Population pharmacokinetics and exposure-overall survival analysis of the transforming growth factor-ß inhibitor galunisertib in patients with pancreatic cancer.
Cancer Chemother Pharmacol
; 84(5): 1003-1015, 2019 Nov.
Article
em En
| MEDLINE
| ID: mdl-31482224
ABSTRACT
PURPOSE:
To evaluate the exposure-overall survival (OS) relationship in patients with advanced pancreatic cancer treated with galunisertib plus gemcitabine (GG) or gemcitabine plus placebo (GP).METHODS:
Galunisertib 300 mg/day was given orally as intermittent dosing and gemcitabine as per label. Galunisertib exposure metrics for each patient in the GG arm (n = 99) of a phase 2 study of pancreatic cancer were calculated. Parametric survival models were used to identify influential baseline and response covariates on OS.RESULTS:
The population pharmacokinetics dataset included data from 297 patients/healthy subjects (age 22-84 years, weight 39-126 kg) across multiple studies, including this pancreatic cancer study. Galunisertib was rapidly absorbed with peak concentrations attained within 0.5-2 h and had an elimination half-life of 8 h. Between-subject variance on apparent clearance was estimated to be 47%. Age was the only characteristic to have a statistically significant effect on apparent clearance. A parametric Weibull survival model with treatment effect (dose) estimated a hazard ratio of 0.796, after adjusting for patient baseline factors that were significantly associated with OS. There was also a flat daily exposure-OS relationship within the observed exposure range, once all significant baseline covariates were included. Response covariates, such as reduction in CA19-9, time on treatment, and cumulative exposure over treatment cycles were also identified as significant factors for OS for patients with pancreatic cancer.CONCLUSIONS:
This analysis suggests that 300 mg/day galunisertib administered as 150 mg twice daily for 14 days on/14 days off treatment is an appropriate dosing regimen for patients with pancreatic cancer.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
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Protocolos de Quimioterapia Combinada Antineoplásica
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Antígeno CA-19-9
Tipo de estudo:
Clinical_trials
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Prognostic_studies
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Systematic_reviews
Limite:
Adult
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Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article