Evaluating a Multiscale Mechanistic Model of the Immune System to Predict Human Immunogenicity for a Biotherapeutic in Phase 1.
AAPS J
; 21(5): 94, 2019 07 24.
Article
em En
| MEDLINE
| ID: mdl-31342199
ABSTRACT
A mechanistic model of the immune response was evaluated for its ability to predict anti-drug antibody (ADA) and their impact on pharmacokinetics (PK) and pharmacodynamics (PD) for a biotherapeutic in a phase 1 clinical trial. Observed ADA incidence ranged from 33 to 67% after single doses and 27-50% after multiple doses. The model captured the single dose incidence well; however, there was overprediction after multiple dosing. The model was updated to include a T-regulatory (Treg) cell mediated tolerance, which reduced the overprediction (relative decrease in predicted incidence rate of 21.5-59.3% across multidose panels) without compromising the single dose predictions (relative decrease in predicted incidence rate of 0.6-13%). The Treg-adjusted model predicted no ADA impact on PK or PD, consistent with the observed data. A prospective phase 2 trial was simulated, including co-medication effects in the form of corticosteroid-induced immunosuppression. Predicted ADA incidences were 0-10%, depending on co-medication dosage. This work demonstrates the utility in applying an integrated, iterative modeling approach to predict ADA during different stages of clinical development.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas
/
Modelos Biológicos
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Anticorpos
Tipo de estudo:
Clinical_trials
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
AAPS J
Ano de publicação:
2019
Tipo de documento:
Article