Effects of H2-Receptor Antagonists on the Exposure of Dacomitinib
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 analysis summarizes the...
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MDPI AG
2024-01-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/16/1/118 |
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| author | Jian Liu Swan Lin Anthony Huynh Weiwei Tan |
| author_facet | Jian Liu Swan Lin Anthony Huynh Weiwei Tan |
| author_sort | Jian Liu |
| collection | DOAJ |
| description | 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 analysis summarizes the effect of Histamine-2 receptor antagonists (H2RAs) on dacomitinib exposure. A within-patient comparison of the steady-state trough concentrations (C<sub>trough,ss</sub>) of dacomitinib and its active metabolite and active moiety with and without concomitant use of H2RAs was conducted using a linear mixed effects model with pooled data from 11 clinical studies in patients with NSCLC. An oral absorption physiologically based pharmacokinetic (PBPK) model was constructed and verified using clinical pharmacokinetic (PK) data after a single dose of dacomitinib in healthy volunteers to estimate the effect of gastric pH altered by an H2RA on dacomitinib’s PKs. The adjusted geometric mean of the dacomitinib C<sub>trough,ss</sub> of the dacomitinib parent, metabolite and active moiety following co-administration with an H2RA was approximately 86%, 104% and 100% relative to that following dacomitinib 45 mg administration without an H2RA (<i>p</i> > 0.05). The PBPK modeling showed negligible change in dacomitinib maximum concentration (C<sub>max</sub>) and area under the drug concentration–time curve (AUC) over 0–24 h after H2RA administration 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. |
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| format | Article |
| id | doaj.art-b84ee7c4393647d6adf0ca8ebfcf2846 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-08T10:37:46Z |
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| series | Pharmaceutics |
| spelling | doaj.art-b84ee7c4393647d6adf0ca8ebfcf28462024-01-26T18:07:54ZengMDPI AGPharmaceutics1999-49232024-01-0116111810.3390/pharmaceutics16010118Effects of H2-Receptor Antagonists on the Exposure of DacomitinibJian Liu0Swan Lin1Anthony Huynh2Weiwei Tan3Clinical Pharmacology, Pfizer Investment Co., Ltd., Beijing 100010, ChinaClinical Pharmacology, Global Product Development, Pfizer Inc., San Diego, CA 92121, USASkaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA 92093, USAClinical Pharmacology, Global Product Development, Pfizer Inc., San Diego, CA 92121, USADacomitinib 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 analysis summarizes the effect of Histamine-2 receptor antagonists (H2RAs) on dacomitinib exposure. A within-patient comparison of the steady-state trough concentrations (C<sub>trough,ss</sub>) of dacomitinib and its active metabolite and active moiety with and without concomitant use of H2RAs was conducted using a linear mixed effects model with pooled data from 11 clinical studies in patients with NSCLC. An oral absorption physiologically based pharmacokinetic (PBPK) model was constructed and verified using clinical pharmacokinetic (PK) data after a single dose of dacomitinib in healthy volunteers to estimate the effect of gastric pH altered by an H2RA on dacomitinib’s PKs. The adjusted geometric mean of the dacomitinib C<sub>trough,ss</sub> of the dacomitinib parent, metabolite and active moiety following co-administration with an H2RA was approximately 86%, 104% and 100% relative to that following dacomitinib 45 mg administration without an H2RA (<i>p</i> > 0.05). The PBPK modeling showed negligible change in dacomitinib maximum concentration (C<sub>max</sub>) and area under the drug concentration–time curve (AUC) over 0–24 h after H2RA administration 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.https://www.mdpi.com/1999-4923/16/1/118dacomitinibEGFR inhibitoroverall survivalpharmacokineticsprogression-free survivalproton-pump inhibitors |
| spellingShingle | Jian Liu Swan Lin Anthony Huynh Weiwei Tan Effects of H2-Receptor Antagonists on the Exposure of Dacomitinib Pharmaceutics dacomitinib EGFR inhibitor overall survival pharmacokinetics progression-free survival proton-pump inhibitors |
| title | Effects of H2-Receptor Antagonists on the Exposure of Dacomitinib |
| title_full | Effects of H2-Receptor Antagonists on the Exposure of Dacomitinib |
| title_fullStr | Effects of H2-Receptor Antagonists on the Exposure of Dacomitinib |
| title_full_unstemmed | Effects of H2-Receptor Antagonists on the Exposure of Dacomitinib |
| title_short | Effects of H2-Receptor Antagonists on the Exposure of Dacomitinib |
| title_sort | effects of h2 receptor antagonists on the exposure of dacomitinib |
| topic | dacomitinib EGFR inhibitor overall survival pharmacokinetics progression-free survival proton-pump inhibitors |
| url | https://www.mdpi.com/1999-4923/16/1/118 |
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