Development of a generalized pharmacokinetic model to characterize clinical pharmacokinetics of monomethyl auristatin E-based antibody-drug conjugates.
Br J Clin Pharmacol
; 90(7): 1637-1655, 2024 Jul.
Article
em En
| MEDLINE
| ID: mdl-38566392
ABSTRACT
AIMS:
This study aims to develop a generalized pharmacokinetic (PK) model for monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs) that can simultaneously capture the PK of multiple ADC analytes commonly measured in the clinic.METHODS:
A comprehensive literature review was conducted to collect PK data on MMAE-based ADCs from clinical trials. From each study, PK profiles of total antibody, the ADC, conjugated MMAE, and unconjugated MMAE, were extracted. These data were pooled and dose-normalized to evaluate the generalizability of PK across various ADCs and dose levels. Upon confirming PK generalizability, a generalized PK model for MMAE-based ADCs was developed using the entire dataset. Furthermore, exposure metrics ( C max and AUC) reported across the range of doses were combined to establish linear relationships between dose and exposure metrics for MMAE-based ADCs.RESULTS:
A total of 109 PK profiles from 18 distinct MMAE-based ADCs were gathered. The dose-normalized PK profiles supported the generalizability of PK for MMAE-based ADCs. A generalized PK model was developed, which enabled capturing the PK data for 4 ADC analytes across all collected MMAE-based ADCs. A linear relationship between dose and PK exposure metrics was established, enabling the prediction of typical exposure values across different doses for MMAE-based ADCs.CONCLUSIONS:
This study comprehensively analysed clinical PK data from different valine-citrulline (vc)-MMAE-based ADCs. The generalized PK model developed here serves as an important tool for a priori prediction of the PK for multiple ADC analytes in clinical settings and lays the foundation for establishing generalized exposure-response and exposure-toxicity correlations for MMAE-based ADCs.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oligopeptídeos
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Imunoconjugados
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Relação Dose-Resposta a Droga
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Modelos Biológicos
Limite:
Humans
Idioma:
En
Revista:
Br J Clin Pharmacol
/
Br. j. clin. pharmacol
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British journal of clinical pharmacology
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos