Evaluation of ABC gene polymorphisms on the pharmacokinetics and pharmacodynamics of capecitabine in colorectal patients: Implications for dosing recommendations.

AIMS: The aims are to develop a population pharmacokinetic model of capecitabine (CAP) and its main metabolites after the oral administration of CAP in colorectal cancer patients with different polymorphisms of the ATP-binding cassette (ABC) gene and a population pharmacokinetic/pharmacodynamic model capable of accounting for the neutropenic effects, and to optimize the dosing strategy based on the polymorphisms of the ABC gene and/or the administration regimen as a single agent or in combination. METHODS: Forty-eight patients diagnosed with colorectal cancer were included, with 432 plasma levels of CAP, 5'-desoxi-5-fluorouridine (5'-DFUR) and 5-fluorouracil (5-FU), and 370 neutrophil observations. Capecitabine doses ranged from 1250 to 2500 mg/m2 /24 h. Plasma measurements of CAP, 5'-DFUR and 5-FU were obtained at 1, 2 and 3 hours post administration. Neutrophil levels were measured between day 15 and day 24 post administration. RESULTS: The pharmacokinetic model incorporates oxaliplatin as a covariate on absorption lag time, rs6720173 (ABCG5 gene) on clearance of 5'-DFUR (182% increase for mutated rs6720173) and rs2271862 (ABCA2 gene) on clearance of 5-FU (184% increase for mutated rs2271862). System- (Circ0 = 3.54 × 109 cells/mL, MTT = 204 hours and γ = 6.0 × 10-2 ) and drug-related (slope [SLP] = 3.1 × 10-2 mL/mg). Co-administration of oxaliplatin resulted in a 2.84-fold increase in SLP. The predicted exposure thresholds to G3/4 neutropenia in combination and monotherapy were 26 and 70 mg·h/L, respectively. CONCLUSIONS: The population pharmacokinetic/pharmacodynamic model characterized the time course of capecitabine and its metabolites in plasma. Dose recommendations of capecitabine in patients with mutated and wild allele for single nucleotide polymorphisms rs2271862 of ≤3000 and ≤2400 mg/m2 /24 h in monotherapy and ≤1750 and ≤600 mg/m2 /24 h in combination with oxaliplatin, respectively, have been proposed.

[Neonates treated with individualized parenteral nutrition who are candidates to receive standardized parenteral nutrition]. / Neonatos en tratamiento con nutriciones parenterales individualizadas, candidatos a recibir nutriciones parenterales estandarizadas.

INTRODUCTION: Objetive: to quantify the number of neonates treated with individualized parenteral nutrition (IPN) who were candidates to receive standardized parenteral nutrition (SPN), and to calculate their treatment duration. Material and methods: this was a prospective, observational, descriptive cohort study. Inclusion criteria were: neonates with indication of parenteral nutrition (PN) and individualized prescription. Exclusion criteria included: patients who had not started diuresis, with specific nutritional needs, altered acid-base balance, and/or contraindication to receive SPN. Included variables were patient-related (gender, weight, weeks of gestation, and days of life) and treatment-related regarding IPN composition. Setting the volume of PN as the conversion criterion, theoretical contributions were calculated with the SPN. The criterion for a patient to be a candidate to receive SPN was that all the theoretical contributions calculated were within the reference requirements range. Results: a total of 33 neonates (9 women) received IPN with 94 prescriptions. The median weight of the patients included in the study was 2.14 (IQR, 0.9) kg, and they were born at 35 (IQR, 3) weeks of gestation. PN began between 0 and 4 days of life. In all, 71 % (22/31) of the patients in 54.1 % of their (46/85) prescriptions were candidates to receive SPN via central administration for 1 to 8 days, whereas no patient was candidate to receive SPN via peripheral administration. Conclusions: in our center, 71 % of neonates treated with central administration of IPN are candidates to receive SPN, thus promoting the normalization of nutritional support in this population.

INTRODUCCIÓN: Objetivo: cuantificar el número de pacientes neonatos en tratamiento con nutriciones parenterales individualizadas (NPI), candidatos a recibir nutriciones parenterales estandarizadas (NPE), así como el número de días. Material y métodos: estudio prospectivo observacional y descriptivo de cohortes. Los criterios de inclusión fueron: pacientes neonatos con indicación de nutrición parenteral (NP) y prescripción individualizada. Los criterios de exclusión fueron: pacientes que no hubieran iniciado la diuresis, con necesidades nutricionales específicas, con alteraciones del equilibrio ácido-base y/o con contraindicación de la NPE. Se emplearon variables relacionadas con el paciente (sexo, peso, semanas de gestación y días de vida) y relacionadas con el tratamiento (aportes de la NPI). Fijando como criterio de conversión el volumen de NP, se calcularon los aportes teóricos con la NPE. El criterio para que un paciente fuera candidato a recibirla fue que todos los aportes teóricos estuvieran dentro de los requerimientos de referencia. Resultados: se incluyeron 33 neonatos (9 mujeres) en tratamiento con NPI y con 94 prescripciones. La mediana de peso de los pacientes incluidos en el estudio fue de 2,14 (RIC: 0,9) kg, nacidos a las 35 (RIC: 3) semanas de gestación y en los que se inició NP entre los días 0 y 4. El 71 % (22/31) de los pacientes en el 54,1 % (46/85) de sus prescripciones fueron candidatos a recibir NPE administrada por vía central durante 1 a 8 días, mientras que ningún paciente fue candidato a recibirla por vía periférica. Conclusiones: en nuestro centro, el 71 % de los pacientes nenonatos en tratamiento con NPI administrada por vía central son candidatos a recibir NPE, lo que fomenta la normalización del soporte nutricional en esta población.

Clinical utility of serum concentrations of adalimumab as predictor of treatment adherence. / Utilidad de las concentraciones séricas de adalimumab como predictores de adherencia al tratamiento.

OBJECTIVE: to evaluate the usefulness of serum concentrations (Sc) of adalimumab (ADA) as a predictor of medication adherence using the medication possession ratio (MPR) and Morisky Green test (MGT) in patients with chronic inflammatory diseases. MATERIAL AND METHOD: Design a prospective descriptive cohort study. INCLUSION CRITERIA: adult patients diagnosed with inflammatory arthropathy (IA) or inflammatory bowel disease (IBD) treated with ADA. EXCLUSION CRITERIA: positive anti-adalimumab antibody. VARIABLES: sex, age, diagnosis, dosage regimen, Sc (mg/mL), MPR (MPR ≥ 80% adherent) and MGT (non-adherent or adherent). Statistical analysis was performed using STATA v13.0. RESULTS: Forty-five patients (23 women) with an age of 52.22 (14.39) years, 17 IBD (37.78%), 26 IA (57.78%) and 2 with both conditions (4.44%) treated with 40mg ADA every 14 days (42/45; 93.33%) or every 7 days (3/45; 6.67%). We detected subtherapeutic Sc in 22.22% of patients (10/45); 10% (1/10) were classified as non-adherent and 90% (9/10) as adherent according to MGT and MPR. The quantification of Sc shows weak agreement with MPR, as was the case with the indirect methods of each (MPR and MGT). The association was slightly greater when the indirect methods were compared to each other (0.244 vs. 0.378). CONCLUSION: the determination of Sc of ADA alone has limited utility in the detection of non-adherent patients.

Effectiveness and Safety of Switching from Innovator Infliximab to Biosimilar CT-P13 in Inflammatory Rheumatic Diseases: A Real-World Case Study.

OBJECTIVE: CT-P13 is a biosimilar with comparable pharmacokinetics, efficacy and safety to its reference product (RP), infliximab. Studies have shown that switching from RP to CT-P13 does not reduce the effectiveness or safety of treatment. METHODS: In this retrospective real-world study, patients with inflammatory diseases treated with RP were switched to CT-P13 (n = 7) or continued on RP (n = 6). Clinical outcomes were compared between groups after four treatment cycles. RESULTS: CT-P13 demonstrated comparable effectiveness to its RP. All patients who switched to the biosimilar maintained or improved their clinical response, including two who remained in remission and three who moved into remission. In the RP group, five patients maintained their clinical response, with one achieving remission. Safety profiles were similar between groups. CONCLUSIONS: CT-P13 was equally effective as infliximab RP in this real-world study. CT-P13 is a valid, lower-cost alternative for patients currently receiving RP.

Clinical outcomes of the inclusion of the therapeutic drug monitoring report in the electronic clinical record.

OBJECTIVES: To assess the inclusion of the Therapeutic Drug Monitoring Report (TDMR) in the Electronic Clinical Record (ECR). METHOD: An observational ambispective cohort study with a duration of 149 days: PRE (retrospective, 49 days) with the TDMR printed in paper, and POST (prospective, 100 days) with the TDMR included in the ECR. EXCLUSION CRITERIA: Patients not hospitalized, applications for Therapeutic Drug Monitoring by Critical Care and Neonatal Units, as well as monitoring with an objective other than dose adjustment. VARIABLES: Number of TDMRs prepared, number of patients admitted with TDMR, time of delay for treatment adjustment, defined as the number of adjustments made to the treatment within over or under 24 hours from the time of TDMR preparation, and medication errors (MEs) associated with said delay, as well as the degree of acceptance of the TDMR. RESULTS: 690 TDMRs were conducted in 391 patients, 339 in PRE (n = 206) and 351 in POST (n = 185). The number of treatment modifications made in under 24 hours increased from 73.9% in PRE to 87.3% in POST [RR = 1.2 (CI95% = 0.97-1.43). We identified 35 patients with ME, 9.7% of them in PRE and 8.1% in POST (RR = 0.84 (CI95% = 0.44-1.58)]. The degree of acceptance of the pharmacist recommendation increased from 53.3% in PRE to 68.3% in POST [RR = 1.3 (CI95% = 1.02- 1.62)]. CONCLUSIONS: The inclusion of the Therapeutic Drug Monitoring Report (TDMR) in the Electronic Clinical Record increases the degree of acceptance of recommendations, and may reduce the delay in treatment modifications, reducing MEs and improving the process quality in terms of efficacy and safety.

Objetivos: Valorar la integración del informe de monitorización farmacocinética (IMFC) en la historia clínica electrónica (HCE). Método: Estudio observacional ambispectivo de cohortes de 149 días de duración: PRE (retrospectiva, 49 días) con emisión del IMFC en papel y POST (prospectiva, 100 días) con emisión del IMFC integrado en HCE. Criterios de exclusión: Pacientes no ingresados, solicitudes de monitorización farmacocinética de unidades de críticos y neonatos, así como monitorizaciones cuyo objetivo no era el ajuste posológico. VARIABLES: Número de IMFC elaborados, número de pacientes ingresados con IMFC, tiempo de demora de las adecuaciones del tratamiento definidas como número de adecuaciones realizadas en el tratamiento en más o en menos 24 horas respecto al momento de emisión del IMFC, y errores de medicación (EM) asociados a dicha demora, así como grado de aceptación del IMFC. Resultados: Se realizaron 690 IFC en 391 pacientes, 339 en PRE (n = 206) y 351 en POST (n = 185). El número de modificaciones realizadas en menos de 24 horas aumentó del 73,9% en PRE al 87,3% en POST [RR = 1,2 (IC95% = 0,97-1,43)]. Se identificaron 35 pacientes con EM, siendo 9,7% en PRE y 8,1% en POST [RR = 0,84 (IC95% = 0,44-1,58)]. El grado de aceptación de la recomendación farmacéutica se incrementó de 53,3% en PRE a 68,3% en POST [RR = 1,3 (IC95% = 1,02-1,62)]. Conclusiones: La integración del informe de monitorización farmacocinética en la historia clínica electrónica incrementa el gra do de aceptación de las recomendaciones y puede disminuir la demora de las adecuaciones del tratamiento reduciendo los EM, mejorando con ello la calidad del proceso en eficacia y seguridad.