INFLIXIMAB AND ADALIMUMAB SERUM TROUGH CONCENTRATIONS THRESHOLD ASSOCIATED WITH DEEP REMISSION IN INFLAMMATORY BOWEL DISEASE.

OBJECTIVE: Deep remission (DR) defined by clinical-biomarker remission and mucosal healing (MH) has emerged as a new therapeutic target in inflammatory bowel disease (IBD). The aim of this study was to define an optimal cut-off concentration for IFX and ADA during maintenance therapy associated with DR. The secondary objective, was to evaluate the influence of variables on anti-TNF concentrations and DR. METHODS: Retrospective study including 120 and 122 patients IBD diagnosed who received maintenance therapy with IFX and ADA. Biomarker remission was considered by C-reactive protein (CRP)<5 mg/L and fecal calprotectin (CF)<100 mcg/g. Crohn's disease (CD) clinical remission was defined by a Harvey Bradshaw score<5 and MH by a simple endoscopic score for CD (SES-CD)<3.  In ulcerative colitis (UC), it was defined as a Mayo total score<3 and Mayo endoscopic subscore<2. Receiver operating characteristic (ROC) test was performed to determine drug concentration thresholds associated with DR. Anti-TNF concentrations were classified into quartiles. X2 and Kruskal-Wallis test were used to compare discrete and continuous variables between quartile groups. Multivariate logistic regression was performed to identify patient characteristics and serological factors associated with DR. RESULTS: Anti-TNF concentrations were higher in patients with DR, in IFX (4.4, IQR: 3.3-6.5 vs 2.3, IQR: 1.1-4.2 µg/mL, P<0.005) and ADA (6.3, IQR: 4.2-8.2 vs 3.9, IQR: 2.4-5.5 µg/mL, P<0.005). A ROC identified a concentration threshold of 3.1 µg/mL in IFX (area under the ROC curve [AUROC], 0.72) and 6.3 µg/mL in ADA (AUROC, 0.75) associated with DR. Factors associated with the highest quartiles of serum IFX concentration were: elevated body mass index (BMI), absence of previous IBD-surgery, CRP<5 mg/L, and FC<100 µg/g. In ADA, higher quartiles were related to concomitant immunosuppressants, low BMI, absence of previous IBD-surgery, and CRP<5 mg/L and FC<100 µg/g. Multivariate regression identified FC<100 µg/g, CRP<5mg/L, IFX ≥3.1µg/mL and ADA concentrations ≥6.3µg/mL as factors significantly associated with DR.  CONCLUSIONS: Trough IFX and ADA concentrations, CRP<5mg/L and FC<100 µg/g are associated with DR during maintenance therapy. Cutoff point of 3.1 and 6.3 g/mL for IFX and ADA respectively, were identified as DR predictors.

Objetivo: La remisión profunda, definida como remisión clínico-analítica y  curación de la mucosa, es el objetivo terapéutico en la enfermedad inflamatoria intestinal. En este estudio se define el punto de  corte óptimo de concentración valle de infliximab y adalimumab asociado a  remisión profunda en fase de mantenimiento. El objetivo secundario es  evaluar las covariables relacionadas con las concentraciones de antifactor de necrosis tumoral y la remisión profunda.Método: Estudio retrospectivo que incluyó 120 y 122 pacientes  diagnosticados de enfermedad inflamatoria intestinal tratados con infliximab y adalimumab. La proteína C reactiva < 5 mg/l y la calprotectina  fecal < 100 µg/g se consideró para remisión analítica. En la enfermedad de Crohn, la remisión clínica se definió mediante puntuación Harvey  Bradshaw < 5; la curación de la mucosa por puntuación endoscópica simple para enfermedad de Crohn < 3; en colitis ulcerosa, por índice total de Mayo < 3 e índice subendoscópico de Mayo < 2. Se realizó un análisis por  curva de eficacia diagnóstica para determinar el cutoff asociado  a remisión profunda. Las concentraciones de antifactor de necrosis tumoral se clasificaron en cuartiles. Se utilizó la prueba X2 y Kruskal-Wallis para comparar variables discretas o continuas. Se realizó una  regresión  logística multivariante para identificar las características de  pacientes y serológicas asociadas a remisión profunda.Resultados: Las concentraciones de antifactor de necrosis tumoral fueron  superiores en remisión profunda en comparación con los que no la  alcanzaron en infliximab (4,4; rango intercuartílico: 3,3-6,5 versus 2,3;  rango intercuartílico: 1,1-4,2 µg/ml; P < 0,005) y adalimumab (6,3; rango  intercuartílico: 4,2-8,2 versus 3,9; rango intercuartílico: 2,4-5,5 µg/ml; P <  0,005). Se identificó un cutoff de 3,1 µg/ml en infliximab (área bajo la curva  de eficacia diagnóstica 0,72), y 6,3 µg/ml en adalimumab (área bajo la curva de eficacia diagnóstica 0,75). Los factores asociados a concentraciones  más elevadas de infliximab fueron: elevado índice de masa  corporal, ausencia de cirugía previa de enfermedad inflamatoria intestinal,  proteína C reactiva < 5 mg/l y calprotectina fecal < 100 µg/g. En  adalimumab, concentraciones más altas se relacionaron con  oadministración  de inmunosupresores, bajo índice de masa corporal,  ausencia de cirugía previa, proteína C reactiva < 5 mg/l y calprotectina fecal  < 100 µg/g. Se identificó calprotectina fecal < 100 µg/g, proteína C reactiva  < 5 mg/l, infliximab ≥ 3,1 µg/ml y adalimumab ≥ 6,3 µg/ml como factores  asociados a remisión profunda.logística multivariante para identificar las características de pacientes yserológicas asociadas a remisión profunda.Resultados: Las concentraciones de antifactor de necrosis tumoral fueronsuperiores en remisión profunda en comparación con los que no la alcanzaronen infliximab (4,4; rango intercuartílico: 3,3-6,5 versus 2,3; rango intercuartílico:1,1-4,2 µg/ml; P < 0,005) y adalimumab (6,3; rango intercuartílico:4,2-8,2 versus 3,9; rango intercuartílico: 2,4-5,5 µg/ml; P < 0,005).Se identificó un cutoff de 3,1 µg/ml en infliximab (área bajo la curva deeficacia diagnóstica 0,72), y 6,3 µg/ml en adalimumab (área bajo la curvade eficacia diagnóstica 0,75). Los factores asociados a concentraciones máselevadas de infliximab fueron: elevado índice de masa corporal, ausenciade cirugía previa de enfermedad inflamatoria intestinal, proteína C reactiva< 5 mg/l y calprotectina fecal < 100 µg/g. En adalimumab, concentracionesmás altas se relacionaron con coadministración de inmunosupresores,bajo índice de masa corporal, ausencia de cirugía previa, proteína C reactiva< 5 mg/l y calprotectina fecal < 100 µg/g. Se identificó calprotectinafecal < 100 µg/g, proteína C reactiva < 5 mg/l, infliximab ≥ 3,1 µg/ml yadalimumab ≥ 6,3 µg/ml como factores asociados a remisión profunda.Conclusiones: Las concentraciones valle de infliximab y adalimumab, proteínaC reactiva < 5 mg/l y calprotectina fecal < 100 µg/g se asocian a remisiónprofunda. Se identifican concentraciones cutoff de 3,1 y 6,3 µg/ml en infliximaby adalimumab, respectivamente, como predictoras de remisión profunda.

Los niveles séricos de infliximab y adalimumab están asociados con remisión profunda en la enfermedad inflamatoria intestinal / Serum levels of infliximab and adalimumab are associated with deep remission in inflammatory bowel disease

Objetivo: La remisión profunda, definida como remisión clínico-analíticay curación de la mucosa, es el objetivo terapéutico en la enfermedadinflamatoria intestinal. En este estudio se define el punto de corte óptimode concentración valle de infliximab y adalimumab asociado a remisiónprofunda en fase de mantenimiento. El objetivo secundario es evaluarlas covariables relacionadas con las concentraciones de antifactor denecrosis tumoral y la remisión profunda.Método: Estudio retrospectivo que incluyó 120 y 122 pacientes diagnosticados de enfermedad inflamatoria intestinal tratados con infliximaby adalimumab. La proteína C reactiva < 5 mg/l y la calprotectina fecal< 100 µg/g se consideró para remisión analítica. En la enfermedad deCrohn, la remisión clínica se definió mediante puntuación Harvey Bradshaw < 5; la curación de la mucosa por puntuación endoscópica simplepara enfermedad de Crohn < 3; en colitis ulcerosa, por índice total deMayo < 3 e índice subendoscópico de Mayo < 2. Se realizó un análisispor curva de eficacia diagnóstica para determinar el cutoff asociado aremisión profunda. Las concentraciones de antifactor de necrosis tumoral se clasificaron en cuartiles. Se utilizó la prueba X2 y Kruskal-Wallispara comparar variables discretas o continuas. Se realizó una regresión logística multivariante para identificar las características de pacientes yserológicas asociadas a remisión profunda.Resultados: Las concentraciones de antifactor de necrosis tumoral fueronsuperiores en remisión profunda en comparación con los que no la alcanzaron en infliximab (4,4; rango intercuartílico: 3,3-6,5 versus 2,3; rango intercuartílico: 1,1-4,2 μg/ml; P < 0,005) y adalimumab (6,3; rango intercuartílico: 4,2-8,2 versus 3,9; rango intercuartílico: 2,4-5,5 μg/ml; P < 0,005).Se identificó un cutoff de 3,1 μg/ml en infliximab (área bajo la curva deeficacia diagnóstica 0,72), y 6,3 μg/ml en adalimumab (área bajo la curvade eficacia diagnóstica 0,75). (AU)

Objective: Deep remission defined by clinical-biomarker remissionand mucosal healing has emerged as a new therapeutic target in inflammatory bowel disease. The aim of this study was to define an optimalcut-off concentration for infliximab and adalimumab during maintenancetherapy associated with deep remission. The secondary objective, wasto evaluate the influence of variables on anti tumor necrosis factor-alphaconcentrations and deep remission.Method: Retrospective study including 120 and 122 patients inflammatory bowel disease diagnosed who received maintenance therapywith infliximab and adalimumab. Biomarker remission was consideredby C-reactive protein < 5 mg/L and fecal calprotectin < 100 µg/g.Crohn’s disease clinical remission was defined by a Harvey Bradshawscore < 5 and mucosal healing by a simple endoscopic score for Crohn'sdisease< 3. In ulcerative colitis, it was defined as a Mayo total score < 3and Mayo endoscopic subscore < 2. Receiver operating characteristictest was performed to determine drug concentration thresholds associatedwith deep remission. Anti tumor necrosis factor-alpha concentrations wereclassified into quartiles. X2 and Kruskal-Wallis test were used to comparediscrete and continuous variables between quartile groups. Multivariate logistic regression was performed to identify patient characteristics andserological facto C-reactive protein rs associated with deep remission.Results: Anti tumor necrosis factor-alpha concentrations were higher inpatients with deep remission, in infliximab (4.4, interquartile range: 3.3-6.5vs 2.3, interquartile range: 1.1-4.2 μg/mL, P < 0.005) and adalimumab(6.3, interquartile range: 4.2-8.2 vs 3.9, interquartile range: 2.4-5.5 μg/mL,P < 0.005). (AU)

Therapeutic drug monitoring of levetiracetam in daily clinical practice: high-performance liquid chromatography versus immunoassay.

Objectives: Although levetiracetam presents an easy dosing and tolerability, therapeutic drug monitoring may be recommended in certain situations. Measurement of levetiracetam in serum plasma is commonly done by high performance liquid chromatography (HPLC). After ARK Diagnostics marketed an enzyme immunoassay (IA) for levetiracetam in serum or plasma, automated determinations are possible. In this study, the performance of this immunoassay and the impact of automation on the follow-up in patients treated with levetiracetam is evaluated. We also detected those subpopulations of patients who may benefit the most from this therapeutic drug monitoring. Methods: Samples from 50 outpatients diagnosed with epilepsy and treated with levetiracetam were collected. This new IA was performed on the Architect c4000 analyser and compared with the HPLC. Then, a retrospective observational study that included serum samples of levetiracetam for 24 months, was conducted to evaluate the impact of automattion and the influence of some variables (age, sex, renal function, and co-administration of valproic acid and glucuronidation-inducing drugs) in levetiracetam apparent oral clearance (CLp/F) by a multivariate linear regression. Results: The mean high-performance liquid chromatography quantified concentration (CpHPLC) was 18.43 mcg/mL (95% CI: 15.48 to 21.39) and immunoassay concentration (CpEI) was 18.35 mcg/mL (95% CI: 15.20 to 21.50) (P=0.861). The Pearson's linear correlation coefficient obtained in the analysis was r2=0.88, according to the following equation: CpHPLC=-0.29+1.01 CpEI. The intraclass correlation coefficient was 0.95 (95% CI: 0.91 to 0.97). After IA implementation, the number of levetiracetam determinations increased in 76.27%. The median of Clp/F was higher (P<0.001) in inducers (4.36 L/h; IQR:3.29-5.44) and lower (P<0.001) in glomerular filtration rate (GFR) <60 mL/min (2.7 L/h; IQR: 0.58-3.85). Conclusions: The Ark method performed on the Architect is fully acceptable and can be used routinely to measure levetiracetam plasmatic concentration levels. It has demonstrated the need for closer monitoring in patients with renal failure or co-administration of glucuronidation-inducing drugs.