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Farmacocinética clínica dos anticorpos monoclonais usados no cancro do pulmão
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Authors
Advisor(s)
Abstract(s)
A neoplasia do pulmão é um problema de saúde major, constituindo a principal causa de
morte por cancro a nível mundial. Em Portugal, cerca de 75% dos casos são diagnosticados
em estadio localmente avançado ou metastático, conferido uma taxa de sobrevivência a cinco
anos de apenas 6%. De acordo com a histologia, esta patologia pode ser classificada em
carcinoma pulmonar de pequenas células e carcinoma pulmonar de não-pequenas células, que
representa a grande maioria dos casos diagnosticados.
Com o decorrer dos avanços científicos e tecnológicos, surgiu uma nova abordagem
terapêutica personalizada e altamente seletiva, a imunoterapia. Através da intervenção do
sistema imunitário na regulação dos mecanismos de controlo e proliferação tumoral, a
imunoterapia tem vindo a melhorar outcomes clínicos e a transformar o prognóstico desta
neoplasia. Um dos exemplos mais representativos das terapêuticas imunológicas são os
inibidores do checkpoint imunitário, com destaque para o atezolizumab, nivolumab e
pembrolizumab.
Apesar do impacto clínico significativo associado à utilização destes fármacos, apenas 20% a
40% dos doentes exibem taxas de sobrevivência duradouras, após o término da terapêutica.
Desta forma, urge investigar e compreender as propriedades farmacocinéticas intrínsecas a
estes fármacos e o seu contributo para as variações intra e interindividuais observadas, tanto
na exposição, como na resposta à terapêutica. Ademais, estudos recentes têm demonstrado
que, ao serem administradas doses previamente estabelecidas pelas autoridades reguladoras
competentes são alcançados níveis sobre-terapêuticos no estado estacionário. Todavia, pouca
importância tem sido atribuída à análise destas discrepâncias e permanecem dúvidas quanto à
metodologia preferencial a adotar no estabelecimento de regimes posológicos para estes
fármacos: doses fixas pré-estabelecidas versus doses ajustadas ao peso corporal.
Com a evolução da medicina de precisão, surge a monitorização farmacocinética da
terapêutica, que através da individualização farmacoterapêutica, assegura a maximização da
eficácia clínica e, reduz a ocorrência de exposições sub-terapêuticas ou níveis de toxicidade
inaceitáveis. Neste âmbito, é também necessário investir na validação de biomarcadores,
capazes de prever e monitorizar a resposta à terapêutica com estes fármacos.
Lung cancer is a major health problem and the leading cause of cancer death worldwide. In Portugal, around 75 per cent of cases are diagnosed at a locally advanced or metastatic stage, giving a five-year survival rate of just 6 per cent. According to histology, this pathology can be classified into small cell lung carcinoma and non-small cell lung carcinoma, which represents the vast majority of diagnosed cases. With scientific and technological advances, a new personalised and highly selective therapeutic approach has emerged: immunotherapy. Through the intervention of the immune system in the regulation of tumor control and proliferation mechanisms, immunotherapy has been improving clinical outcomes and transforming the prognosis of this neoplasm. One of the most representative examples of immunological therapies are immune checkpoint inhibitors, particularly atezolizumab, nivolumab and pembrolizumab. Despite the significant clinical impact associated with the use of these drugs, only 20% to 40% of patients have long-lasting survival rates after the end of therapy. There is therefore an urgent need to investigate and understand the intrinsic pharmacokinetic properties of these drugs and their contribution to the intra- and inter-individual variations observed in both exposure and response to therapy. In addition, recent studies have shown that when administered doses previously established by the competent regulatory authorities, overtherapeutic levels are achieved at steady state. However, little importance has been attached to analysing these discrepancies and doubts remain as to the preferred methodology to adopt when establishing dosage regimens for these drugs: fixed pre-established doses versus doses adjusted to body weight. With the evolution of precision medicine comes pharmacokinetic monitoring of therapy, which, through pharmacotherapeutic individualisation, ensures the maximisation of clinical efficacy and reduces the occurrence of sub-therapeutic exposures or unacceptable levels of toxicity. In this context, it is also necessary to invest in the validation of biomarkers capable of predicting and monitoring the response to therapy with these drugs.
Lung cancer is a major health problem and the leading cause of cancer death worldwide. In Portugal, around 75 per cent of cases are diagnosed at a locally advanced or metastatic stage, giving a five-year survival rate of just 6 per cent. According to histology, this pathology can be classified into small cell lung carcinoma and non-small cell lung carcinoma, which represents the vast majority of diagnosed cases. With scientific and technological advances, a new personalised and highly selective therapeutic approach has emerged: immunotherapy. Through the intervention of the immune system in the regulation of tumor control and proliferation mechanisms, immunotherapy has been improving clinical outcomes and transforming the prognosis of this neoplasm. One of the most representative examples of immunological therapies are immune checkpoint inhibitors, particularly atezolizumab, nivolumab and pembrolizumab. Despite the significant clinical impact associated with the use of these drugs, only 20% to 40% of patients have long-lasting survival rates after the end of therapy. There is therefore an urgent need to investigate and understand the intrinsic pharmacokinetic properties of these drugs and their contribution to the intra- and inter-individual variations observed in both exposure and response to therapy. In addition, recent studies have shown that when administered doses previously established by the competent regulatory authorities, overtherapeutic levels are achieved at steady state. However, little importance has been attached to analysing these discrepancies and doubts remain as to the preferred methodology to adopt when establishing dosage regimens for these drugs: fixed pre-established doses versus doses adjusted to body weight. With the evolution of precision medicine comes pharmacokinetic monitoring of therapy, which, through pharmacotherapeutic individualisation, ensures the maximisation of clinical efficacy and reduces the occurrence of sub-therapeutic exposures or unacceptable levels of toxicity. In this context, it is also necessary to invest in the validation of biomarkers capable of predicting and monitoring the response to therapy with these drugs.
Description
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2023, Universidade de Lisboa, Faculdade de Farmácia.
Keywords
Cancro do pulmão Imunoterapia Inibidores do checkpoint imunitário Propriedades farmacocinéticas Monitorização terapêutica de fármacos Mestrado Integrado - 2023