Time-to-event modelling of effect of codrituzumab on overall survival in patients with hepatocellular carcinoma.
Br J Clin Pharmacol
; 84(5): 944-951, 2018 05.
Article
en En
| MEDLINE
| ID: mdl-29381229
AIMS: Codrituzumab (GC33) is a recombinant, humanized mAb that binds to glypican-3 (GPC3), an oncofetal protein highly expressed in hepatocellular carcinoma (HCC). This investigation aimed to identify clinically relevant factors that may affect the overall survival (OS) in HCC patients treated with codrituzumab and to quantitatively annotate their effects. METHODS: Codrituzumab exposure was estimated by a population pharmacokinetics model with a nonlinear elimination pathway. Analysis of OS was performed using a time-to-event model in 181 patients with advanced HCC. The model was tested with the addition of various covariates, including levels of immune biomarkers, such as CD16 (measured in terms of molecules of equivalent soluble fluorophore; CD16MESF ) and CD4, codrituzumab exposure and potential prognostic biomarkers of HCC such as baseline tumour size and soluble GPC3. RESULTS: The time-to-event model estimated a prolonged OS (>3 months) in patients with codrituzumab exposure of ≥230 µg ml-1 and high CD16MESF level (>5.26 × 105 MESF at least). The Weibull model was selected as the base hazard model. The baseline tumour size was included in the hazard model as a parameter independent of the drug effect. A logistic model was applied to explain the effects of drug exposure and CD16MESF level. CONCLUSIONS: The final model indicates that adequate drug exposure plus a favourable immune environment are associated with prolonged OS. This quantitative model should be further validated with emerging data so as to guide study design in future clinical trials.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
4_TD
/
6_ODS3_enfermedades_notrasmisibles
Problema de salud:
4_aids
/
6_digestive_diseases
/
6_liver_cancer
Asunto principal:
Antígenos CD4
/
Receptores de IgG
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Carcinoma Hepatocelular
/
Glipicanos
/
Anticuerpos Monoclonales Humanizados
/
Neoplasias Hepáticas
Tipo de estudio:
Clinical_trials
/
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Br J Clin Pharmacol
Año:
2018
Tipo del documento:
Article
País de afiliación:
Japón