Publication: Impacto de la monitorización farmacocinética proactiva de adalimumab en pacientes con enfermedades inflamatorias reumáticas
Authors
Ortiz Fernández, Patricia
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Escuelas::Escuela Internacional de Doctorado
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Iniesta Navalón, Carles ; Urbieta Sanz, Elena Pilar
Publisher
Universidad de Murcia
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DOI
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info:eu-repo/semantics/doctoralThesis
Description
Abstract
Introducción
Las enfermedades reumáticas inflamatorias y musculoesqueléticas (ERM) constituyen un reto terapéutico por su heterogeneidad clínica y la variabilidad interindividual en la respuesta a fármacos biológicos. Adalimumab, un anticuerpo monoclonal frente al factor de necrosis tumoral alfa (TNF-α), ha demostrado una eficacia y seguridad sostenidas en el tratamiento de distintas ERM. En este contexto, la monitorización farmacocinética proactiva de fármacos biológicos se presenta como una herramienta útil para optimizar la exposición al fármaco, mejorar la respuesta clínica y anticipar la aparición de inmunogenicidad.
Objetivos
El objetivo principal del estudio fue evaluar la utilidad de la monitorización farmacocinética proactiva temprana (TDM) de adalimumab como estrategia para optimizar el tratamiento en pacientes con ERM, determinando su capacidad predictiva sobre la persistencia terapéutica. De forma específica, se planteó caracterizar demográfica y clínicamente a la población tratada, analizar la variabilidad farmacocinética y la adecuación de las concentraciones séricas a los rangos terapéuticos recomendados, así como estudiar la frecuencia y los factores asociados al desarrollo de inmunogenicidad. Se identificaron los determinantes clínicos y farmacocinéticos de la persistencia del tratamiento a 52 semanas.
Metodología
Se realizó un estudio observacional, retrospectivo y unicéntrico llevado a cabo en un hospital de referencia entre octubre de 2015 y enero de 2024. Se incluyeron pacientes ≥18 años con artritis reumatoide, artritis psoriásica o espondilitis anquilosante en tratamiento con adalimumab, con monitorización farmacocinética temprana, en las primeras 26 semanas de tratamiento. Se cuantificaron concentraciones séricas de adalimumab y anticuerpos anti-adalimumab mediante ELISA. Se evaluaron la persistencia del tratamiento, factores asociados a CsA infraterapéuticas, inmunogenicidad y respuesta a recomendaciones farmacocinéticas.
Resultados
Los resultados muestran que más de la mitad de los pacientes (56,7%) presentaron concentraciones séricas de adalimumab por debajo del rango terapéutico, con mayor riesgo en pacientes con espondilitis anquilosante y aquellos con mayor peso corporal. La inmunogenicidad se detectó en el 19,6% de los pacientes, principalmente durante el primer año y se relacionó con concentraciones séricas de adalimumab <1 μg/mL y una reducción significativa en la persistencia del tratamiento. La persistencia a 52 semanas fue significativamente mayor en pacientes con concentraciones séricas en rango terapéutico (66,7 % vs. 37,0 %; p<0,001) y en quienes recibían metotrexato concomitante. La intensificación posológica, basada en las recomendaciones farmacocinéticas, permitió mejorar significativamente la exposición al fármaco y aumentar la persistencia del tratamiento a corto y medio plazo.
Conclusiones
La monitorización farmacocinética proactiva de adalimumab permite identificar de forma temprana a pacientes con exposición subóptima o inmunogenicidad, optimizar la posología y mejorar la persistencia al tratamiento en pacientes con enfermedades reumáticas inflamatorias y musculoesqueléticas. Estos resultados apoyan su integración en la práctica clínica habitual como estrategia de medicina personalizada.
Introduction Inflammatory rheumatic and musculoskeletal diseases (RMDs) represent a therapeutic challenge due to their clinical heterogeneity and the high interindividual variability in response to biological agents. Adalimumab, a monoclonal antibody targeting tumor necrosis factor alpha (TNF-α), has demonstrated sustained efficacy and safety in the treatment of various RMDs. In this context, proactive pharmacokinetic monitoring of biological therapies has emerged as a valuable tool to optimize drug exposure, enhance clinical response, and anticipate the development of immunogenicity. Objectives The primary objective of this study was to evaluate the utility of early proactive therapeutic drug monitoring (TDM) of adalimumab as a strategy to optimize treatment in patients with RMDs, by assessing its predictive value for treatment persistence. Specifically, the study aimed to characterize the demographic and clinical profile of the treated population, analyze pharmacokinetic variability and serum concentration adequacy relative to therapeutic targets, and examine the frequency and associated factors of immunogenicity. Additionally, clinical and pharmacokinetic determinants of 52-week treatment persistence were identified. Methods A retrospective, monocentric observational study was conducted in a tertiary hospital between October 2015 and January 2024. Adult patients (≥18 years) diagnosed with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis receiving adalimumab and undergoing early pharmacokinetic monitoring within the first 26 weeks of treatment were included. Serum concentrations of adalimumab and anti-adalimumab antibodies were quantified using ELISA. Treatment persistence, factors associated with subtherapeutic drug levels, immunogenicity, and adherence to pharmacokinetic recommendations were evaluated. Results More than half of the patients (56.7%) exhibited serum adalimumab concentrations below the therapeutic range, with a higher risk observed in patients with ankylosing spondylitis and those with higher body weight. Immunogenicity was detected in 19.6% of patients, primarily within the first year of treatment, and was associated with adalimumab levels <1 μg/mL and a marked reduction in treatment persistence. Persistence at 52 weeks was significantly higher among patients with therapeutic-range drug levels (66.7% vs. 37.0%; p<0.001) and those receiving concomitant methotrexate. Dose intensification guided by pharmacokinetic recommendations significantly improved drug exposure and enhanced short- and mid-term treatment persistence. Conclusions Proactive pharmacokinetic monitoring of adalimumab enables the early identification of patients with suboptimal exposure or immunogenicity, allowing for timely dose optimization and improved treatment persistence in inflammatory rheumatic and musculoskeletal diseases. These findings support the integration of TDM into routine clinical practice as a personalized medicine strategy.
Introduction Inflammatory rheumatic and musculoskeletal diseases (RMDs) represent a therapeutic challenge due to their clinical heterogeneity and the high interindividual variability in response to biological agents. Adalimumab, a monoclonal antibody targeting tumor necrosis factor alpha (TNF-α), has demonstrated sustained efficacy and safety in the treatment of various RMDs. In this context, proactive pharmacokinetic monitoring of biological therapies has emerged as a valuable tool to optimize drug exposure, enhance clinical response, and anticipate the development of immunogenicity. Objectives The primary objective of this study was to evaluate the utility of early proactive therapeutic drug monitoring (TDM) of adalimumab as a strategy to optimize treatment in patients with RMDs, by assessing its predictive value for treatment persistence. Specifically, the study aimed to characterize the demographic and clinical profile of the treated population, analyze pharmacokinetic variability and serum concentration adequacy relative to therapeutic targets, and examine the frequency and associated factors of immunogenicity. Additionally, clinical and pharmacokinetic determinants of 52-week treatment persistence were identified. Methods A retrospective, monocentric observational study was conducted in a tertiary hospital between October 2015 and January 2024. Adult patients (≥18 years) diagnosed with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis receiving adalimumab and undergoing early pharmacokinetic monitoring within the first 26 weeks of treatment were included. Serum concentrations of adalimumab and anti-adalimumab antibodies were quantified using ELISA. Treatment persistence, factors associated with subtherapeutic drug levels, immunogenicity, and adherence to pharmacokinetic recommendations were evaluated. Results More than half of the patients (56.7%) exhibited serum adalimumab concentrations below the therapeutic range, with a higher risk observed in patients with ankylosing spondylitis and those with higher body weight. Immunogenicity was detected in 19.6% of patients, primarily within the first year of treatment, and was associated with adalimumab levels <1 μg/mL and a marked reduction in treatment persistence. Persistence at 52 weeks was significantly higher among patients with therapeutic-range drug levels (66.7% vs. 37.0%; p<0.001) and those receiving concomitant methotrexate. Dose intensification guided by pharmacokinetic recommendations significantly improved drug exposure and enhanced short- and mid-term treatment persistence. Conclusions Proactive pharmacokinetic monitoring of adalimumab enables the early identification of patients with suboptimal exposure or immunogenicity, allowing for timely dose optimization and improved treatment persistence in inflammatory rheumatic and musculoskeletal diseases. These findings support the integration of TDM into routine clinical practice as a personalized medicine strategy.
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