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Simplificación de la posología de dolutegravir en coinfección VIH/TB tratada con rifampicina: análisis mediante modelado farmacocinético de base fisiológica
Simplification of dolutegravir dosing in HIV/TB patients receiving rifampicin: a physiologicallybased pharmacokinetic modeling analysis
Simplificação da dosagem de dolutegravir em coinfecção HIV/TB tratada com rifampicina: análise utilizando modelagem farmacocinética de base fisiológica
DOI:
https://doi.org/10.15446/rcciquifa.v54n2.118462Palabras clave:
dolugetravir, rifampicina, terapia antrirretroviral, modelado farmacocinético de base fisiológica, interacciones medicamentosas (es)dolutegravir, rifampicin, antiretroviral therapy, physiologically based pharmacokinetic modelling., drug-drug interactions (en)
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Introducción: En pacientes coinfectados con VIH/TB que reciben dolutegravir y rifampicina se recomienda aumentar la dosis diaria de dolutegravir administrando 50mg cada 12 horas, atendiendo la inducción enzimática provocada por rifampicina y su efecto en la eliminación de dolutegravir. Esto aumenta la complejidad del esquema posológico y disminuye la probabilidad de adherencia. El objetivo de este trabajo fue evaluar simplificaciones al tratamiento utilizando un modelo farmacocinético de base fisiológica (PBPK). Métodos: Se desarrolló y validó un modelo PBPK de interacción fármaco-fármaco en PK-Sim®, describiendo las concentraciones plasmáticas de dolutegravir y rifampicina tras distintas dosis. El modelo permitió realizar simulaciones poblacionales de la exposición de dolutegravir en esquemas posológicos simplificados, evaluando la probabilidad de alcanzar el objetivo terapéutico. Resultados: Se proyecta que bajo tratamiento con rifampicina 600mg diarios, los tratamientos con dolutegravir 50mg o 100mg en una única toma diaria alcanzarían el objetivo terapéutico en 72.6% y 89% de la población, respectivamente. Estas proyecciones coinciden con resultados de ensayos clínicos previos. Conclusión: La administración de dolutegravir 100mg en una única toma sería una alternativa efectiva para simplificar el tratamiento en pacientes con VIH/TB que reciben rifampicina, favoreciendo la adherencia, mejorando la cobertura y contribuyendo al manejo eficiente de la coinfección VIH/TB.
Introduction: In HIV/TB coinfected patients receiving dolutegravir (DTG) with rifampicin (RFP), increasing the daily DTG dose to 50mg every 12 hours is recommended, addressing the enzymatic induction caused by RFP and its effect on DTG elimination. This additional administration results in a more complex dosing regimen with lower probability of patient adherence. The aim of this study was to evaluate simplifications to the recommended posology using a physiologically-based pharmacokinetic model (PBPK). Methods: A drug-drug interaction PBPK model was developed and validated in PK-Sim® software, describing plasma concentrations of DTG and RFP administered at different doses, both jointly and independently. The model was used to perform population simulations of DTG exposure resulting from simplified dosing regimens, evaluating the probability of target attainment. Results: Under treatment with RFP 600mg daily, DTG regimens of single daily doses of 50mg or 100mg are projected to achieve therapeutic target in 72.6% and 89% of the population, respectively. These projections align with previously reported clinical trial results. Conclusion: Administration of DTG as a single daily dose of 100mg would be an effective alternative to simplify treatment in HIV/TB patients receiving RFP, promoting adherence, improving treatment coverage, and contributing to efficient management of HIV/TB coinfection.
Introdução: Em pacientes coinfectados por HIV/TB em uso de dolutegravir e rifampicina, recomendase aumentar a dose diária de dolutegravir, administrando 50 mg a cada 12 horas, levando em consideração a indução enzimática causada pela rifampicina e seu efeito na eliminação do dolutegravir. Isso aumenta a complexidade do regime posológico e diminui a probabilidade de adesão. O objetivo deste estudo foi avaliar simplificações no tratamento utilizando um modelo farmacocinético de base fisiológica (PBPK). Métodos: Um modelo de interação medicamentosa PBPK foi desenvolvido e validado no PK-Sim®, descrevendo as concentrações plasmáticas de dolutegravir e rifampicina após diferentes doses. O modelo permitiu simulações populacionais da exposição ao dolutegravir utilizando regimes posológicos simplificados, avaliando a probabilidade de atingir a meta terapêutica. Resultados: Projeta-se que, sob tratamento com 600 mg de rifampicina por dia, os tratamentos com dolutegravir 50 mg ou 100 mg em dose única diária atingiriam a meta terapêutica em 72,6% e 89% da população, respectivamente. Essas projeções são consistentes com os resultados de ensaios clínicos anteriores. Conclusão: A administração de dolutegravir 100 mg em dose única seria uma alternativa eficaz para simplificar o tratamento em pacientes com HIV/TB em uso de rifampicina, promovendo a adesão, melhorando a cobertura e contribuindo para o manejo eficiente da coinfecção HIV/TB
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