Kirschbrown, WP, Kagedal, M, Wang, B et al. (15 more authors) (2019) Pharmacokinetic and exploratory exposure-response analysis of pertuzumab in patients with operable HER2-positive early breast cancer in the APHINITY study. Cancer Chemotherapy and Pharmacology, 83 (6). pp. 1147-1158. ISSN 0344-5704
Abstract
Purpose: To characterize the pharmacokinetics (PK) of, and perform an exploratory exposure–response (E–R) analysis for, pertuzumab in patients with HER2-positive early breast cancer (EBC) within the APHINITY study (NCT01358877, BIG 4–11/BO25126/TOC4939G).
Methods: A previously developed pertuzumab two-compartment linear population pharmacokinetic (popPK) model was subjected to external validation to examine appropriateness for describing pertuzumab concentrations from the APHINITY study. Pharmacokinetic drug–drug interactions (DDIs) between pertuzumab, trastuzumab, and chemotherapy were assessed by comparing observed serum or plasma Cmax, Cmin, and AUClast geometric mean ratios with 90% CIs. Predictions of pertuzumab Cmax,ss, Cmin,ss, and AUCss were derived from individual parameter estimates and used in an exploratory E–R analysis.
Results: Using data from 72 patients, based on goodness-of-fit, the popPK model was deemed appropriate for predictions of individual exposures for subsequent comparisons to historical data, assessment of DDIs, and E–R analyses. No evidence of DDIs for pertuzumab on trastuzumab, trastuzumab on pertuzumab, or pertuzumab on chemotherapy PK was observed. Analyses of differences in exposure between patients with and without invasive disease-free survival events did not indicate improved efficacy with increased exposure. Overall Grade ≥ 3 diarrhea prevalence was higher with pertuzumab versus placebo, but was not greater with increasing pertuzumab exposure. No apparent E–R relationship was suggested with respect to other grade ≥ 3 AEs.
Conclusion: Overall, the limited available data from this exploratory study suggest that no dose adjustments are needed for pertuzumab when administered in combination with trastuzumab and an EBC chemotherapy regimen.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (c) 2019, The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
Keywords: | Pharmacokinetics; Exposure-response; Drug-drug interactions; Pertuzumab |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cancer and Pathology (LICAP) > Clinical Cancer Research (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 15 Jul 2019 15:42 |
Last Modified: | 15 Jul 2019 15:42 |
Status: | Published |
Publisher: | Springer |
Identification Number: | 10.1007/s00280-019-03826-1 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:148303 |