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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 4/2018

Open Access 01-04-2018 | Original Article

Monitoring of erlotinib in pancreatic cancer patients during long-time administration and comparison to a physiologically based pharmacokinetic model

Authors: Andrea Gruber, Martin Czejka, Philipp Buchner, Marie Kitzmueller, Nairi Kirchbaumer Baroian, Christian Dittrich, Azra Sahmanovic Hrgovcic

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2018

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Abstract

Purpose

In this study, a therapeutic drug monitoring (TDM) of erlotinib in pancreatic cancer patients was performed over 50 weeks to reveal possible alterations in erlotinib plasma concentrations. Additionally, a physiologically based pharmacokinetic (PBPK) model was created to assess such variations in silico.

Methods

Patients with advanced pancreatic cancer received a chemotherapeutic combination of 100 mg erlotinib q.d., 500–900 mg capecitabine b.d. and 5 mg/kg bevacizumab q.2wks. Samples were analyzed by HPLC and the results were compared to a PBPK model, built with the software GastroPlus™ and based on calculated and literature data.

Results

The erlotinib plasma concentrations did not show any accumulation, but displayed a high inter-patient variability over the whole investigated period. Trough plasma concentrations ranged from 0.04 to 1.22 µg/ml after day 1 and from 0.01 to 2.4 µg/ml in the long-term assessment. 7% of the patients showed concentrations below the necessary activity threshold of 0.5 µg/ml during the first week. The impact of some co-variates on the pharmacokinetic parameters Cmax and AUC0–24 were shown in a PBPK model, including food effects, changes in body weight, protein binding or liver function and the concomitant intake of gastric acid reducing agents (ARAs).

Conclusion

This study presents the approach of combining TDM and PBPK modeling for erlotinib, a drug with a high interaction potential. TDM is an important method to monitor drugs with increased inter-patient variability, additionally, the PBPK model contributed valuable insights to the interaction mechanisms involved, resulting in an effective combination from a PK perspective to ensure a safe treatment.
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Metadata
Title
Monitoring of erlotinib in pancreatic cancer patients during long-time administration and comparison to a physiologically based pharmacokinetic model
Authors
Andrea Gruber
Martin Czejka
Philipp Buchner
Marie Kitzmueller
Nairi Kirchbaumer Baroian
Christian Dittrich
Azra Sahmanovic Hrgovcic
Publication date
01-04-2018
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 4/2018
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-018-3545-4

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