Validación de cuestionarios para la medición de variables en salud: conceptos fundamentales / Validation of questionnaires for the measurement of health variables: Fundamental concepts

Dentro de la práctica clínica, así como en la salud poblacional, es habitual utilizar cuestionarios que permiten evaluar condiciones o variables que no son directamente observables. No obstante, la construcción y validación de estos instrumentos o cuestionarios suele ser poco conocida. El objetivo de esta revisión narrativa es sintetizar de manera general el proceso de construcción y validación de estos cuestionarios, para así tener una mejor comprensión de este proceso, de los aspectos que se evalúan y de la mejor forma de utilizarlos. La validación de cuestionarios corresponde a un proceso de análisis de este, cuya finalidad es medir una variable latente o constructo, así como sus dimensiones, las que no pueden ser observadas directamente. Una variable latente puede ser inferida a través de un conjunto de atributos específicos que forman parte de ella, como los ítems de un cuestionario y que sí son observables. En este artículo se abordan de manera teórica los conceptos fundamentales de validación de cuestionarios o test, variables latentes o constructos, estudio de la confiabilidad y de la validez, así como los factores que afectan a estas dos últimas características, a través de una revisión narrativa. En el texto, se presentan ejemplos sobre estos conceptos.

In clinical practice and population health, it is common to use questionnaires to assess conditions or variables that are not directly observable. However, the construction and validation of these instruments or questionnaires are often poorly understood. This narrative review aims to summarize in a general way the process of construction and validation of these questionnaires in order to have a better understanding of this process, the aspects that are evaluated, and the best way to use them. The validation of questionnaires corresponds to a process of analysis of the questionnaire, aiming to measure a latent variable and its dimensions, which cannot be observed directly. A latent variable can be inferred through a set of specific attributes that are part of it, such as the items of a questionnaire, which are observable. Through a narrative review, this article addresses the fundamental concepts of questionnaire or test validation, latent variables or constructs, reliability and validity studies, and the factors that theoretically affect the latter two characteristics. Examples of these concepts are presented in the text.

Validation of questionnaires for the measurement of health variables: Fundamental concepts. / Validación de cuestionarios para la medición de variables en salud: conceptos fundamentales.

In clinical practice and population health, it is common to use questionnaires to assess conditions or variables that are not directly observable. However, the construction and validation of these instruments or questionnaires are often poorly understood. This narrative review aims to summarize in a general way the process of construction and validation of these questionnaires in order to have a better understanding of this process, the aspects that are evaluated, and the best way to use them. The validation of questionnaires corresponds to a process of analysis of the questionnaire, aiming to measure a latent variable and its dimensions, which cannot be observed directly. A latent variable can be inferred through a set of specific attributes that are part of it, such as the items of a questionnaire, which are observable. Through a narrative review, this article addresses the fundamental concepts of questionnaire or test validation, latent variables or constructs, reliability and validity studies, and the factors that theoretically affect the latter two characteristics. Examples of these concepts are presented in the text.

Dentro de la práctica clínica, así como en la salud poblacional, es habitual utilizar cuestionarios que permiten evaluar condiciones o variables que no son directamente observables. No obstante, la construcción y validación de estos instrumentos o cuestionarios suele ser poco conocida. El objetivo de esta revisión narrativa es sintetizar de manera general el proceso de construcción y validación de estos cuestionarios, para así tener una mejor comprensión de este proceso, de los aspectos que se evalúan y de la mejor forma de utilizarlos. La validación de cuestionarios corresponde a un proceso de análisis de este, cuya finalidad es medir una variable latente o constructo, así como sus dimensiones, las que no pueden ser observadas directamente. Una variable latente puede ser inferida a través de un conjunto de atributos específicos que forman parte de ella, como los ítems de un cuestionario y que sí son observables. En este artículo se abordan de manera teórica los conceptos fundamentales de validación de cuestionarios o test, variables latentes o constructos, estudio de la confiabilidad y de la validez, así como los factores que afectan a estas dos últimas características, a través de una revisión narrativa. En el texto, se presentan ejemplos sobre estos conceptos.

Feasibility of steroid-free tacrolimus-basiliximab immunosuppression in pediatric liver transplantation and predictors for steroid requirement.

Avoidance of steroids in pediatric liver transplantation may reduce toxicity and morbidity. The aim of this study was to analyze the feasibility of a steroid-free tacrolimus-basiliximab immunosuppression scheme, the risk factors associated with steroid requirement, and safety parameters. Patients who underwent liver transplantation for biliary atresia between 2011 and 2019 were included and followed for 6 months after transplantation. Immunosuppression consisted of tacrolimus-based treatment with basiliximab induction. Steroid-free survival was estimated, and risk factors for steroid requirement were evaluated using multivariate Cox regression analysis. A total of 76 patients were included, of whom 42 (55.3%) required steroids (>14 d) due to biopsy-proven acute rejection (47.6%, n = 20), instability in liver function tests (35.7%, n = 15), tacrolimus-related adverse drug reactions (14.3%, n = 6), or other reasons (bronchospasm episode, n = 1). Steroid-free survival was 45.9% (95% CI, 35.9-58.8). Independent factors associated with steroid requirement included tortuosity in tacrolimus trough levels (≥1.76 vs. <1.76: HR 5.8, 95% CI, 2.6-12.7; p < 0.001) and mean tacrolimus trough levels (≥ 6.4 ng/mL vs. < 6.4 ng/mL: HR 0.4, 95% CI, 0.2-0.7; p = 0.002). The rate of bacterial and viral infections was comparable between patients with and without steroids, although in the former group, cytomegalovirus infection developed earlier ( p = 0.03). Patients receiving steroids had higher total cholesterol, LDL, and HDL levels ( p < 0.05) during follow-up, but no changes in the height Z-score were observed 1 year after transplantation. Basiliximab induction in combination with tacrolimus-based treatment avoided steroid requirements in 45% of the patients. Tacrolimus variability and trough levels below 6.4 ng/mL independently increased the risk of steroid requirement. Further efforts should be focused on personalizing immunosuppressive treatment.

Population Pharmacodynamic Modelling of the CD19+ Suppression Effects of Rituximab in Paediatric Patients with Neurological and Autoimmune Diseases.

BACKGROUND: Limited pharmacotherapy and the failure of conventional treatments in complex pathologies in children lead to increased off-label use of rituximab. We aimed to characterize the time course of CD19+ B lymphocytes (CD19+) under treatment with intravenous rituximab in children with neurologic and autoimmune diseases and to evaluate the impact of covariates (i.e., demographics, diagnosis and substitution between innovator and biosimilar product) on rituximab pharmacodynamics and disease activity. METHODS: Pre- and post-drug infusion CD19+ in peripheral blood were prospectively registered. A population pharmacodynamic model describing the time course of CD19+ was developed with NONMEM v7.4. Simulations of three different rituximab regimens were performed to assess the impact on CD19+. Logistic regression analysis was performed to identify predictors of clinical response recorded through disease activity scores. RESULTS: 281 measurements of CD19+ lymphocyte counts obtained from 63 children with neurologic (n = 36) and autoimmune (n = 27) diseases were available. The time course of CD19+ was described with a turn-over model in which the balance between synthesis and degradation rates is disrupted by rituximab, increasing the latter process. The model predicts half-lives (percent coefficient of variation, CV(%)) of rituximab and CD19+ of 11.6 days (17%) and 173.3 days (22%), respectively. No statistically significant effect was found between any of the studied covariates and model parameters (p > 0.05). Simulations of different regimens showed no clinically significant differences in terms of CD19+ repopulation times. A trend towards a lack of clinical response was observed in patients with lower CD19+ repopulation times and higher areas under the CD19+ versus time curve. CONCLUSIONS: Rituximab pharmacodynamics was described in a real-world setting in children suffering from autoimmune and neurologic diseases. Diagnosis, substitution between innovator rituximab and its biosimilars or type of regimen did not affect rituximab-induced depletion of CD19+ nor the clinical response in this cohort of patients. According to this study, rituximab frequency and dosage may be chosen based on clinical convenience or safety reasons without affecting CD19+ repopulation times. Further studies in larger populations are required to confirm these results.

Population pharmacokinetics of sublingually administered tacrolimus in infants and young children with liver transplantation.

AIMS: Pharmacokinetics of tacrolimus after sublingual administration is not characterized in paediatric liver transplant patients. Therefore, we aimed to develop a population pharmacokinetic model of sublingually administered tacrolimus in patients who cannot swallow the capsules due to their age, sedation status and/or mechanical ventilation during the first weeks post-transplantation. METHODS: Demographic, clinical and pharmacological variables, including tacrolimus whole blood concentrations obtained from therapeutic drug monitoring and data from dense-sampling pharmacokinetic profiles, were recorded in 26 paediatric patients with biliary atresia who underwent liver transplantation between 2016 and 2021. Population pharmacokinetic analysis was performed with NONMEM v7.4. RESULTS: Disposition of tacrolimus was best characterized by a 2-compartment model with clearance achieving half of the maximum elimination capacity (CLMAX  = 4.1 L/h) at 4.6 days post-transplantation (T50 ). Compared to sedated patients, nonsedated status showed an increased first-order absorption rate constant (1.1 vs. 0.1 h-1 ) and a 24% reduction in bioavailability (FNS ) at 14 days post-transplant. The model was able to explain the oral absorption pattern in nonsedated patients as the result of gut bioavailability (0.9) and hepatic extraction ratio, with the latter being responsible for first-pass effects. Estimates of interindividual variability remained moderate (25.9% for the gut bioavailability) to high (79.8% for the apparent volume of distribution of the central compartment, and 101% for T50 ). CONCLUSION: A population pharmacokinetic model of sublingually administered tacrolimus in paediatric patients was developed to characterize different absorption mechanisms. Once the model is externally validated, the effect of post-transplant time on clearance and the sedation status may be considered in routine dosing management.

[Performance evaluation of a precision dosing service for vancomycin in a tertiary level pediatric hospital]. / Una evaluación de desempeño del servicio de dosificación de precisión para vancomicina en un hospital pediátrico de nivel terciario.

Background: Plasma level-based therapeutic drug monitoring of vancomycin is recommended in the treatment of complex pediatric infections in order to increase the probability of achieving safe and effective pharmacotherapy. Objective: To retrospectively evaluate the activities and performance of pharmacotherapeutic optimization based on vancomycin levels at a tertiary pediatric hospital between 2007 and 2020. Métodos: Vancomycin levels of pediatric patients were analyzed, assessing care quality indicators and analytical verifications, as well as aspects related to teaching and research. The predictive performance of vancomycin levels was evaluated after adjustment of the therapeutic regimen using a population pharmacokinetic optimization program (BestDose v1.126) considering the coefficient of determination (R2), the mean absolute percentage error (MAPE), and the root mean square error (RMSE). Results: 13269 vancomycin level determinations were analyzed; 70% were trough levels and 81% belonged to patients in the intensive care units. Forty percent of the trough levels were within the therapeutic range when adjusted without software. Three hundred seventy-four pharmacotherapeutic interventions, of which 97% were accepted by the treating physician; 75% of the post-adjustment trough levels were within the therapeutic range, compared to 40% when the approach was empirical, a difference that was statistically significant (p=0.03). The values associated with predictive performance (n subgroup of patients = 91) were: R2=0.61, MAPE=28.16%, and RMSE=3.3, which all showed to be adequate. Conclusion: The performance of therapeutic vancomycin monitoring and related pharmacokinetic clinical activities showed to be good.

Introducción: La dosificación de precisión a través del monitoreo de vancomicina basado en sus concentraciones plasmáticas (vancocinemia) es una práctica recomendada en el tratamiento de infecciones pediátricas de alta complejidad para aumentar la probabilidad de lograr una farmacoterapia segura y eficaz. Objetivo: Evaluar retrospectivamente las actividades y el desempeño relacionado a la optimización farmacoterapéutica basada en las vancocinemias (período 2007-2020) de un hospital pediátrico terciario. Métodos: Se analizaron las vancocinemias de pacientes pediátricos, estimándose indicadores de calidad asistencial y verificaciones analíticas, así como también aspectos relacionados a docencia e investigación. Se evaluó el desempeño predictivo de las concentraciones de vancomicina cuando se ajustaron los regímenes terapéuticos con un programa de optimización farmacocinética (BestDose v1.126) considerando el coeficiente de determinación (R2), el error porcentual absoluto medio (MAPE) y la raíz del error cuadrático medio (RMSE). Resultados: Se analizaron 13269 vancocinemias. El 70% fueron valles y el 81% pertenecieron a pacientes de Unidades de Cuidados Intensivos. El 40% de los valles se encontró dentro del margen terapéutico al ajustarse sin programa informático. Se realizaron 347 intervenciones farmacoterapéuticas, el 97% de las cuales fueron aceptadas por el médico tratante; el 75% de los valles posteriores al ajuste entraron en el margen terapéutico, valor significativamente mayor respecto al 40% de cuando el abordaje fue empírico (p=0.03). Los valores asociados al desempeño predictivo, (n subgrupo de pacientes = 91) fueron: R2=0.61, MAPE=28.16% y RMSE=3.3, mostrándose todos adecuados. Conclusión: Las actividades de monitoreo y farmacocinética clínica de vancomicina mostraron un buen rendimiento clínico. Resultados: Se analizaron 13269 vancocinemias. El 70% fueron valles y el 81% pertenecieron a pacientes de Unidades de Cuidados Intensivos. El 40% de los valles se encontró dentro del margen terapéutico al ajustarse sin programa informático. Se realizaron 347 intervenciones farmacoterapéuticas, el 97% de las cuales fueron aceptadas por el médico tratante; el 75% de los valles posteriores al ajuste entraron en el margen terapéutico, valor significativamente mayor respecto al 40% de cuando el abordaje fue empírico (p=0.03). Los valores asociados al desempeño predictivo, (n subgrupo de pacientes = 91) fueron: R2=0.61, MAPE=28.16% y RMSE=3.3, mostrándose todos adecuados. Conclusión: Las actividades de monitoreo y farmacocinética clínica de vancomicina mostraron un buen rendimiento clínico.

Intensive Safety Monitoring of Rituximab (Biosimilar Novex® and the Innovator) in Pediatric Patients With Complex Diseases.

Although rituximab is widely used off-label for complex pediatric diseases, safety reports are limited. We aimed to report evidence of its use in clinical practice, to describe the incidence of adverse drug reactions (ADR) to rituximab biosimilar Novex® and innovator, and to identify risk factors for the development of ADR in a real-life follow-up cohort of pediatric patients with complex diseases. We conducted a prospective, longitudinal, observational, single-centre study in patients that received rituximab for any complex disease, and as part of an intensive pharmacovigilance program. Demographic, pharmacological, clinical, and drug-related data were collected for all patients. ADR-free survival, including infusion-related reactions (IRR) and delayed ADR (dADR), was estimated using Kaplan-Meier curves. Risk factors were evaluated by multivariable Cox regression models. In total, 77 patients (<19 y.o.) received 187 infusions of rituximab Novex® (n = 155) or innovator rituximab (n = 32) for neurologic (Neu), immune-hematologic-rheumatic (IHR), oncologic (O) diseases, and hematopoietic stem-cell transplantation (HSCT) or solid-organ transplantation (SOT). We recorded 29 IRR and 58 dADR that occurred in 27 (35.1%) and 29 (37.7%) patients, respectively. The respiratory tract was the most affected during IRR (29.6%) and hypogammaglobulinemia (37.9 %) was the most frequent dADR. First versus subsequent infusions (HR 5.4, CI95% 2.4-12.1, p<0.05), sex (boys vs. girls, HR 0.3, CI95% 0.1-0.8, and p<0.05), and diagnosis (Neu-IHR diseases vs. O-HSCT-SOT, HR 2.3, CI95% 1.02-5.4, and p < 0.05) were significantly associated with the development of IRR. For dADR, risk factors were diagnosis (Neu-IHR diseases vs. O-HSCT-SOT, HR 0.4, CI95% 0.2-0.9, and p < 0.05) and cumulative body surface area-normalized dosage (HR 1.0003, CI95% 1.0001-1.0006, and p < 0.05). The present is the largest real-world safety assessment of rituximab in Latin-American children with complex diseases supporting its use based on the overall acceptable safety. Identification of risk factors may contribute to optimization of off-label rituximab treatment in pediatrics.

Pre-procedural antibody testing for SARS-CoV-2 in the routine endoscopic practice.

METHODS: a retrospective multicenter cohort study was performed of all endoscopic procedures performed between April 27 and June 15, 2020. A screening questionnaire (SQ) was performed with patients three days prior to the procedure and 14 days after. Furthermore, a serologic SARS-CoV-2 test was performed 48 hours before. RESULTS: two hundred and eleven consecutive patients with endoscopic procedures were included. No patients had a positive SQ, either on entry to the study or 14 days later. Only four patients (1.9 % [95 % CI: 0.07-4.8 %]) were positive for antibodies. CONCLUSION: the pre-endoscopy seroprevalence of SARS-CoV-2 is low in this cohort. Pre-procedural SARS-CoV-2 antibody testing does not add any benefit over clinical SQ to identify active COVID-19 patients.

Pharmacokinetics of cannabidiol in children with refractory epileptic encephalopathy.

Growing interest in the clinical use of cannabidiol (CBD) as adjuvant therapy for pediatric refractory epileptic encephalopathy emphasizes the need for drug treatment optimization. The aim of this study was to characterize the pharmacokinetics of CBD in pediatric patients with refractory epileptic encephalopathy receiving an oil-based oral solution. To evaluate CBD concentrations, six serial blood samples per patient were collected after the morning dose of CBD, at least 21 days after the beginning of treatment. Twelve patients who received a median (range) dose of 12.2 (5.3-19.4) mg/kg/d (twice daily) were included in the analysis. Median (range) CBD time to maximum plasma concentration, maximum plasma concentration, and area under the concentration versus time curve up to 6 hours after dosing were 3.2 hours (1.9-6.2), 49.6 ng/mL (14.4-302.0), and 226.3 ng ⋅ h/mL (70.5-861.3), respectively. CBD systemic exposure parameters were in the lower range of previous reports in pediatric patients receiving doses in a similar range. Most of our patients (83%) showed little CBD plasma level fluctuation during a dosing interval, comparable to that encountered after oral administration of an extended release drug delivery system. CDB administration was generally safe and well tolerated, and a novel levothyroxine-CBD interaction was recorded. Similar to other studies, large interindividual variability in CBD exposure was observed, encouraging the use of CBD therapeutic drug monitoring.

Clinical pharmacology of cannabidiol in refractory epilepsy.

OBJECTIVE: The aim of this article is to provide a systematic and updated review  on the pharmacology of cannabidiol in the context of refractory epilepsy, with  special emphasis on its pharmacokinetics, adverse drug reactions and drug-drug interactions. METHOD: A review of the literature related to cannabidiol pharmacokinetics, adverse drug reactions and drug-drug interactions was  carried out in the context of refractory epilepsy, through a search in PubMed and LILACS. RESULTS: Original studies that exhaustively describe the pharmacokinetics of  cannabidiol are limited but informative. Cannabidiol is rapidly absorbed and its  bioavailability increases when administered with high fat meals. Cannabidiol  exhibits a linear pharmacokinetic profile for doses up to 3,000 mg/day and  accumulates after multiple administrations. Elimination half-life has been  reported between 14 h and 60 h depending on the sampling times of each  study; changes in cannabidiol elimination due to continuous administration  cannot be discarded. Of all reported drugdrug interactions with anticonvulsants  or other co-administered drugs in patients with epilepsy, the strongest evidence  is provided with clobazam. The most frequent cannabidiol-related adverse drug  reactions were low to moderate and included somnolence, mainly related to  concomitant administration of clobazam, and gastrointestinal alterations. Also,  liver function abnormalities were reported during the use of cannabidiol and valproic acid. CONCLUSIONS: Given the increased use of cannabidiol in refractory epilepsy, a  comprehensive understanding of its pharmacological profile is essential for the  clinical team. Specifically, clinical pharmacists play an important role in  monitoring cannabidiol's safety and efficacy. This approach leads to treatment  optimization, allowing to maximizing the pharmacological activity and minimizing the occurrence of adverse events as well as drug-to-drug interactions. Clinical  follow-up is essential to avoid discontinuation of treatment or exacerbation of  adverse events, which may impair the patients' quality of life.

Objetivo: El objetivo del presente trabajo es brindar una revisión sistemática y  actualizada acerca de la farmacología de cannabidiol, con especial énfasis en la  farmacocinética, eventos adversos e interacciones, vinculada al uso de este  fármaco en epilepsias refractarias.Método: Se realizó una revisión de los trabajos publicados y relacionados con la farmacocinética y los eventos adversos e interacciones farmacológicas de  cannabidiol utilizado para el tratamiento de las epilepsias refractarias mediante  una búsqueda en PubMed y LILACS.Resultados: Los estudios originales que describen la farmacocinética de cannabidiol de manera exhaustiva son limitados aunque informativos. La absorción de cannabidiol es rápida y se incrementa la biodisponibilidad por la  ingesta conjunta de comidas ricas en grasas. El cannabidiol presenta farmacocinética lineal hasta dosis de 3.000 mg/día y se acumula por la  administración continua. La semivida de eliminación se referencia entre 14 y 60  horas dependiendo de los tiempos de toma de muestra del estudio farmacocinético y no se descartan modificaciones en la eliminación por la administración en dosis múltiples. De las interacciones farmacológicas entre  cannabidiol con otros fármacos antiepilépticos referenciadas hasta el momento,  aquella con clobazam es la que presenta mayor evidencia científica. Los eventos  adversos más frecuentes asociados al uso de cannabidiol fueron de gravedad  leve o moderada e incluyeron somnolencia, principalmente por el uso conjunto  de clobazam, y alteraciones gastrointestinales. Se evidenciaron asimismo  anormalidades en la función hepática concomitantes con el uso de ácido  valproico.Conclusiones: Ante la creciente demanda de la utilización de cannabidiol en  epilepsias refractarias, es fundamental el conocimiento de su farmacología por  parte del equipo de salud. En especial, el farmacéutico clínico juega un papel  primordial en la monitorización de su seguridad y eficacia. Esto permite la  optimización del tratamiento clínico del cannabidiol administrado conjuntamente  con otros fármacos antiepilépticos de mayor uso, lo que conduce a maximizar la  actividad farmacológica y minimizar la aparición de eventos adversos al igual  que de interacciones farmacológicas. El seguimiento clínico del paciente resulta  fundamental para evitar la discontinuación del tratamiento o exacerbación de  eventos adversos que afecten la calidad de vida del paciente.

Medicinal cannabis in Latin America: History, current state of regulation, and the role of the pharmacist in a new clinical experience with cannabidiol oil.

OBJECTIVE: Cannabis sativa was introduced in Latin America in the 16th century. Nevertheless, many years have elapsed, and scientific progress and the medicinal use of C sativa have been restricted by the national laws of the countries in the region. SUMMARY: In Argentina, the first law on medical cannabis, approved in 2017 (#17,350), establishes a regulatory framework for the medical use and scientific research of this plant and its derivatives. In 2018, the first clinical research protocol in Latin America was approved at Hospital de Pediatria Garrahan (Buenos Aires, Argentina) to evaluate the efficacy and safety of cannabidiol (CBD) oil for the treatment of pediatric patients with refractory epilepsy. In this context, the role of pharmacists in the health care system related to the study protocol and the medicinal use of CBD has evolved from dispensing to active participation in clinical follow-up and research protocols. CONCLUSION: Considering this experience, here we discuss the active role of the clinical pharmacist in the use of medicinal cannabis. Medicinal cannabis should be controlled in a legal framework based on clinical evidence, and the participation of the pharmacist in research and clinical protocols, as well as the dispensing and provision of information on the medicinal products should be emphasized in the clinical setting.

Identification of Factors Affecting Tacrolimus Trough Levels in Latin American Pediatric Liver Transplant Patients.

Tacrolimus is the cornerstone in pediatric liver transplant immunosuppression. Despite close monitoring, fluctuations in tacrolimus blood levels affect safety and efficacy of immunosuppressive treatments. Identifying the factors related to the variability in tacrolimus exposure may be helpful in tailoring the dose. The aim of the present study was to characterize the clinical, pharmacological, and genetic variables associated with systemic tacrolimus exposure in pediatric liver transplant patients. De novo transplant patients with a survival of more than 1 month were considered for inclusion and were genotyped for cytochrome P450 3A5 (CYP3A5). Peritransplant clinical factors and laboratory covariates were recorded retrospectively between 1 month and 2 years after transplant, including alanine aminotransferase (ALT), aspartate aminotransferase, hematocrit, and tacrolimus predose steady-state blood concentrations collected 12 hours after tacrolimus dosing. A linear mixed effect (LME) model was used to assess the association of these factors and the log-transformed tacrolimus dose-normalized trough concentration (logC0/D) levels. Bootstrapping was used to internally validate the final model. External validation was performed in an independent group of patients who matched the original population. The developed LME model described that logC0/D increases with increases in time after transplant (ß = 0.019, 95% confidence interval [CI], 0.010-0.028) and ALT values (ß = 0.00030, 95% CI, 0.00002-0.00056), whereas logC0/D is significantly lower in graft CYP3A5 expressers compared with nonexpressers (ß = -0.349, 95% CI, -0.631 to -0.062). In conclusion, donor CYP3A5 genotype, time after transplant, and ALT values are associated with tacrolimus disposition between 1 month and 2 years after transplant. A better understanding of tacrolimus exposure is essential to minimize the occurrence of an out-of-range therapeutic window that may lead to adverse drug reactions or acute rejection.

Survival Time to Biopsy-Proven Acute Rejection and Tacrolimus Adverse Drug Reactions in Pediatric Liver Transplantation.

BACKGROUND: Despite advances in surgical procedures and the optimization of immunosuppressive therapies in pediatric liver transplantation, acute rejection (AR) and serious adverse drug reaction (ADR) to tacrolimus still contribute to morbidity and mortality. Identifying risk factors of safety and efficacy parameters may help in optimizing individual immunosuppressive therapies. This study aimed to identify peritransplant predictors of AR and factors related to the risk of ADR to tacrolimus in a large Latin American cohort of pediatric liver transplant patients. METHODS: We performed a retrospective cohort study in a pediatric liver transplant population (n = 72). Peritransplant variables were collected retrospectively including demographic, clinical, laboratory parameters, genomic (CYP3A5 donor and recipients polymorphism), and tacrolimus trough concentrations (C0) over a 2-year follow-up period. Variability in tacrolimus C0 was calculated using percent coefficient of variation and tortuosity. ADR- and AR-free survival rates were calculated using the Kaplan-Meier method, and risk factors were identified by multivariate Cox regression models. RESULTS: Cox-proportional hazard models identified that high tortuosity in tacrolimus C0 was associated with an 80% increased risk of AR [hazard ratio (HR), 1.80; 95% confidence interval (CI), 1.01-3.22; P < 0.05], whereas steroid in maintenance doses decreased this risk (HR, 0.56; 95% CI, 0.31-0.99; P < 0.05). Forty-six patients experienced at least one ADR including hypomagnesemia, nephrotoxicity, hypertension, malignancies, and tremor as a first event. Multivariate analysis showed that C0 values 10 days before the event (HR, 1.25; 95% CI, 1.21-1.39; P < 0.0001) and CYP3A5 expresser recipients (HR, 2.05; 95% CI, 1.03-4.06; P < 0.05) were independent predictors of ADR. CONCLUSIONS: Tacrolimus C0 values, its variability, and CYP3A5 polymorphisms were identified as risk factors of AR and tacrolimus ADR. This knowledge may help to control and reduce their incidence in pediatric liver transplant patients. Prospective studies are important to validate these results.

Pharmacoepidemiology of tacrolimus in pediatric liver transplantation.

AEs during immunosuppressive treatment with tacrolimus are very common. We retrospectively evaluated FK safety and efficacy in a large pediatric liver transplant cohort in Latin America. During 2-year follow-up, we analyzed data from patients who underwent liver transplantation over the period 2010-2012 and recorded FK exposure, AEs, and AR episodes. AEs were classified according causality and severity. Tacrolimus exposure before and during AE was compared using Wilcoxon matched-pairs test. Kaplan-Meier curves were used for survival analysis. In total, 46 patients (out of 72 patients) experienced 69 AEs, such as hypomagnesemia (49%), PTLD (6%), hypertension (6%), and/or nephrotoxicity (22%). 43% of AEs were classified as moderate or serious, and 89% were assigned as probable or definitive. Patients who had one or more AR episodes accounted for 65%. The 12-month acute rejection-free survival was 41% (95% CI, 30.1%-53.1%). A significant difference was observed in FK trough concentrations before and during hypomagnesemia and nephrotoxicity (P<.05). This study is the first report of FK safety in a large group of pediatric liver transplant patients in Latin America. Children experience AEs, even in protocols with low FK doses. Therapeutic monitoring is an important tool to manage immunosuppressive schemes containing tacrolimus in vulnerable populations.

Therapeutic monitoring of pediatric transplant patients with conversion to generic tacrolimus.

OBJECTIVE: Therapeutic monitoring during interchange of tacrolimus commercial formulations is essential to ensure similar exposure in transplant patients. However, there are limited data in the pediatric transplant population. This study aims to evaluate exposure, safety and efficacy in maintenance pediatric transplant patients under generic tacrolimus substitution. METHOD: Pediatric patients who underwent interchange of tacrolimus formulations were detected by the Service of Pharmacy and included in this study. Tacrolimus trough levels (C0), laboratory parameters and clinical characteristics were recorded before and after the switch. Statistical analysis was performed using Wilcoxon matched pair t-test. RESULTS: In total, 10 patients with kidney, liver, heart and hematopoietic stem cell transplantation received the innovator and switched to the generic product. The median (range) of the C0 normalized by the dose before and after switch was 74.8 [(ng/ml)/(mg/kg)] (13.8-518.4) and 65.1 [(ng/ml)/(mg/kg)] (13.5-723.5), respectively (p>0.05). Tacrolimus dose was 0.070(mg/kg) (0.024-0.461) and 0.069(mg/kg) (0.017- 0.571) for the innovator and generic formulation, respectively, with no difference when comparing both values (p>0.05). Laboratory parameters did not change after conversion (p>0.05). Adverse events, acute rejection, death and graft loss were not observed. CONCLUSION: In our study population, no significant differences in terms of laboratory parameters, drug exposure and dose were observed. We emphasize the need of close monitoring to ensure a safe interchange, especially in vulnerable populations such as the pediatric.

Objetivo: La monitorización terapéutica durante el intercambio de marcas comerciales de inmunosupresores es esencial para mantener una similar exposición al fármaco en pacientes trasplantados. Sin embargo, la información disponible en trasplante pediátrico es limitada. El objetivo del trabajo fue evaluar la exposición, seguridad y eficacia en pacientes pediátricos trasplantados en etapa de mantenimiento, sujetos a intercambio entre el producto innovador y el genérico de tacrolimus. Método: El Área de Farmacia del hospital detectó aquellos pacientes sujetos a intercambio de formulaciones según la disponibilidad de medicamentos. Se obtuvieron las concentraciones de tacrolimus en el valle (C0), parámetros de laboratorio y características clínicas antes y después del intercambio. El análisis estadístico se realizó mediante el test de muestras pareadas de Wilcoxon. Resultados: Se incluyeron 10 pacientes con trasplante renal, hepático, cardíaco y de células hematopoyéticas. La mediana (rango) del C0 normalizado por la dosis pre y post intercambio fue 74,8[(ng/ml)/(mg/kg)](13,8-518,4) y 65,1[(ng/ml)/(mg/kg)] (13,5-723,5), respectivamente (p>0,05). La dosis de tacrolimus fue 0,070(mg/kg) (0,024-0,461) y 0,069(mg/kg) (0,017-0,571) para el innovador y el genérico, respectivamente (p>0,05). Los parámetros de laboratorio de funcionalidad renal y hepática no cambiaron con la conversión de marcas (p>0,05). No se observaron eventos adversos, rechazo agudo, muerte o pérdida del injerto durante el periodo analizado. Conclusiones: En la población estudiada, no se observaron diferencias significativas en los parámetros de laboratorio, exposición al tacrolimus o dosis en el intercambio de marcas comerciales. Destacamos el rol de la monitorización terapéutica a la hora de garantizar una sustitución segura, especialmente en poblaciones vulnerables.

[Current status and regulation of bioanalytical laboratories engaged in quantifying immunosuppressants for transplant patients in Argentina]. / Estado de situación y regulación de laboratorios bioanalíticos que cuantifican inmunosupresores para trasplantes en Argentina.

Objective Determine the status of analytical laboratories that quantify immunosuppressants in transplant patients who are under therapeutic drug monitoring (TDM) for these drugs in Argentina in order to identify potential perfectible areas for action. Methods A survey of the clinical and analytical TDM centers in Argentina was conducted between September 2013 and November 2014 under the direction of the Garrahan Hospital Clinical Pharmacokinetics Unit and the National Unified Central Institute for Ablation and Implant Coordination. Results A nationally representative sample of 27 clinical and analytical centers was identified, of which 45% were public hospitals. Most of these centers (95%) monitor ciclosporin and tacrolimus, and to a lesser extent, sirolimus and everolimus; a small number of them also monitor mycophenolic acid. The median number of samples of these five drugs analyzed per month was 251 (range: 10-2024). Nearly 60% of the samples were analyzed in private institutions. Only four of the respondents (17%) reported values within the therapeutic margin. Of all the centers, 92% use immunoassay as the analytical methodology. Of the bioanalytical installations that have their own facilities, 68% reported that they also have their own quality assurance program. Conclusions TDM of immunosuppressants is a recommended practice for transplant patients in Argentina. Initiatives need to be taken at the national level to develop uniform guidelines for analytical laboratories that include TDM-related quality assurance processes with regulatory force. There is also a need to train technical and professional personnel and to invite the participation of public and private organizations in the regulatory, public health, and research areas.

Estado de situación y regulación de laboratorios bioanalíticos que cuantifican inmunosupresores para trasplantes en Argentina / Current status and regulation of bioanalytical laboratories engaged in quantifying immunosuppressants for transplant patients in Argentina

RESUMEN Objetivo Establecer el estado de situación de los laboratorios analíticos que cuantifican inmunosupresores en pacientes con trasplantes que se encuentran bajo monitoreo terapéutico de drogas (TDM) de estos fármacos en Argentina, para establecer potenciales áreas de actuación perfectibles. Métodos Se realizó una encuesta en centros clínicos y analíticos de TDM de Argentina, coordinada por la Unidad de Farmacocinética Clínica del Hospital Garrahan y el Instituto Nacional Central Único Coordinador de Ablación e Implante, desde setiembre de 2013 hasta noviembre de 2014. Resultados Se incluyeron 27 centros clínicos y analíticos (muestra representativa nacional). El 45% fueron hospitales públicos. La mayoría (95%) monitorizan ciclosporina y tacrolimús; en menor medida, sirolimús y everolimús, y muy pocos el ácido micofenólico. La cantidad (mediana, rango) de muestras analizadas por mes para estos cinco fármacos fue de 251 (10 - 2024). Casi 60% de las muestras se analizaron en instituciones privadas. Solo cuatro (17%) de los encuestados informan valores del margen terapéutico. El 92% usa inmunoensayos como metodología analítica. El 68% de los encuestados que contaban con instalaciones bioanalíticas propias informaron poseer algún programa de garantía de calidad. Conclusiones El TDM de inmunosupresores es una práctica recomendada para pacientes con trasplante en Argentina. Se requiere generar iniciativas nacionales que desarrollen guías armonizadas para laboratorios analíticos que incluyan procesos de garantía de calidad con alcance regulatorio relacionados con el TDM. Por otra parte, también es necesario capacitar al personal técnico y profesional, e invitar a participar a organizaciones públicas y privadas del ámbito regulatorio, sanitario y de la investigación.

ABSTRACT Objective Determine the status of analytical laboratories that quantify immunosuppressants in transplant patients who are under therapeutic drug monitoring (TDM) for these drugs in Argentina in order to identify potential perfectible areas for action. Methods A survey of the clinical and analytical TDM centers in Argentina was conducted between September 2013 and November 2014 under the direction of the Garrahan Hospital Clinical Pharmacokinetics Unit and the National Unified Central Institute for Ablation and Implant Coordination. Results A nationally representative sample of 27 clinical and analytical centers was identified, of which 45% were public hospitals. Most of these centers (95%) monitor ciclosporin and tacrolimus, and to a lesser extent, sirolimus and everolimus; a small number of them also monitor mycophenolic acid. The median number of samples of these five drugs analyzed per month was 251 (range: 10-2024). Nearly 60% of the samples were analyzed in private institutions. Only four of the respondents (17%) reported values within the therapeutic margin. Of all the centers, 92% use immunoassay as the analytical methodology. Of the bioanalytical installations that have their own facilities, 68% reported that they also have their own quality assurance program. Conclusions TDM of immunosuppressants is a recommended practice for transplant patients in Argentina. Initiatives need to be taken at the national level to develop uniform guidelines for analytical laboratories that include TDM-related quality assurance processes with regulatory force. There is also a need to train technical and professional personnel and to invite the participation of public and private organizations in the regulatory, public health, and research areas.

Dosing algorithms for initiation of immunosuppressive drugs in solid organ transplant recipients.

INTRODUCTION: Starting doses of tacrolimus and ciclosporin are typically chosen on a calculated mg/kg bodyweight basis. After initiation of treatment, doses are adjusted with therapeutic drug monitoring (TDM). This trial-and-error approach has been accepted by most physicians and pharmacists involved in the care of transplanted patients. AREAS COVERED: Dosing algorithms have only fairly recently been proposed to better individualize the starting dose. This review provides an overview of all the currently available dosing algorithms in adult and children for the starting dose of ciclosporin, tacrolimus and mycophenolic acid. In these algorithms, multiple other covariates influencing the starting dose, such as age, hematocrit, comedication and genotype are taken into account. After selecting the starting dose with an algorithm and after initiation of treatment, TDM will, however, remain necessary. Whether or not implementation of such algorithms will improve clinical outcome remains to be demonstrated. EXPERT OPINION: First of all an algorithm needs to be validated, against an independent dataset. Second, in a prospective study the algorithm should prove to reduce the time to reach the target concentration, and to reduce the number of patients with drug concentrations (far) outside the therapeutic window. Finally, a clinical trial demonstrating a benefit on clinical outcome will be crucial in achieving broad acceptance of calculating starting dose using individualized dosing algorithms.

Therapeutic monitoring of pediatric renal transplant patients with conversion to generic cyclosporin.

BACKGROUND: Cyclosporin is a calcineurin inhibitor widely used in renal transplant patients to prevent organ rejection. Several position papers have been published but no reports on the practical experience in pediatric patients undergoing conversion between cyclosporin innovator and generic products are available. OBJECTIVE: To evaluate the pharmacokinetics and safety as part of therapeutic monitoring of cyclosporin in renal transplant pediatric patients who switch from the innovator to the generic formulation in Argentina. SETTING: Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina. METHODS: Stable pediatric renal transplant patients (6 months post-transplant) switched from the innovator to the generic formulation of cyclosporin microemulsion capsule. Cyclosporin pharmacokinetic parameters were obtained while taking the innovator and after starting with the generic formulation. Blood samples were drawn before and 1, 2, and 3 h after drug administration and subsequently quantified. Pharmacokinetic parameters were obtained by means of a Bayesian approach. MAIN OUTCOMES MEASURE: Cyclosporin pharmacokinetic parameters (area under the curve, AUC; Blood concentration after 2 h, C2), adverse events and graft rejection. RESULTS: A total of 12 patients were included. Median (range) age and time post-transplant were 10.7 years (6.5-17.7) and 8.3 years (3.4-14.0), respectively. Two patients or their parents did not consent to the switch. Median (range) dose normalized cyclosporin AUC and C2 were 1.15 (mg*h/L)/mg/kg (0.72-3.0) and 265.5 (ng/ml)/mg/kg (120.8-725.7), respectively, on the innovator therapy and 1.05 (mg*h/L)/mg/kg (0.54-2.22) and 317.1 (ng/ml)/mg/kg (116.7-564.7) for the generic drug after the switch. The median (range) percentage of change in the AUC and C2 when switching between formulations were 16.7 % (0.7-56.7) and 13.1 % (3.7-68.6), respectively. No significant changes in serum creatinine levels were registered when comparing before and after substitution of products. Adverse events (number of events) recorded 5 months before and after the switch included hirsutism (2), hypertension (2), and gingival hyperplasia (1). CONCLUSION: Conversion of cyclosporin from innovator brand to generic in pediatric renal transplant patients needs to be closely monitored.