Optimizing the Therapeutic Window of Targeted Drugs in Oncology: Potency-Guided First-in-Human Studies.
Clin Transl Sci
; 14(2): 536-543, 2021 03.
Article
em En
| MEDLINE
| ID: mdl-33048459
ABSTRACT
Many targeted therapies are administered at or near the maximum tolerated dose (MTD). With the advent of precision medicine, a larger therapeutic window is expected. Therefore, dose optimization will require a new approach to early clinical trial design. We analyzed publicly available data for 21 therapies targeting six kinases, and four poly (ADP-ribose) polymerase inhibitors, focusing on potency and exposure to gain insight into dose selection. The free average steady-state concentration (Css ) at the approved dose was compared to the in vitro cell potency (half-maximal inhibitory concentration (IC50 )). Average steady-state area under the plasma concentration-time curve, the fraction unbound drug in plasma, and the cell potency were taken from the US drug labels, US and European regulatory reviews, and peer-reviewed journal articles. The Css was remarkably similar to the IC50 . The median Css /IC50 value was 1.2, and 76% of the values were within 3-fold of unity. However, three drugs (encorafenib, erlotinib, and ribociclib) had a Css /IC50 value > 25. Seven other therapies targeting the same 3 kinases had much lower Css /IC50 values ranging from 0.5 to 4. These data suggest that these kinase inhibitors have a large therapeutic window that is not fully exploited; lower doses may be similarly efficacious with improved tolerability. We propose a revised first-in-human trial design in which dose cohort expansion is initiated at doses less than the MTD when there is evidence of clinical activity and Css exceeds a potency threshold. This potency-guided approach is expected to maximize the therapeutic window thereby improving patient outcomes.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
/
Prevencao_e_fatores_de_risco
/
Agentes_cancerigenos
/
Tipos_de_cancer
/
Outros_tipos
Base de dados:
MEDLINE
Assunto principal:
Ensaios Clínicos Fase I como Assunto
/
Inibidores de Proteínas Quinases
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Inibidores de Poli(ADP-Ribose) Polimerases
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Neoplasias
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Clin Transl Sci
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos