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Obesity alters endoxifen plasma levels in young breast cancer patients: pharmacometric simulation approach

Obesity alters endoxifen plasma levels in young breast cancer patients: pharmacometric simulation approach
Obesity alters endoxifen plasma levels in young breast cancer patients: pharmacometric simulation approach
Endoxifen is the most important metabolite of the prodrug tamoxifen. High interindividual variability in endoxifen steady-state concentrations (CSS,min ENDX) is observed under tamoxifen standard dosing breast cancer patients that do not reach endoxifen concentrations above a proposed therapeutic threshold of 5.97 ng/mL may be at higher recurrence risk. In this investigation, 10 clinical tamoxifen studies were pooled (nPatients=1388) to investigate influential factors on CSS,min ENDX using nonlinear mixed-effects modelling. Age and body weight were found to significantly impact CSS,min ENDX in addition to CYP2D6 phenotype. Compared to post-menopausal patients, pre-menopausal patients had a 30% higher risk for subtarget CSS,min ENDX at tamoxifen 20 mg per day. In treatment simulations for distinct patient subpopulations, young overweight patients had a 3.1-13.8-fold higher risk for subtarget CSS,min ENDX compared to elderly low-weight patients. Considering ever-rising obesity rates and the clinical importance of tamoxifen for pre-menopausal patients, this subpopulation may benefit most from individualised tamoxifen dosing.
0009-9236
661-670
Mueller-Schoell, Anna
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Klopp-Schulze, Lena
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Schroth, Werner
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Murdter, Thomas
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Michelet, Robin
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Brauch, Hiltrud
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Huisinga, Wilhelm
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Joerger, Markus
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Neven, Patrick
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Koolen, Stijn L.W.
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Mathijssen, Ron H.J.
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Copson, Ellen
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Eccles, Diana
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Chen, Sylvia
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Chowbay, Balram
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Tfayli, Arafat
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Khoueiry-Zgheib, Nathalie
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Schwab, Matthias
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Kloft, Charlotte
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Mueller-Schoell, Anna
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Klopp-Schulze, Lena
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Schroth, Werner
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Murdter, Thomas
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Michelet, Robin
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Brauch, Hiltrud
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Huisinga, Wilhelm
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Joerger, Markus
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Neven, Patrick
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Koolen, Stijn L.W.
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Mathijssen, Ron H.J.
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Copson, Ellen
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Eccles, Diana
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Chen, Sylvia
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Chowbay, Balram
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Tfayli, Arafat
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Khoueiry-Zgheib, Nathalie
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Schwab, Matthias
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Kloft, Charlotte
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Mueller-Schoell, Anna, Klopp-Schulze, Lena, Schroth, Werner, Murdter, Thomas, Michelet, Robin, Brauch, Hiltrud, Huisinga, Wilhelm, Joerger, Markus, Neven, Patrick, Koolen, Stijn L.W., Mathijssen, Ron H.J., Copson, Ellen, Eccles, Diana, Chen, Sylvia, Chowbay, Balram, Tfayli, Arafat, Khoueiry-Zgheib, Nathalie, Schwab, Matthias and Kloft, Charlotte (2020) Obesity alters endoxifen plasma levels in young breast cancer patients: pharmacometric simulation approach. Clinical Pharmacology and Therapeutics, 108 (3), 661-670. (doi:10.1002/cpt.1960).

Record type: Article

Abstract

Endoxifen is the most important metabolite of the prodrug tamoxifen. High interindividual variability in endoxifen steady-state concentrations (CSS,min ENDX) is observed under tamoxifen standard dosing breast cancer patients that do not reach endoxifen concentrations above a proposed therapeutic threshold of 5.97 ng/mL may be at higher recurrence risk. In this investigation, 10 clinical tamoxifen studies were pooled (nPatients=1388) to investigate influential factors on CSS,min ENDX using nonlinear mixed-effects modelling. Age and body weight were found to significantly impact CSS,min ENDX in addition to CYP2D6 phenotype. Compared to post-menopausal patients, pre-menopausal patients had a 30% higher risk for subtarget CSS,min ENDX at tamoxifen 20 mg per day. In treatment simulations for distinct patient subpopulations, young overweight patients had a 3.1-13.8-fold higher risk for subtarget CSS,min ENDX compared to elderly low-weight patients. Considering ever-rising obesity rates and the clinical importance of tamoxifen for pre-menopausal patients, this subpopulation may benefit most from individualised tamoxifen dosing.

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Submitted date: 22 April 2020
Accepted/In Press date: 29 May 2020
e-pub ahead of print date: 23 June 2020
Published date: 23 July 2020

Identifiers

Local EPrints ID: 439679
URI: http://eprints.soton.ac.uk/id/eprint/439679
ISSN: 0009-9236
PURE UUID: 6c81113a-fd91-47fd-89f5-d8d27e1a897a
ORCID for Diana Eccles: ORCID iD orcid.org/0000-0002-9935-3169

Catalogue record

Date deposited: 29 Apr 2020 16:31
Last modified: 29 Jul 2021 04:01

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Contributors

Author: Anna Mueller-Schoell
Author: Lena Klopp-Schulze
Author: Werner Schroth
Author: Thomas Murdter
Author: Robin Michelet
Author: Hiltrud Brauch
Author: Wilhelm Huisinga
Author: Markus Joerger
Author: Patrick Neven
Author: Stijn L.W. Koolen
Author: Ron H.J. Mathijssen
Author: Ellen Copson
Author: Diana Eccles ORCID iD
Author: Sylvia Chen
Author: Balram Chowbay
Author: Arafat Tfayli
Author: Nathalie Khoueiry-Zgheib
Author: Matthias Schwab
Author: Charlotte Kloft

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