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01-11-2019 | Pharmacokinetics | Original Article

Population pharmacokinetics and exposure–overall survival analysis of the transforming growth factor-β inhibitor galunisertib in patients with pancreatic cancer

Authors: Ivelina Gueorguieva, Josep Tabernero, Davide Melisi, Teresa Macarulla, Valeria Merz, Timothy H. Waterhouse, Colin Miles, Michael M. Lahn, Ann Cleverly, Karim A. Benhadji

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2019

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.

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Title: Population pharmacokinetics and exposure–overall survival analysis of the transforming growth factor-β inhibitor galunisertib in patients with pancreatic cancer
Authors: Ivelina Gueorguieva
Josep Tabernero
Davide Melisi
Teresa Macarulla
Valeria Merz
Timothy H. Waterhouse
Colin Miles
Michael M. Lahn
Ann Cleverly
Karim A. Benhadji
Publication date: 01-11-2019
Publisher: Springer Berlin Heidelberg
Keywords: Pharmacokinetics
Pancreatic Cancer
Pancreatic Cancer
Published in: Cancer Chemotherapy and Pharmacology / Issue 5/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-019-03931-1

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