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Time-to-event modelling of effect of codrituzumab on overall survival in patients with hepatocellular carcinoma.
Nakamura, Mikiko; Xu, Chao; Diack, Cheikh; Ohishi, Norihisa; Lee, Ruey-Min; Iida, Satofumi; Kawanishi, Takehiko; Ohtomo, Toshihiko; Abou-Alfa, Ghassan K; Chen, Ya-Chi.
Afiliación
  • Nakamura M; Translational Clinical Research Science & Strategy Dept., Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
  • Xu C; Translational and Clinical Research Center, Hoffmann-La Roche Inc., New York City, USA.
  • Diack C; Clinical Pharmacology, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
  • Ohishi N; Translational Clinical Research Science & Strategy Dept., Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
  • Lee RM; Translational and Clinical Research Center, Hoffmann-La Roche Inc., New York City, USA.
  • Iida S; Translational Clinical Research Science & Strategy Dept., Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
  • Kawanishi T; Translational Clinical Research Science & Strategy Dept., Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
  • Ohtomo T; Project Planning & Coordination Dept., Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
  • Abou-Alfa GK; Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Chen YC; Translational and Clinical Research Center, Hoffmann-La Roche Inc., New York City, USA.
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.
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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 / 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

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 / 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
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