Article
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Preserved in Portico This version is not peer-reviewed
Effects of H2-Receptor Antagonists on the Exposure of Dacomitinib
Version 1
: Received: 26 October 2023 / Approved: 26 October 2023 / Online: 27 October 2023 (07:06:07 CEST)
A peer-reviewed article of this Preprint also exists.
Liu, J.; Lin, S.; Huynh, A.; Tan, W. Effects of H2-Receptor Antagonists on the Exposure of Dacomitinib. Pharmaceutics 2024, 16, 118. Liu, J.; Lin, S.; Huynh, A.; Tan, W. Effects of H2-Receptor Antagonists on the Exposure of Dacomitinib. Pharmaceutics 2024, 16, 118.
Abstract
Dacomitinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for the treatment of patients with advanced non-small cell lung cancer (NSCLC) and EGFR-activating mutations. Proton pump inhibitors decreased dacomitinib exposure. This anal-ysis summarizes the effect of H2RA on dacomitinib exposure. A within-patient comparison of steady-state trough concentrations (Ctrough,ss) of dacomitinib and its active metabolite and active moiety with and without concomitant use of H2RA was conducted using a linear mixed effects model with pooled data from 11 clinical studies in patients with NSCLC. An oral absorption PBPK model was constructed and verified using clinical PK data after a single dose of dacomitinib in healthy volunteers to estimate the effect of gastric pH altered by an H2RA on dacomitinib PK. The adjusted geometric mean of dacomitinib Ctrough,ss of dacomitinib parent, metabolite and active moiety following co-administration with H2RA was approximately 86%, 104% and 100% relative to that following dacomitinib 45 mg administration without H2RA (P>0.05). The PBPK modeling showed negligible change in dacomitinib Cmax and AUC over 0-24 hours after H2RA administra-tion, when compared with those administered dacomitinib alone. Co-administration of an H2RA with dacomitinib is not expected to have any clinically relevant effect on dacomitinib exposure.
Keywords
dacomitinib; EGFR inhibitor; overall survival; pharmacokinetics; progression-free survival; proton pump inhibitors
Subject
Medicine and Pharmacology, Medicine and Pharmacology
Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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