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Farmacocinética e monitorização das concentrações séricas do tacrolimus
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O tacrolimus é um inibidor da calcineurina e um dos principais fármacos utilizados na
terapêutica imunossupressora após transplante. Contudo, apresenta marcados efeitos
adversos, variabilidade farmacocinética e farmacodinâmica intra e interindividual e
índice terapêutico estreito, pelo que é alvo de monitorização farmacoterapêutica para
assegurar que a concentração do fármaco no sangue se encontra dentro da margem
terapêutica. Esta monitorização é essencial para garantir a eficácia da ação
imunossupressora do tacrolimus, prevenindo a rejeição do órgão transplantado, e
minimizar a sua toxicidade. Atualmente, a monitorização do tacrolimus é realizada
através do doseamento do fármaco no sangue, numa frequência que depende do tempo
após o transplante e das características do doente, sendo as doses subsequentes
definidas com base nos resultados obtidos. A presente dissertação teve como objetivo
realizar uma revisão da bibliografia existente acerca da farmacocinética e
monitorização do tacrolimus, procurando identificar as principais problemáticas atuais
e desafios futuros, no que diz respeito à utilização deste fármaco. Devido à sua elevada
variabilidade farmacocinética e farmacodinâmica, é difícil definir a dose mais adequada
de tacrolimus a administrar a cada doente para que as concentrações séricas do fármaco
se encontrem dentro da margem terapêutica. Sabe-se que os principais fatores
relacionados com a variabilidade deste fármaco são a idade, etnia, género, função renal
e hepática, terapêutica concomitante e fatores genéticos, como os polimorfismos
associados às isoenzimas do CYP450, especialmente o CYP3A5. Deste modo,
concluiu-se que a caracterização dos doentes sob terapêutica com tacrolimus,
recorrendo nomeadamente à farmacogenética para otimizar e individualizar a dose a
administrar, tem um papel extremamente importante na minimização da toxicidade do
fármaco e prevenção de concentrações subterapêuticas e, consequentemente, na
prevenção da rejeição e perda do órgão transplantado. As estratégias que integram
algoritmos baseados em indicadores farmacogenéticos e outros, como o tipo de
formulação e características dos doentes, devem ser implementadas de forma a reduzir
a rejeição do órgão transplantado.
Tacrolimus is a calcineurin inhibitor and one of the main drugs used in immunosuppressive therapy after organ transplantation. However, it has marked adverse effects, intra and interindividual pharmacokinetic and pharmacodynamic variability and a narrow therapeutic index, so it must undergo therapeutic drug monitoring in order to ensure that the drug whole blood levels lie within the therapeutic margin. Therapeutic drug monitoring is essential to ensure the effectiveness of tacrolimus immunosuppressive action, preventing rejection of the transplanted organ, and to minimize this drug toxicity. Currently, monitoring of tacrolimus is performed by measuring the drug whole blood levels at a frequency that depends on the time elapsed since transplantation and the patient's profile with the subsequent doses being determined based on the results obtained. The present article aimed to carry out a review of the existing literature on tacrolimus pharmacokinetics and therapeutic drug monitoring, identify the main current problems and future challenges, with regard to the use of this drug. Due to its high pharmacokinetic and pharmacodynamic variability, it is difficult to determine the most adequate dose to be administered to each patient so that tacrolimus whole blood levels are within the therapeutic margin. It is well-known that the main factors related to this drug variability are age, ethnicity, gender, kidney and liver function, concomitant therapy and genetic factors, such as polymorphisms associated with CYP450 isoenzymes, specially CYP3A5. Thus, it was concluded that the characterization of patients undergoing tacrolimus therapy, using pharmacogenetics to optimize and personalize tacrolimus dosing, has an extremely important role in minimizing its toxicity, preventing subtherapeutic drug levels and, consequently, avoiding rejection and loss of the transplanted organ. Strategies that integrate algorithms based on pharmacogenetic indicators and others such as the type of formulation and the patients characteristics must be implemented to reduce the rejection of the transplanted organ.
Tacrolimus is a calcineurin inhibitor and one of the main drugs used in immunosuppressive therapy after organ transplantation. However, it has marked adverse effects, intra and interindividual pharmacokinetic and pharmacodynamic variability and a narrow therapeutic index, so it must undergo therapeutic drug monitoring in order to ensure that the drug whole blood levels lie within the therapeutic margin. Therapeutic drug monitoring is essential to ensure the effectiveness of tacrolimus immunosuppressive action, preventing rejection of the transplanted organ, and to minimize this drug toxicity. Currently, monitoring of tacrolimus is performed by measuring the drug whole blood levels at a frequency that depends on the time elapsed since transplantation and the patient's profile with the subsequent doses being determined based on the results obtained. The present article aimed to carry out a review of the existing literature on tacrolimus pharmacokinetics and therapeutic drug monitoring, identify the main current problems and future challenges, with regard to the use of this drug. Due to its high pharmacokinetic and pharmacodynamic variability, it is difficult to determine the most adequate dose to be administered to each patient so that tacrolimus whole blood levels are within the therapeutic margin. It is well-known that the main factors related to this drug variability are age, ethnicity, gender, kidney and liver function, concomitant therapy and genetic factors, such as polymorphisms associated with CYP450 isoenzymes, specially CYP3A5. Thus, it was concluded that the characterization of patients undergoing tacrolimus therapy, using pharmacogenetics to optimize and personalize tacrolimus dosing, has an extremely important role in minimizing its toxicity, preventing subtherapeutic drug levels and, consequently, avoiding rejection and loss of the transplanted organ. Strategies that integrate algorithms based on pharmacogenetic indicators and others such as the type of formulation and the patients characteristics must be implemented to reduce the rejection of the transplanted organ.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2020, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Tacrolimus Farmacocinética Farmacogenética Monitorização farmacoterapêutica Transplante renal Mestrado integrado - 2020