Population Pharmacokinetics of Digoxin in Nonagenarian Patients: Optimization of the Dosing Regimen.

OBJECTIVE: The aim of this study was to develop a population pharmacokinetic model of digoxin in patients over 90 years old and to propose an equation for adjusting digoxin dose in this population. METHODS: We included 326 nonagenarian patients admitted to Severo Ochoa University Hospital (Spain) who received digoxin and were under therapeutic drug monitoring. All data were retrospectively collected, and population modeling was performed with non-linear mixed-effect modeling software (NONMEM®). One- and two-compartment models were tested to calculate digoxin clearance (Cl), volume of distribution (Vd), absorption rate constant (Ka), and bioavailability (bioavailable fraction, F). The covariates were evaluated by stepwise covariate model building, and the final model was internally validated by bootstrap analysis with 1000 resamples. External validation was performed with another population of 95 patients with the same characteristics as the modeling group. RESULTS: The population was 26% males, with a mean age of 93.2 years (90-103 years), mean creatinine 1.11 mg/dL (0.42-3.81 mg/dL), and mean total body weight 61.2 kg (40-100 kg). The pharmacokinetics of digoxin were best described by a one-compartment model (ADVAN2 TRANS2), with first-order conditional estimation with interaction. The covariates with influence on our model were creatinine clearance based on the Cockcroft-Gault equation (CG), serum potassium (K), co-administration of loop diuretics, and sex: Cl/F = 4.55 · (CG/36.4)0.468 · 0.83LD · 1.21SEX; Vd/F = 355 · (K/4.3)-0.849; Ka = 1.22 h-1 [where LD indicates loop diuretics (1 for administered, 0 for otherwise) and SEX indicates patient sex (1 for male, 0 for female)]. Based on our results, we proposed an equation to adjust the digoxin dosing regimen in nonagenarian patients: dose (mg) = 0.144 · (CG/36.4)0.468 · 0.83LD · 1.21SEX. CONCLUSIONS: The greatest influence on digoxin clearance came from renal function calculated by the Cockcroft-Gault equation. Vd was decreased by K. The model developed showed a precise predictive performance to be applied for therapeutic drug monitoring.

Schnitzler syndrome refractory to anakinra: successful treatment with canakinumab.

Schnitzler syndrome (SchS) is a rare autoimmune and inflammatory disease mediated by interleukin-1 beta (IL-1ß). Recurrent monoclonal gammopathy and chronic urticarial rash are the symptoms required for diagnosis according to the Strasbourg criteria. The low prevalence of this syndrome (around 300 cases have been reported) and confusion with other inflammatory disorders may delay the diagnosis for up to 5 years. Although the most effective treatment for SchS is anakinra, some patients do not respond to this treatment. We report a case of SchS in a 64-year-old woman with multiple episodes of fever, severe rash, erythema, arthralgia and dyspnea. The patient was successfully treated with canakinumab after anakinra intolerance and failure of colchicine, prednisone, methotrexate and dapsone. After the first dose of canakinumab the skin wounds rapidly improved and the patient did not require any concomitant treatments. The cause of SchS is still unknown and a differential diagnosis is recommended, especially with adult-onset Still´s disease due to their similar symptoms. Canakinumab, a specific anti-IL-1ß antibody, blocks its binding to receptors, thereby preventing IL-1ß-induced gene activation and production of inflammatory mediators. Canakinumab has proven to be an effective drug in SchS, providing an alternative to anakinra.

Population pharmacokinetics of digoxin in elderly patients: A systematic review.

OBJECTIVE: To resume the available literature about digoxin population pharmacokinetic studies in elderly patients. To identify the  pathophysiological changes in this subpopulation with clinical implications on  digoxin pharmacokinetics. METHOD: A systematic review was performed regarding the population pharmacokinetic studies in elderly patients receiving digoxin. Pub-Med, ISI Web of Science, SCOPUS and Science Direct were used to identify the articles with the descriptors ("Digoxin"[Mesh]) AND ("Pharmacokinetics"[Mesh]) AND ("Aged"[Mesh] OR "Elderly"[Mesh]), followed by a manual search. RESULTS: Nine studies were found and reviewed, five of them carried out in  Asian patients. NONMEM was used for pharmacokinetic analysis of digoxin  blood levels, being mostly described by a one-compartment model. Serum  creatinine, body weight and concomitant administration of calcium channel  blockers are the covariates that most frequently influence digoxin  pharmacokinetics in elderly patients. CONCLUSIONS: Elderly people present pathophysiological changes with influence  on the pharmacokinetics of many drugs. The covariates with most influence on digoxin pharmacokinetics should be considered when adjusting this drug dosage in elder patients to achieve optimum health benefits and prevent possible side effects.

OBJETIVO: Resumir la literatura disponible sobre los estudios de farmacocinética poblacional de digoxina en pacientes de edad avanzada e  identificar los cambios fisiopatológicos en esta subpoblación, que conllevan implicaciones clínicas en la farmacocinética de la digoxina.Método: Se realizó una revisión sistemática de los estudios de farmacocinética poblacional en pacientes ancianos que recibían digoxina. Se  utilizaron PubMed, ISI Web of Science, SCOPUS y Science Direct para  identificar los artículos con los descriptores ("Digoxin"[Mesh]) AND ("Pharmacokinetics"[Mesh]) AND ("Aged"[Mesh] OR "Elderly"[Mesh]), seguido de una búsqueda manual. RESULTADOS: Se encontraron y revisaron nueve estudios, cinco de los cuales  de desarrollaron en pacientes asiáticos. Se utilizó NONMEM para el análisis  farmacocinético de los niveles plasmáticos de la digoxina, mayoritariamente  descrita como un modelo monocompartimental. Conclusiones: Los pacientes ancianos presentan cambios fisiopatológicos con  gran influencia en la farmacocinética de muchos fármacos. Las covariables con  un mayor impacto en la farmacocinética de la digoxina deben tenerse en  cuenta al ajustar la dosis de este medicamento en pacientes de edad avanzada  con el fin de lograr beneficios óptimos para la salud y prevenir  posibles efectos adversos en esta subpoblación.

Farmacocinética poblacional de la digoxina en pacientes de edad avanzada: Una revisión sistemática / Population pharmacokinetics of digoxin in elderly patients: A systematic review

Objetivo: Resumir la literatura disponible sobre los estudios de farmacocinética poblacional de digoxina en pacientes de edad avanzada e identificar los cambios fisiopatológicos en esta subpoblación, que conllevanimplicaciones clínicas en la farmacocinética de la digoxina.Método: Se realizó una revisión sistemática de los estudios de farmacocinética poblacional en pacientes ancianos que recibían digoxina.Se utilizaron PubMed, ISI Web of Science, SCOPUS y Science Directpara identificar los artículos con los descriptores (“Digoxin”[Mesh]) AND(“Pharmacokinetics”[Mesh]) AND (“Aged”[Mesh] OR “Elderly”[Mesh]),seguido de una búsqueda manual.Resultados: Se encontraron y revisaron nueve estudios, cinco de loscuales de desarrollaron en pacientes asiáticos. Se utilizó NONMEMpara el análisis farmacocinético de los niveles plasmáticos de la digoxina, mayoritariamente descrita como un modelo monocompartimental.Conclusiones: Los pacientes ancianos presentan cambios fisiopatológicos con gran influencia en la farmacocinética de muchos fármacos. Lascovariables con un mayor impacto en la farmacocinética de la digoxinadeben tenerse en cuenta al ajustar la dosis de este medicamento enpacientes de edad avanzada con el fin de lograr beneficios óptimospara la salud y prevenir posibles efectos adversos en esta subpoblación. (AU)

Objective: To resume the available literature about digoxin populationpharmacokinetic studies in elderly patients. To identify the pathophysiological changes in this subpopulation with clinical implications on digoxinpharmacokinetics.Method: A systematic review was performed regarding the population pharmacokinetic studies in elderly patients receiving digoxin. PubMed, ISI Web of Science, SCOPUS and Science Direct were usedto identify the articles with the descriptors (“Digoxin”[Mesh]) AND(“Pharmacokinetics”[Mesh]) AND (“Aged”[Mesh] OR “Elderly”[Mesh]),followed by a manual search.Results: Nine studies were found and reviewed, five of them carriedout in Asian patients. NONMEM was used for pharmacokinetic analysisof digoxin blood levels, being mostly described by a one-compartmentmodel. Serum creatinine, body weight and concomitant administration ofcalcium channel blockers are the covariates that most frequently influencedigoxin pharmacokinetics in elderly patients.Conclusions: Elderly people present pathophysiological changes withinfluence on the pharmacokinetics of many drugs. The covariates withmost influence on digoxin pharmacokinetics should be considered whenadjusting this drug dosage in elder patients to achieve optimum healthbenefits and prevent possible side effects. (AU)

Comparación de cuatro métodos de predicción de la concentración de ácido valproico libre en la práctica clínica / Comparison of four valproic acid free fraction determination methods used in clinical practice

Objetivo: La fracción de ácido valproico libre aumenta en pacientescon hipoalbuminemia. Se han publicado diferentes métodos para su estimación.El objetivo de este estudio es valorar la fiabilidad de dichosmétodos en nuestra población y proponer un nuevo método de estimación.Método: Análisis retrospectivo realizado por el Servicio de Farmaciadel Hospital Universitario Severo Ochoa en pacientes ingresados entreoctubre de 2017 y febrero de 2019 con al menos una concentraciónvalle de ácido valproico. Los métodos de estimación empleados fueronlos de Kodama, Hermida, Doré y un nuevo método propuesto, diseñadopor García. A partir de 17 mediciones de ácido valproico se comparóel ácido valproico libre estimado con cada método y el obtenido en ellaboratorio. Se calcularon la exactitud y la precisión mediante el errormedio y el error cuadrático medio, respectivamente.Resultados: La comparación entre los valores observados y predichosde ácido valproico libre por los distintos métodos evaluados pone demanifiesto que el de mayor fiabilidad es el diseñado por García, alpresentar la mejor exactitud y precisión. Los peores resultados son los delmétodo Kodama, al no considerar la albuminemia, variable fundamental que condiciona la concentración, el efecto terapéutico y la toxicidad deeste fármaco.Conclusiones: El método diseñado por García ha demostrado ser mejorque otros métodos, por lo que puede ser propuesto para estimar con fiabilidadel ácido valproico libre en pacientes con hipoalbuminemia, aunque seprecisa aplicarlo en un mayor número de pacientes para confirmar su utilidad

Objective: Given that hypoalbuminemia tends to result in higher freefraction concentrations of valproic acid, different methods have beendeveloped to determine the latter in patients with this condition. The aimof this study is to assess the reliability of these methods and, if necessary,design a new estimation method.Method: A retrospective analysis was carried out by the PharmacyDepartment of Severo Ochoa University Hospital of admitted patientswith at least one trough concentration of valproic acid between October2017 and February 2019. The estimation methods used were those developedby Kodama, Hermida, Doré, as well as a new method proposed inthe study. A total of 17 serum valproic acid concentrations were used todetermine the free fraction of valproic acid with each method; the valuesobtained were compared with the results obtained following laboratorydeterminations. Accuracy and precision were calculated using mean errorand root mean square error, respectively.Results: The comparison between observed and predicted free valproicacid values using the methods under investigation showed that the methodproposed in this study provides the highest reliability as it presents the highestaccuracy and precision. The worst results were those obtained using the Kodama method, which does not consider albuminemia, an essentialvariable that determines the concentration, therapeutic effect and toxicityof valproic acid.Conclusions: Given that the method proposed in this study proved to besuperior to the other methods analyzed, we believe it can be reliably usedto estimate free valproic acid levels in patients with hypoalbuminemia.

Flúter auricular posiblemente relacionado con pazopanib: descripción de un caso / Atrial flutter probably related to pazopanib: A case report

No disponible

Reacción paradójica psoriaforme por infliximab / Psoriasiform paradojic reaction associated with infliximab infusion

No disponible

Infiltrados pulmonares asociados a la administración de sertralina / Lung infiltrates associated with sertraline administration

No disponible