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Pharmacokinetic and exposure–response analyses of pertuzumab in combination with trastuzumab and docetaxel during neoadjuvant treatment of HER2+ early breast cancer

PURPOSE: The NeoSphere trial evaluated pertuzumab in the neoadjuvant setting [early breast cancer (EBC)] with pathological complete response (pCR) as the primary efficacy end point. This analysis of pertuzumab aimed to (1) compare its pharmacokinetics (PK) in patients with EBC versus advanced cancer...

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Autores principales: Quartino, Angelica L., Li, Hanbin, Jin, Jin Y., Wada, D. Russell, Benyunes, Mark C., McNally, Virginia, Viganò, Lucia, Nijem, Ihsan, Lum, Bert L., Garg, Amit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5306091/
https://www.ncbi.nlm.nih.gov/pubmed/28074265
http://dx.doi.org/10.1007/s00280-016-3218-0
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author Quartino, Angelica L.
Li, Hanbin
Jin, Jin Y.
Wada, D. Russell
Benyunes, Mark C.
McNally, Virginia
Viganò, Lucia
Nijem, Ihsan
Lum, Bert L.
Garg, Amit
author_facet Quartino, Angelica L.
Li, Hanbin
Jin, Jin Y.
Wada, D. Russell
Benyunes, Mark C.
McNally, Virginia
Viganò, Lucia
Nijem, Ihsan
Lum, Bert L.
Garg, Amit
author_sort Quartino, Angelica L.
collection PubMed
description PURPOSE: The NeoSphere trial evaluated pertuzumab in the neoadjuvant setting [early breast cancer (EBC)] with pathological complete response (pCR) as the primary efficacy end point. This analysis of pertuzumab aimed to (1) compare its pharmacokinetics (PK) in patients with EBC versus advanced cancers, (2) to further evaluate PK drug–drug interactions (DDIs) when given in combination with trastuzumab, and (3) to assess the relationship between exposure and efficacy to assess the clinical dosing regimen in the EBC patients. METHODS: Pertuzumab serum concentration data from 180 patients in NeoSphere were compared to historical observations and potential DDI was assessed, by applying simulation techniques using a population PK model. The impact of pertuzumab exposure on pCR rate was evaluated using a logit response model (n = 88). RESULTS: The observed PK matched the population PK model simulations, confirming that the PK in neoadjuvant EBC appear to be in agreement with the historical observations. No evidence of a DDI effect of trastuzumab or docetaxel on pertuzumab was observed supporting the doses when given in combination. In NeoSphere >90% of EBC patients achieved the non-clinical target serum concentration. There was no association between the pertuzumab serum concentration and pCR within the range observed in this study (20–100 μg/mL) supporting no dose adjustments needed for patients with lower exposure. CONCLUSIONS: This analysis further supports the lack of DDI between the two therapeutic proteins and the appropriateness of the approved fixed non-body-weight-adjusted pertuzumab dose in the treatment of neoadjuvant EBC with pertuzumab in combination with trastuzumab and docetaxel. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00280-016-3218-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-53060912017-02-24 Pharmacokinetic and exposure–response analyses of pertuzumab in combination with trastuzumab and docetaxel during neoadjuvant treatment of HER2+ early breast cancer Quartino, Angelica L. Li, Hanbin Jin, Jin Y. Wada, D. Russell Benyunes, Mark C. McNally, Virginia Viganò, Lucia Nijem, Ihsan Lum, Bert L. Garg, Amit Cancer Chemother Pharmacol Original Article PURPOSE: The NeoSphere trial evaluated pertuzumab in the neoadjuvant setting [early breast cancer (EBC)] with pathological complete response (pCR) as the primary efficacy end point. This analysis of pertuzumab aimed to (1) compare its pharmacokinetics (PK) in patients with EBC versus advanced cancers, (2) to further evaluate PK drug–drug interactions (DDIs) when given in combination with trastuzumab, and (3) to assess the relationship between exposure and efficacy to assess the clinical dosing regimen in the EBC patients. METHODS: Pertuzumab serum concentration data from 180 patients in NeoSphere were compared to historical observations and potential DDI was assessed, by applying simulation techniques using a population PK model. The impact of pertuzumab exposure on pCR rate was evaluated using a logit response model (n = 88). RESULTS: The observed PK matched the population PK model simulations, confirming that the PK in neoadjuvant EBC appear to be in agreement with the historical observations. No evidence of a DDI effect of trastuzumab or docetaxel on pertuzumab was observed supporting the doses when given in combination. In NeoSphere >90% of EBC patients achieved the non-clinical target serum concentration. There was no association between the pertuzumab serum concentration and pCR within the range observed in this study (20–100 μg/mL) supporting no dose adjustments needed for patients with lower exposure. CONCLUSIONS: This analysis further supports the lack of DDI between the two therapeutic proteins and the appropriateness of the approved fixed non-body-weight-adjusted pertuzumab dose in the treatment of neoadjuvant EBC with pertuzumab in combination with trastuzumab and docetaxel. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00280-016-3218-0) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2017-01-10 2017 /pmc/articles/PMC5306091/ /pubmed/28074265 http://dx.doi.org/10.1007/s00280-016-3218-0 Text en © The Author(s) 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://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.
spellingShingle Original Article
Quartino, Angelica L.
Li, Hanbin
Jin, Jin Y.
Wada, D. Russell
Benyunes, Mark C.
McNally, Virginia
Viganò, Lucia
Nijem, Ihsan
Lum, Bert L.
Garg, Amit
Pharmacokinetic and exposure–response analyses of pertuzumab in combination with trastuzumab and docetaxel during neoadjuvant treatment of HER2+ early breast cancer
title Pharmacokinetic and exposure–response analyses of pertuzumab in combination with trastuzumab and docetaxel during neoadjuvant treatment of HER2+ early breast cancer
title_full Pharmacokinetic and exposure–response analyses of pertuzumab in combination with trastuzumab and docetaxel during neoadjuvant treatment of HER2+ early breast cancer
title_fullStr Pharmacokinetic and exposure–response analyses of pertuzumab in combination with trastuzumab and docetaxel during neoadjuvant treatment of HER2+ early breast cancer
title_full_unstemmed Pharmacokinetic and exposure–response analyses of pertuzumab in combination with trastuzumab and docetaxel during neoadjuvant treatment of HER2+ early breast cancer
title_short Pharmacokinetic and exposure–response analyses of pertuzumab in combination with trastuzumab and docetaxel during neoadjuvant treatment of HER2+ early breast cancer
title_sort pharmacokinetic and exposure–response analyses of pertuzumab in combination with trastuzumab and docetaxel during neoadjuvant treatment of her2+ early breast cancer
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5306091/
https://www.ncbi.nlm.nih.gov/pubmed/28074265
http://dx.doi.org/10.1007/s00280-016-3218-0
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