treatment de-escalation. The aim of this document is to establish recommendations regarding the utility of therapeutic drug monitoring of biologics in patients with inflammatory bowel disease, in different clinical practice scenarios, and to identify areas where its utility is evident, promising, or controversial.

Modelo de atención farmacéutica en medicina de precision en China / Pharmaceutical care model in precision medicine in China

Pharmacy service is to provide individualized pharmaceutical care for patients, which should follow the current evidence-based pharmacy, and constantly verify the evidence and then produce new evidence. In pharmaceutical care, differences are often found in the efficacy and adverse reactions of drugs among individuals, even within individuals, which are closely related to patient's genetics, liver and kidney functions, disease states, and drug interactions. Back in the 1980s, therapeutic drug monitoring (TDM) has been applied to routinely monitor the blood drug concentration of patients taking antiepileptic drugs or immunosuppressants after transplantation to provide individualized dosage recommendations and accumulate a large amount of pharmacokinetic (PK)/pharmacodynamic (PD) data. As individualized pharmaceutical care proceeds, the concept of precision medicine was introduced into pharmacy services in combination with evidence-based pharmacy, PK/PD theories and big data to further promote the TDM technology and drugs, and carry out pharmacogenomics analysis. The TDM and pharmacogenomics have been applied gradually to the fields of antimicrobial, antitumor and antipsychotic drugs and immunosuppressants. Based on the concept of precision pharmacy, we adpoted approaches including PK/PD, quantitative pharmacology, population pharmacokinetics, and big data machine learning to provide more personalized pharmacy services, which is mainly for special patients, such as critical patients, patients with interaction risk of multiple drugs, patients with liver and renal insufficiency, pregnant women, children and elderly patients. As the service pattern of precision pharmacy has been constructed and constantly improved, better evidence in clinical practice will be produced to provide patients with better precision pharmacy service. (AU)

El servicio de farmacia se encarga de prestar atención farmacéutica personalizada a los pacientes. Los servicios de farmacia deben utilizar aquellas prácticas con mayor nivel de evidencia, y realizar una continua validación de dicha evidencia antes de elaborar nuevas prácticas. En la terapia farmacológica, se observan diferencias inter e intra individuales respecto a los efectos terapéuticos y a las reacciones adversas de los medicamentos, lo que está estrechamente relacionado con las variaciones genéticas, la función hepática y renal, el estado de la enfermedad y la interacción entre medicamentos. Desde la década de los 80 del siglo pasado, se utiliza la monitorización terapéutica de fármacos (MTF) de forma rutinaria para controlar las concentraciones sanguíneas de fármacos antiepilépticos o de inmunosupresores postrasplante y elaborar recomendaciones de dosis personalizadas y recoger una gran cantidad de datos farmacocinéticos (PC)/farmacodinámicos (PD). Con el desarrollo de la atención farmacéutica personalizada, el concepto de medicina de precisión se introduce en la atención farmacéutica, combinando la farmacia basada en evidencias, los enfoques PC/PD y los macrodatos (big data), promover técnicas de MTF en medicamentos, y la realización de análisis farmacogenómicos. La MTF y la farmacogenómica se están aplicando de forma gradual en el tratamiento con antimicrobianos, antitumorales, antipsicóticos e inmunosupresores. Sobre la base del concepto de farmacia de precisión, utilizamos métodos de PC/PD, farmacología cuantitativa, farmacocinética poblacional y aprendizaje automático con big data para ofrecer una atención farmacéutica más personalizada, principalmente a pacientes con necesidades especiales, como los pacientes en estado crítico, con riesgo de interacciones farmacológicas múltiples, pacientes con insuficiencia hepática y renal, mujeres embarazadas, niños y ancianos... (AU)

Pharmaceutical care model in precision medicine in China. / [Artículo traducido] Modelo de atención farmacéutica en medicina de precisión en China.

Pharmacy service is to provide individualized pharmaceutical care for patients, which should follow the current evidence-based pharmacy, and constantly verify the evidence and then produce new evidence. In pharmaceutical care, differences are often found in the efficacy and adverse reactions of drugs among individuals, even within individuals, which are closely related to patients' genetics, liver and kidney functions, disease states, and drug interactions. Back in the 1980s, therapeutic drug monitoring (TDM) has been applied to routinely monitor the blood drug concentration of patients taking antiepileptic drugs or immunosuppressants after transplantation to provide individualized dosage recommendations and accumulate a large amount of pharmacokinetic (PK)/pharmacodynamic (PD) data. As individualized pharmaceutical care proceeds, the concept of precision medicine was introduced into pharmacy services in combination with evidence-based pharmacy, PK/PD theories, and big data to further promote the TDM technology and drugs, and carry out pharmacogenomics analysis. The TDM and pharmacogenomics have been applied gradually to the fields of antimicrobial, antitumor, and antipsychotic drugs and immunosuppressants. Based on the concept of precision pharmacy, we adopted approaches including PK/PD, quantitative pharmacology, population pharmacokinetics, and big data machine learning to provide more personalized pharmacy services, which is mainly for special patients, such as critical patients, patients with interaction risk of multiple drugs, patients with liver and renal insufficiency, pregnant women, children, and elderly patients. As the service pattern of precision pharmacy has been constructed and constantly improved, better evidence in clinical practice will be produced to provide patients with better precision pharmacy service.

Pharmaceutical care model in precision medicine in China.

Pharmacy service is to provide individualized pharmaceutical care for patients, which should follow the current evidence-based pharmacy, and constantly verify the evidence and then produce new evidence. In pharmaceutical care, differences are often found in the efficacy and adverse reactions of drugs among individuals, even within individuals, which are closely related to patient's genetics, liver and kidney functions, disease states, and drug interactions. Back in the 1980s, therapeutic drug monitoring (TDM) has been applied to routinely monitor the blood drug concentration of patients taking antiepileptic drugs or immunosuppressants after transplantation to provide individualized dosage recommendations and accumulate a large amount of pharmacokinetic (PK)/pharmacodynamic (PD) data. As individualized pharmaceutical care proceeds, the concept of precision medicine was introduced into pharmacy services in combination with evidence-based pharmacy, PK/PD theories and big data to further promote the TDM technology and drugs, and carry out pharmacogenomics analysis. The TDM and pharmacogenomics have been applied gradually to the fields of antimicrobial, antitumor and antipsychotic drugs and immunosuppressants. Based on the concept of precision pharmacy, we adpoted approaches including PK/PD, quantitative pharmacology, population pharmacokinetics, and big data machine learning to provide more personalized pharmacy services, which is mainly for special patients, such as critical patients, patients with interaction risk of multiple drugs, patients with liver and renal insufficiency, pregnant women, children and elderly patients. As the service pattern of precision pharmacy has been constructed and constantly improved, better evidence in clinical practice will be produced to provide patients with better precision pharmacy service.

Dried Blood Spot (DBS) as a useful tool to improve clozapine, aripiprazole and paliperidone treatment: From adherence to efficiency.

INTRODUCTION: Therapeutic Drug Monitoring (TDM) of antipsychotics in schizophrenia is a powerful tool that allows tailoring the treatment in an individualized approach. Our goals are to develop and validate a Dried Blood Spot (DBS) method for monitoring some commonly used antipsychotics (aripiprazole, clozapine, and paliperidone) and to evaluate its usefulness as a compliance biomarker, as well as in drug-dose adjustment to personalize the antipsychotic treatment to improve its efficacy and safety. METHODS: 31 first-psychotic episode (FEP) and schizophrenia patients were included; 5 refer to naïve FEP who started antipsychotic treatment; 26, to patients with more than one episode and under antipsychotic treatment: aripiprazole (7 cases), clozapine (17), paliperidone (11). For DBS sample collection, 25µl of capillary blood were placed in the spot of a FTA™DMPK-C-card. After completely dryness, antipsychotics were extracted and analyzed by a validated UHPLC-MS/MS-method. DBS antipsychotic results were compared with those obtained in venous blood/plasma. RESULTS: Aripiprazole, paliperidone and clozapine showed from good to excellent correlations between concentrations in venous blood and DBS capillary blood (r2, from 0.500 to 0.721). The correlation between conventional plasma and DBS concentrations for paliperidone, aripiprazole, clozapine, and their metabolites were moderate, suggesting that optimal drug target concentrations should be established for DBS. CONCLUSIONS: In this study, for aripiprazole, dehydroaripiprazole, paliperidone, clozapine and desmethylclozapine, DBS has provided good analytical performance for TDM. Thus, DBS sampling can offer a great alternative over conventional sampling for plasma measurement. The assay provides good analytical performances for TDM and clinical research applicability, suggesting that DBS is a promising clinical application in TDM in psychiatry.

Valproate, obesity and other causes of clozapine poor metabolism in the context of rapid titration may explain clozapine-induced myocarditis: A re-analysis of a Turkish case series.

INTRODUCTION: Clozapine-induced myocarditis or any clozapine-induced inflammation may be a hypersensitivity reaction due to titration that was too rapid for the patient's clozapine metabolism. Clozapine metabolism is influenced by ancestry, sex, smoking and the presence of confounders including obesity, infections, and inhibitors (e.g., valproate) causing the patient to behave as a clozapine poor metabolizer (PM). A published study in a Turkish hospital identified 1 case of clozapine-induced pancreatitis and hepatitis and 9 cases of clozapine-induced myocarditis. To explore the hypothesis that the 10 patients were clozapine PMs, their serum clozapine concentrations were investigated using concentration-to-dose (C/D) ratios and their titrations carefully reviewed. METHODS: Dividing the trough serum concentration by the dose produces the clozapine C/D ratio. The dose required to reach 350ng/ml was considered the minimum therapeutic dosage and was used to classify patients according to clozapine PM status. Titration speed was assessed. RESULTS: All 10 patients were possibly clozapine PMs (3 of them had as minimum therapeutic doses: 72, 82 or 83mg/day). Nine of the 10 patients may have behaved as clozapine PMs due to obesity and/or valproate co-prescription during titration. One also had an undiagnosed infection. Of the 10 patients, 9 had at least 1 of 3 factors: too-rapid titration in the first or second weeks, or a final dosage that was too high. CONCLUSIONS: Future studies using clozapine levels and considering the role of clozapine PM status should explore whether or not all cases of clozapine-induced inflammation could be explained by lack of individualized titration.

Dried Blood Spot (DBS) as a useful tool to improve clozapine, aripiprazole and paliperidone treatment: From adherence to efficiency / Análisis de sangre seca (Dried Blood Spot [DBS]) como herramienta útil para mejorar el tratamiento con clozapina, aripiprazol y paliperidona: de la adherencia a la eficacia

Introduction: Therapeutic Drug Monitoring (TDM) of antipsychotics in schizophrenia is a powerful tool that allows tailoring the treatment in an individualized approach. Our goals are to develop and validate a Dried Blood Spot (DBS) method for monitoring some commonly used antipsychotics (aripiprazole, clozapine, and paliperidone) and to evaluate its usefulness as a compliance biomarker, as well as in drug-dose adjustment to personalize the antipsychotic treatment to improve its efficacy and safety. Methods: 31 first-psychotic episode (FEP) and schizophrenia patients were included; 5 refer to naïve FEP who started antipsychotic treatment; 26, to patients with more than one episode and under antipsychotic treatment: aripiprazole (7 cases), clozapine (17), paliperidone (11). For DBS sample collection, 25μl of capillary blood were placed in the spot of a FTA™DMPK-C-card. After completely dryness, antipsychotics were extracted and analyzed by a validated UHPLC-MS/MS-method. DBS antipsychotic results were compared with those obtained in venous blood/plasma. Results: Aripiprazole, paliperidone and clozapine showed from good to excellent correlations between concentrations in venous blood and DBS capillary blood (r2, from 0.500 to 0.721). The correlation between conventional plasma and DBS concentrations for paliperidone, aripiprazole, clozapine, and their metabolites were moderate, suggesting that optimal drug target concentrations should be established for DBS. (AU)

Introducción: La monitorización terapéutica de medicamentos (Therapeutic Drug Monitoring [TDM]) de los antipsicóticos en la esquizofrenia es una potente herramienta que permite adaptar el tratamiento de forma individualizada y personalizada. Los objetivos del presente estudio son desarrollar y validar un método de análisis en sangre seca (Dried Blood Spot [DBS]) para la monitorización de algunos antipsicóticos de uso común (aripiprazol, clozapina y paliperidona) y evaluar su utilidad como biomarcador de cumplimiento y adherencia terapéutica, así como en el ajuste de la dosis del fármaco para personalizar el tratamiento antipsicótico para mejorar su eficacia y su seguridad. Metodología: Se incluyeron 31 pacientes con un primer episodio psicótico (PEP) o un diagnóstico de esquizofrenia; 5 eran PEP que iniciaron tratamiento antipsicótico, y 26 eran pacientes con más de un episodio y que seguían tratamiento con antipsicóticos: aripiprazol (7 casos), clozapina (17), paliperidona (11). Para la recogida de muestras de DBS se colocaron 25μl de sangre capilar en el punto de una tarjeta FTATMDMPK-C. Tras secarse completamente, se extrajeron los antipsicóticos y se analizaron mediante un método UHPLC-MS/MS validado. Los resultados de los antipsicóticos según la DBS se compararon con los obtenidos en sangre venosa/plasma. Resultados: El aripiprazol, la paliperidona y la clozapina mostraron de buenas a excelentes correlaciones entre las concentraciones en sangre venosa y en sangre capilar del DBS (r2, de 0,500 a 0,721). La correlación entre las concentraciones plasmáticas convencionales y las del DBS para la paliperidona, el aripiprazol, la clozapina y sus metabolitos fue moderada, lo que sugiere que se deberían definir y establecer concentraciones óptimas del fármaco para el DBS. (AU)

Valproate, obesity and other causes of clozapine poor metabolism in the context of rapid titration may explain clozapine-induced myocarditis: A re-analysis of a Turkish case series / El valproato, la obesidad y otras causas de metabolismo deficiente de la clozapina en el contexto de una titulación rápida de las dosis pueden explicar la miocarditis inducida por clozapina: un nuevo análisis de una serie de casos turca

Introduction: Clozapine-induced myocarditis or any clozapine-induced inflammation may be a hypersensitivity reaction due to titration that was too rapid for the patient's clozapine metabolism. Clozapine metabolism is influenced by ancestry, sex, smoking and the presence of confounders including obesity, infections, and inhibitors (e.g., valproate) causing the patient to behave as a clozapine poor metabolizer (PM). A published study in a Turkish hospital identified 1 case of clozapine-induced pancreatitis and hepatitis and 9 cases of clozapine-induced myocarditis. To explore the hypothesis that the 10 patients were clozapine PMs, their serum clozapine concentrations were investigated using concentration-to-dose (C/D) ratios and their titrations carefully reviewed. Methods: Dividing the trough serum concentration by the dose produces the clozapine C/D ratio. The dose required to reach 350ng/ml was considered the minimum therapeutic dosage and was used to classify patients according to clozapine PM status. Titration speed was assessed. Results: All 10 patients were possibly clozapine PMs (3 of them had as minimum therapeutic doses: 72, 82 or 83mg/day). Nine of the 10 patients may have behaved as clozapine PMs due to obesity and/or valproate co-prescription during titration. One also had an undiagnosed infection. Of the 10 patients, 9 had at least 1 of 3 factors: too-rapid titration in the first or second weeks, or a final dosage that was too high. Conclusions: Future studies using clozapine levels and considering the role of clozapine PM status should explore whether or not all cases of clozapine-induced inflammation could be explained by lack of individualized titration. (AU)

Introducción: Cualquier inflamación inducida por la clozapina, incluida la miocarditis, podría ser una reacción de hipersensibilidad asociada a una titulación demasiado rápida de del fármaco para el metabolismo del paciente. El metabolismo de la clozapina está influenciado por la ascendencia, el sexo, el tabaquismo, y por la presencia de factores de confusión como obesidad, infecciones e inhibidores, como el valproato, que hacen que el paciente se comporte como un metabolizador lento (PM). Un estudio publicado identificó un caso de pancreatitis y hepatitis, y 9 casos de miocarditis inducidos por clozapina. Para explorar la hipótesis de que los 10 pacientes eran PM de clozapina, se investigaron sus concentraciones séricas de clozapina utilizando relaciones concentración/dosis (C/D) y revisando sus titulaciones. Métodos: La dosis necesaria para alcanzar 350ng/ml se consideró la dosis terapéutica mínima y clasificó a los pacientes según el estado de PM de clozapina. Se evaluó la velocidad de titulación. Resultados: Los 10 pacientes eran posiblemente PM de clozapina (3 tenían dosis terapéuticas mínimas: 72, 82 u 83mg/día). Nueve pacientes pueden haberse comportado como PM de clozapina debido a obesidad y/o prescripción conjunta de valproato durante la titulación. Uno también tenía una infección no diagnosticada. Nueve de los 10 pacientes tenían al menos uno de los 3 factores siguientes: titulación demasiado rápida en la primera o segunda semana, o una dosis final excesiva. Conclusiones: Futuros estudios que utilicen niveles de clozapina y consideren el PM deberían explorar si la inflamación inducida por clozapina podría explicarse por la falta de titulaciones individualizadas. (AU)

Evaluación de la dosificación de voriconazol intravenoso tres veces al día vs dos veces al día para el tratamiento de aspergilosis invasora en niños inmunocomprometidos: monitorización terapéutica y seguridad / Evaluation dosing intravenous voriconazole three times a day vs twice daily for the treatment of invasive aspergillosis in immunocompromised children: therapeutic drugs monitoring and safety

INTRODUCCIÓN: Voriconazol es el antifúngico de elección para el tratamiento de la aspergilosis invasora (AI). Concentraciones plasmáticas (CPs) > 1 μg/mL se han asociado a mejores resultados terapéuticos, las que no siempre se alcanzan durante el tratamiento en niños inmunocomprometidos. Dada la necesidad de iniciar una terapia precoz y efectiva de la infección, es relevante establecer el régimen de administración de voriconazol que se asocie con CPs óptimas en esta población. OBJETIVO: Comparar las CPs y seguridad de voriconazol intravenoso (IV), dosificado BID y TID en niños inmunocomprometidos con indicación de tratamiento antifúngico. MÉTODO: Estudio observacional retrospectivo de enero de 2015 a julio de 2018 en un hospital pediátrico de alta complejidad de Santiago de Chile, en pacientes de 0 a 17 años que recibieron tratamiento con voriconazol IV. Se excluyeron aquellos con terapia de reemplazo renal, falla hepática y/o falla renal. Se compararon las CPs valles entre un grupo con régimen de dosificación BID y otro grupo con administración TID. Se evaluaron las reacciones adversas en ambos grupos. RESULTADOS: Se obtuvieron 137 CPs valles en 76 niños, con una mediana de edad de 9 años (0-17 años) en el grupo BID y 9 años (0-16 años) en el grupo TID, con una mediana de peso de 27 kg (6-83 kg) y 28 kg (9,3-60 kg), respectivamente. Resultados: Pacientes 1 gg/mL en comparación con la administración BID (p = 0,001). Se reportaron ocho reacciones adversas, principalmente fotofobia, sin encontrarse diferencias significativas entre grupo BID y TID. CONCLUSIÓN: Dosificaciones TID están asociadas a una mayor probabilidad de obtener una adecuada exposición a voriconazol en pacientes < 12 años en comparación a dosificaciones BID, con baja frecuencia de reacciones adversas.

BACKGROUND: Voriconazole is the antifungal of choice for the treatment of invasive aspergillosis (IA). Plasma concentrations (PCs) > 1 μg / mL llave been associated with better therapeutic results which have not always been achieved during treatment in immunocompromised children. In the necessity to initiate early and effective therapy for the infection, it is relevant to establish the voriconazole administration regimen that is associated with optimal PCs in this population. AIM: To compare the PC and safety of intravenous (IV) voriconazole, dosed BID and TID in immunocompromised children with indication of antifungal treatment. METHOD: Retrospective observational study since January 2015 until July 2018 in a highly complex pediatric hospital in Santiago of Chile, in patients aged 0 to 17 years who received treatment with IV voriconazole. Those with renal replacement therapy, liver failure and / or renal failure were excluded. Trough PCs were compared between a group with BID dosing regimen versus another group with TID administration. Adverse reactions were evaluated in both groups. RESULTS: 137 trough PCs were obtained in 76 children, with a median age of 9 years (0-17 years) in the BID group and 9 years (0-16) in the TID group with a median weight of 27 kg (6-83 kg) and 28 kg (9.3-60 kg), respectively. Patients 1 gg/mL compared to BID administration (p = 0.001). Eight adverse reactions were reported, mainly photophobia, with no significant difference found between the BID and TID groups. CONCLUSION: TID dosages are associated with a greater probability of obtaining adequate exposure to voriconazole in patients < 12 years old compared to BID dosages, with a low frequency of adverse reactions.

Impacto del monitoreo terapéutico de vancomicina y amikacina en la optimización de dosis de antimicrobianos en pacientes pediátricos / Impact of the vancomycin and amikacin therapeutic monitoring in the optimization of antimicrobial dose in pediatric patients

INTRODUCCIÓN: La monitorización de antimicrobianos mediante sus concentraciones plasmáticas permite determinar la posología óptima de éstos, conducta esencial en pediatría. OBJETIVOS: Describir la monitorización de concentraciones plasmáticas de antimicrobianos y el ajuste de dosis en población pediátrica para determinar si las dosis utilizadas alcanzan rangos terapéuticos. PACIENTES Y MÉTODOS: Estudio descriptivo, retrospectivo, utilizando una base de datos con medición de concentraciones plasmáticas de amikacina y vancomicina en pacientes pediátricos del Hospital San Borja Arriarán, entre 2015-2018. Se determinó el número de pacientes que alcanzó rango terapéutico con dosis inicial, cuántos requirieron ajuste y sus características. RESULTADOS: Se monitorizó 104 concentraciones totales. Para vancomicina 65 concentraciones plasmáticas eran basales encontrándose fuera de rango terapéutico 56,5%; de los que requirieron ajuste, 25% fueron neonatos con mayor probabilidad de estar fuera de rango versus otros (p = 0,022). Para amikacina la Cpeak estuvo en rango en 60% de mediciones; 15,4% requirió ajuste incluyendo pacientes con fibrosis quística y oncológicos. No fue necesario efectuar ajustes en pacientes sin co-morbilidad. CONCLUSIÓN: La medición de concentraciones plasmáticas es necesaria para ajustar de forma individualizada la dosis, especialmente en pacientes pediátricos con fibrosis quística, oncológicos y en neonatología, donde es más probable no alcanzar rango terapéutico con las dosis iniciales.

BACKGROUND: The monitoring of antimicrobial therapy through plasma levels makes it possible to determine the optimal dosage of antimicrobials, an essential approach in pediatrics. AIM: To describe the monitoring of plasma antimicrobial levels and dose adjustment in the pediatric population to determine if the doses used reach therapeutic ranges. METHODS: Retrospective, descriptive study using a database with measurement of plasma levels of amikacin and vancomycin in pediatric patients at San Borja Arriarán Hospital between 2015-2018. The number of patients who reached the therapeutic range with the initial dose, how many required adjustment and their characteristics were determined. RESULTS: 104 total levels were monitored. For vancomycin 65 plasmatic levels were baseline, being outside the therapeutic range 56.5%; 25% of those requiring adjustment were neonates with a higher probability of being out of range versus others (p = 0.022). For amikacin, Cpeak was in range in 60% of measurements; 15.4% required adjustment, including patients with cystic fibrosis and cancer, without adjustments in patients without comorbidity. CONCLUSION: Measurement of plasma levels is necessary to individually adjust the dose, especially in pediatric patients with cystic fibrosis, oncology and in neonatology where it is more likely not to reach a therapeutic range with initial doses.

Farmacoterapia personalizada en oncología: Aplicación de criterios farmacocinéticos-farmacodinámicos / Personalized pharmacotherapy in oncology: Application of pharmacokinetic-pharmacodynamic criteria

Objetivo: La indicación de una farmacoterapia personalizada en oncología se sustenta en la selección del tratamiento óptimo (fármacos, dosis,vías y métodos de administración y duración) y en el método de ajuste dela dosis para alcanzar la máxima eficacia antineoplásica, expresada entérminos de remisión de la enfermedad o de tiempo libre de recaída, conuna toxicidad aceptable para el paciente. El objetivo de este trabajo esexplorar la contribución, en la personalización terapéutica en oncologíaclínica asistencial, de la monitorización terapéutica de las concentraciones plasmáticas y la aplicación de la información farmacocinética y farmacodinámica disponible para algunos fármacos ampliamente utilizados.Método: Se ha realizado una revisión bibliográfica no sistemática completa de los criterios farmacocinéticos y farmacodinámicos de los antineoplásicos, así como de los resultados derivados de su utilización en la prácticaclínica asistencial. En la búsqueda de artículos de alta calidad sobre lostemas planteados se han incluido fuentes bibliográficas primarias y secundarias. La utilidad de la monitorización terapéutica se ha centrado en fármacoscitotóxicos parenterales, antineoplásicos orales, anticuerpos monoclonales yotras terapias biológicas utilizadas en la práctica clínica asistencial.Resultados: La personalización terapéutica de fármacos antineoplásicos basada en la monitorización terapéutica de las concentraciones plasmáticas, y la información que proporcionan los modelos farmacocinéticos-farmacodinámicos, permite reducir la toxicidad y aumentar laefectividad asociada al tratamiento. (AU)

Objective: Indication of personalized pharmacotherapy in oncologicpatients is based on the selection of the optimal treatment (drugs, dosing,routes and methods of administration and duration) and on the mostappropriate dosing method to achieve maximum antineoplastic efficacy,expressed in terms of remission or relapse-free time and acceptable toxicity for the patients. The aim of this study was to explore the contribution oftherapeutic monitoring of plasma concentrations and of the applicationof the pharmacokinetic and pharmacodynamic information available forsome widely used drugs to therapeutic personalization to the care ofoncologic patients.Method: A complete non-systematic literature review was carried outof the pharmacokinetic and pharmacodynamic properties of antineoplastic agents, as well as of the results of their use in clinical practice.The search for high quality articles included primary and secondarybibliographic sources. The benefits of therapeutic monitoring wereevaluated for parenteral cytotoxic drugs, oral antineoplastic drugs,monoclonal antibodies and other biological therapies used in clinicalpractice.Results: Therapeutic personalization of antineoplastic drugs based ontherapeutic monitoring of plasma concentrations together with the information provided by pharmacokinetic-pharmacodynamic models makesit possible to reduce toxicity and increase the effectiveness of treatment.When personalized treatment is established with high-dose methotrexatein patients with osteosarcoma, target maximum concentrations are reached in 70% of the cycles (49% when fixed doses are used). When5-fluorouracil is used in patients with colorectal cancer, the responserate is 33.7% (18.3% with fixed doses). Similar benefit rates are obtained with asparaginase, busulfan, oral antineoplastics and monoclonalantibodies. (AU)

Modelos farmacocinéticos poblacionales de sirólimus en pacientes trasplantados renales: Revisión sistemática / Population pharmacokinetics models of sirolimus in renal transplant patients: A systematic review

Objetivo: Sirólimus es un fármaco utilizado en los esquemas terapéuticos inmunosupresores en pacientes con trasplante renal. La elevada variabilidad farmacocinética de sirólimus hace que la monitorización farmacocinética y la individualización posológica de la terapia inmunosupresorasea un proceso crucial para conseguir mejores resultados de eficacia. Ladisponibilidad de un modelo farmacocinético poblacional permite realizar un mejor ajuste farmacocinético de las concentraciones plasmáticasde sirólimus y así conseguir un mayor beneficio clínico.Método: Se realizó un análisis sistemático de la literatura disponible enlas bases de datos Medline, Embase y Scopus para identificar y posteriormente analizar los modelos farmacocinéticos poblacionales de sirólimusadministrado por vía oral en pacientes adultos con trasplante renal. Seutilizaron como descriptores MeSH: kidney transplantation, pharmacokinetic y sirolimus. De cada artículo seleccionado se evaluó: la poblacióna estudio, el esquema de tratamiento inmunosupresor, los tiempos demuestreo de las extracciones de sangre, las covariables analizadas, eltipo de modelo farmacocinético, el programa informático utilizado, losparámetros farmacocinéticos estimados, la variabilidad interindividual de los parámetros farmacocinéticos, la variabilidad residual y las ecuacionesmatemáticas del modelo farmacocinético.Resultados: Se obtuvieron un total de 548 resultados, excluyendo175 registros tras identificarse en más de una base de datos. Finalmentese seleccionaron siete artículos que cumplían los criterios de inclusión.La mayoría de los modelos farmacocinéticos encontrados siguen unmodelo bicompartimental. Covariables como edad, peso, función hepática, exposición y dosis de ciclosporina, dosis de sirólimus, polimorfismosgenéticos del CYP3A5, creatinina sérica y tratamiento concomitante explican la variabilidad interindividual de sirólimus. (AU)

Objective: Sirolimus is used in the immunosuppressive therapeutictreatment of kidney transplant patients. The high pharmacokinetic variability of sirolimus makes pharmacokinetic monitoring and dosage individualization of immunosuppressive therapy a key process to achieve betterefficacy results. The availability of a population pharmacokinetic modelcan be used to provide better pharmacokinetic adjustment of plasma concentrations of sirolimus and thus achieve greater clinical benefit.Method: We conducted a systematic review of the literature availablein the Medline, Embase, and Scopus databases to identify and subsequently analyze population pharmacokinetic models of orally administered sirolimus in adult patients after kidney transplant. The descriptorsused MeSH were kidney transplantation, pharmacokinetics, and sirolimus.The following variables from the selected studies were assessed: studypopulation, immunosuppressive treatment, blood sampling times, covariates analyzed, type of pharmacokinetic model, computer software used,estimated pharmacokinetic parameters, interindividual variability of pharmacokinetic parameters, residual variability and mathematical equationsof the pharmacokinetic model. Results: A total of 548 results were obtained, excluding 175 records thatwere identified in more than one database. Finally, seven articles that met theinclusion criteria were selected. Most of the pharmacokinetic models foundfit a two-compartment model. The interindividual variability of sirolimus wasexplained by covariates such as age, weight, liver function, cyclosporineexposure and dose, sirolimus doses, CYP3A5 genetic polymorphisms, serumcreatinine, and concomitant treatment. (AU)

Software de contenido farmacocinético para la monitorización terapéutica de fármacos: Protocolo de revisión exploratoria / Pharmacokinetic software for therapeutic drug monitoring: A scoping review protoco

Objetivo: Los nomogramas, ecuaciones y software de contenido farmacocinético se consideran las principales herramientas disponibles para la monitorización farmacocinética clínica. Debido a su gran aplicabilidad en numerososgrupos de fármacos, el empleo de software se encuentra ampliamente extendido en la práctica clínica. Generalmente, el objetivo principal de los estudiosque incluyen el uso de estos software no es la descripción de los mismos, porlo que la información disponible es escasa y, además, no se dispone de unarevisión que aúne toda la información disponible referente a este tipo de softwareEl objetivo de este estudio será sintetizar la evidencia disponible sobre losdistintos software de aplicación en la monitorización farmacocinética parafacilitar a los usuarios su identificación, evaluación y selección.Método: Se realizará una revisión exploratoria de la literatura cuyo protocolo se describe en este artículo, de acuerdo con las recomendacionesPRISMA para la elaboración de revisiones exploratorias y publicaciónde protocolos. Se realizará una búsqueda bibliográfica en las bases dedatos Medline, Embase, OpenAire y Bielefeld Academic Search Engine.Se incluirán en el estudio aquellos software detectados de los que se disponga de la siguiente información: nombre del software, desarrollador/comercializador, tipo de análisis farmacocinético y fármacos incluidos.Resultados: En este estudio se espera realizar una síntesis de lascaracterísticas más relevantes en la práctica clínica de los software decontenido farmacocinético disponibles en el mercado. Se realizará una síntesis narrativa crítica de las fuentes de información utilizadas. Además,se llevará a cabo, si es posible, una comparación de los mismos parafacilitar la evaluación y selección por parte de los usuarios. (AU)

Objective: Nomograms, equations and pharmacokinetic software areconsidered the main tools available for therapeutic drug monitoring. Dueto its great applicability to various groups of drugs, the use of software iswidely extended in clinical practice. The main goals of the studies usingthis type of software do not normally include the description of its features,therefore, the information about its characteristic is scarce. Moreover, noreview of the literature has been published that brings together all theinformation available about these software. The present study aimed tosynthesize the available evidence regarding software applied to therapeutic drug monitoring to facilitate its identification, evaluation and selectionby users.Method: This article describe a scoping review protocol, developedfollowing the PRISMA-P and PRISMA-ScR guidelines. An electronic literature search was performed in MEDLINE, EMBASE, OpenAire and BASE(Bielefeld Academic Search Engine) databases. Only those software forwhich the following information was available were included: name of thesoftware, developer/marketer, type of pharmacokinetic analysis allowed,and drugs included in the analysis.Results: In this study we will synthesized the most relevant characteristics for the clinical practice of the pharmacokinetic software available.A critical appraisal of the sources if information will be included. Also,if it is possible, a comparison of the available tools will be carried out in order to facilitate the evaluation and selection of pharmacokineticsoftware. (AU)

Relación entre niveles plasmáticos de efavirenz y alteraciones lipémicas / Efavirenz plasma levels and dyslipidemia

El objetivo del presente trabajo es evaluar si existe relación entre los niveles plasmáticos de efavirenz y la aparición de dislipemia como hipercolesterolemia, hipretrigliceridemia o aumento de LDL-c.Se realizaron niveles plasmáticos de efavirenz a los pacientes en tratamiento con este fármaco desde septiembre de 2012 hasta junio de 2015. Se registraron los parámetros lipídicos correspondientes a cada analítica. Las determinaciones de efavirenz se realizaron mediante cromatografía líquida de alta eficacia. Los datos se manejaron mediante el programa Quick Statistics Calculator y Excel 2007.Los niveles plasmáticos de efavirenz superiores a 4.000 ng/ml se asocian en nuestro estudio con una mayor frecuencia de niveles de colesterol superiores a 200 mg/dl.Este estudio puede ser de utilidad para aquellas zonas en las que usen pautas de tratamiento con este fármaco de manera frecuente. (AU)

The aim of this study is to evaluate if there is a relationship between plasma levels of efavirenz and the occurrence of dyslipidemia such as hypercholesterolemia, hypretrigiceridemia or increased LDL-c.Plasma levels of efavirenz were performed to patients under treatment with this drug during the period from September 2012 to June 2015. Lipid parameters corresponding to each analytical were recorded. Determinations of efavirenz were analyzed by high performance liquid chromatography. Data were managed using the Quick Statistics Calculator and Excel 2007 program.Plasma levels of efavirenz higher than 4,000 ng/ml were associated, in our study, with a higher frequency of cholesterol levels higher than 200 mg/dl.This study may be useful to those areas where treatment guidelines with this drug are used on a frequent basis. (AU)

Carbohydrate antigen 125 in heart failure. New era in the monitoring and control of treatment. / Antígeno carbohidrato 125 en insuficiencia cardiaca. Nueva era en la monitorización y control del tratamiento.

In recent years, we have seen a great interest in the search for new biomarkers in heart failure (HF), fundamentally in the field of diagnosis, prognosis, monitoring and as a therapeutic guide. However, most of them do not meet the required criteria for daily clinical practice. The carbohydrate antigen 125 (CA 125) is the mucin 16 glycoprotein (MUC16) antibody, and its use has been restricted to the therapeutic monitoring of ovarian cancer; however, its elevation is confirmed in other non-tumour processes such as HF. In this last scenario, CA 125 is synthesised by serous epithelial cells in response to congestion and/or inflammatory stimuli. In recent years, increasing evidence has emerged suggesting that plasma levels of this glycoprotein could be useful as a biomarker in HF. CA 125 levels correlate with clinical, haemodynamic and echocardiographic parameters related to the severity of the disease, as well as being independently associated with mortality or readmission due to HF. From the clinical perspective, CA 125 provides information on the degree of extravascular congestion present in HF. Recent evidence consistently shows that its kinetics after admission due to decompensation offer an excellent predictive capacity for adverse events and to guide treatment, mainly diuretic. These qualities make it an ideal candidate for use in evolutionary monitoring and to guide depletive treatment in HF.

Farmacocinética de posaconazol en la profilaxis y tratamiento de la infección fúngica invasora en niños inmunocomprometidos en un hospital pediátrico / Pharmacokinetics of posaconazol in the prophylaxis and treatment of invasive fungal infection in immunocompromised children in a pediatric hospital

Resumen Introducción En pediatría no existe consenso en la dosificación de posaconazol (PSC) para profilaxis y tratamiento de la infección fúngica invasora (IFI), usándose la medición de concentraciones plasmáticas (CPs) del fármaco. Objetivo Describir la experiencia de monitoreo de las CPs de PSC en niños inmunocomprometidos con IFI y determinar si las dosis recomendadas alcanzan CPs efectivas en profilaxis (≥ 0,7 µg/mL) y tratamiento (≥ 1,25 µg/mL). Método Análisis retrospectivo en niños que recibieron PSC suspensión como profilaxis o tratamiento entre enero de 2012 y octubre de 2016, en las unidades de Oncología y Trasplante de Médula Ósea del Hospital Calvo Mackenna. Resultados 78 CPs en seis pacientes (4 indicaciones de profilaxis y 4 tratamientos) fueron revisados. La mediana de dosis de PSC fue de 12,5 y 18,8 mg/kg/d para profilaxis y tratamiento, respectivamente, resultando CP mediana de 0,97 y 1,8 μg/mL, respectivamente. En profilaxis, se registraron 40/67 (60%) con CP ≥ 0,70 μg/mL recibiendo una mediana de dosis de 12,5 mg/kg/d. Mientras que para el tratamiento: 5/11 (46%), presentaron CP ≥ 1,25 μg/mL, recibiendo una mediana de dosis de 18 mg/kg/d. Conclusión Nuestros resultados se ajustan a lo recomendado para la dosificación de PSC, pero evidencian una necesidad de realizar una monitorización individualizada para mantener adecuadas CPs.

Background There is no consensus on the optimal dosage use of posaconazole (PSC) for invasive fungal infection (IFI) in pediatric patients and normally it is adjusted with drug levels (DLs) ≥ 0.7 μg/ml and ≥ 1.25 μg/ml for prophylaxis and treatment, respectively. Objective To describe the experience of monitoring DLs of PSC in immunocompromised pediatric patients with IFI and to determine if the recommended doses reach CP effective in prophylaxis (≥ 0.7 μg/mL) and treatment (≥ 1.25 μg/mL). Method A retrospective analysis in children who received PSC from January 2012 to October 2016, in the Oncology and Bone Marrow Transplant units at Hospital Calvo Mackenna was done Six patients with 78 DLs were reviewed (4 prophylaxis and 4 treatment). Median PSC dose was 12.5 and 18.8 mg/kg/d for prophylaxis and treatment, resulting in mean DLs of 0.97 and 1.8 μg/mL respectively. In prophylaxis 40/67 (60%) were recorded with DLs ≥ 0.70 μg/mL receiving a median dose of 12.5 mg/kg/d. While for treatment: 5/11 (46%) presented DLs ≥ 1.25 μg/mL, receiving a median dose of 18 mg/kg/d. Conclusion Our results are in line with the recommended for PSC dosage, but individualized monitoring is required to maintain adequate DLs.

[Standardisation and validation of an HPLC method for determining serum posaconazole levels in Colombia]. / Estandarización y validación en Colombia de una metodología basada en HPLC para la determinación de la concentración sérica de posaconazol.

BACKGROUND: Colombia currently does not have a specialised service for measuring antifungal levels in serum, which is of prime importance for the proper treatment and correct management of invasive fungal infections. AIMS: To standardise and validate a simple, sensitive, and specific protocol, based on high performance liquid chromatography, complying with the parameters recommended by the Food and Drug Administration, to detect, identify, and quantify serum concentrations of posaconazole. METHODS: A high performance liquid chromatography Agilent series-1 200 equipment was used with ultraviolet diode array detector and analytical column-Eclipse XDB-C18. Posaconazole-SCH56592 (batch IRQ-PAZ-10-X-103) was used as the primary control and itraconazole (batch ZR051211PUC921) was used as an internal control. The validation was performed taking into account all criteria recommended by the Food and Drug Administration (selectivity, calibration curves, recovery, accuracy, precision, sensitivity, reproducibility, and stability of the sample). RESULTS: The most suitable chromatographic conditions were the following: column temperature 25°C, ultraviolet detection at 261nm, 50µl injection volume, flow volume 0.8ml/min, 10min running time, mobile phase of acetonitrile:water (70:30), and final retention times of 3.4 and 7.2min for posaconazole and itraconazole, respectively, with a wide and reliable quantification range (0.125µg/ml to 16µg/ml). Using these parameters, the method was selective, R2 in the calibration curves was≥0.99, and the percentage recovery was 98.7%, with a coefficient of variation less than 10%. The relative error for accuracy and the coefficient of variation for precision were less than 15%, all meeting the acceptance criteria recommended by the Food and Drug Administration. CONCLUSIONS: The selectivity and chromatographic purity of the obtained signal, as well as the standardised limits of detection and quantification, make this method an excellent tool for therapeutic monitoring of patients treated with posaconazole.