Toward model-informed precision dosing for tamoxifen: A population-pharmacokinetic model with a continuous CYP2D6 activity scale

Bram C Agema; Sanne M Buijs; Sebastiaan D T Sassen; Thomas E Mürdter; Mathias Schwab; Birgit C P Koch; Agnes Jager; Ron H N van Schaik; Ron H J Mathijssen; Stijn L W Koolen

doi:10.1016/j.biopha.2023.114369

Toward model-informed precision dosing for tamoxifen: A population-pharmacokinetic model with a continuous CYP2D6 activity scale

Bram C Agema^*, Sanne M Buijs, Sebastiaan D T Sassen, Thomas E Mürdter, Mathias Schwab, Birgit C P Koch, Agnes Jager, Ron H N van Schaik, Ron H J Mathijssen, Stijn L W Koolen

^*Corresponding author for this work

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Abstract

BACKGROUND: Tamoxifen is important in the adjuvant treatment of breast cancer. A plasma concentration of the active metabolite endoxifen of > 16 nM is associated with a lower risk of breast cancer-recurrence. Since inter-individual variability is high and > 20 % of patients do not reach endoxifen levels > 16 nM with the standard dose tamoxifen, therapeutic drug monitoring is advised. However, ideally, the correct tamoxifen dose should be known prior to start of therapy. Our aim is to develop a population pharmacokinetic (POP-PK) model incorporating a continuous CYP2D6 activity scale to support model informed precision dosing (MIPD) of tamoxifen to determine the optimal tamoxifen starting dose.

METHODS: Data from eight different clinical studies were pooled (539 patients, 3661 samples) and used to develop a POP-PK model. In this model, CYP2D6 activity per allele was estimated on a continuous scale. After inclusion of covariates, the model was subsequently validated using an independent external dataset (378 patients). Thereafter, dosing cut-off values for MIPD were determined.

RESULTS: A joint tamoxifen/endoxifen POP-PK model was developed describing the endoxifen formation rate. Using a continuous CYP2D6 activity scale, variability in predicting endoxifen levels was decreased by 37 % compared to using standard CYP2D6 genotype predicted phenotyping. After external validation and determination of dosing cut-off points, MIPD could reduce the proportion of patients with subtherapeutic endoxifen levels at from 22.1 % toward 4.8 %.

CONCLUSION: Implementing MIPD from the start of tamoxifen treatment with this POP-PK model can reduce the proportion of patients with subtherapeutic endoxifen levels at steady-state to less than 5 %.

Original language	English
Article number	114369
Journal	Biomedicine and Pharmacotherapy
Volume	160
DOIs	https://doi.org/10.1016/j.biopha.2023.114369
Publication status	Published - Apr 2023

Bibliographical note

Funding Information:
Funding for the prospective studies are available at the original manuscripts as cited in this paper. M.S., and T.E.M. were supported in part by the Robert Bosch Stiftung (Stuttgart, Germany) and the Federal Ministry of Education and Research (BMBF; 01EK1509A ), Germany. M.S was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy —EXC 2180—390900677 ).

Publisher Copyright:
© 2023 The Authors

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Agema, B. C., Buijs, S. M., Sassen, S. D. T., Mürdter, T. E., Schwab, M., Koch, B. C. P., Jager, A., van Schaik, R. H. N., Mathijssen, R. H. J., & Koolen, S. L. W. (2023). Toward model-informed precision dosing for tamoxifen: A population-pharmacokinetic model with a continuous CYP2D6 activity scale. Biomedicine and Pharmacotherapy, 160, [114369]. https://doi.org/10.1016/j.biopha.2023.114369

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title = "Toward model-informed precision dosing for tamoxifen: A population-pharmacokinetic model with a continuous CYP2D6 activity scale",

abstract = "BACKGROUND: Tamoxifen is important in the adjuvant treatment of breast cancer. A plasma concentration of the active metabolite endoxifen of > 16 nM is associated with a lower risk of breast cancer-recurrence. Since inter-individual variability is high and > 20 % of patients do not reach endoxifen levels > 16 nM with the standard dose tamoxifen, therapeutic drug monitoring is advised. However, ideally, the correct tamoxifen dose should be known prior to start of therapy. Our aim is to develop a population pharmacokinetic (POP-PK) model incorporating a continuous CYP2D6 activity scale to support model informed precision dosing (MIPD) of tamoxifen to determine the optimal tamoxifen starting dose.METHODS: Data from eight different clinical studies were pooled (539 patients, 3661 samples) and used to develop a POP-PK model. In this model, CYP2D6 activity per allele was estimated on a continuous scale. After inclusion of covariates, the model was subsequently validated using an independent external dataset (378 patients). Thereafter, dosing cut-off values for MIPD were determined.RESULTS: A joint tamoxifen/endoxifen POP-PK model was developed describing the endoxifen formation rate. Using a continuous CYP2D6 activity scale, variability in predicting endoxifen levels was decreased by 37 % compared to using standard CYP2D6 genotype predicted phenotyping. After external validation and determination of dosing cut-off points, MIPD could reduce the proportion of patients with subtherapeutic endoxifen levels at from 22.1 % toward 4.8 %.CONCLUSION: Implementing MIPD from the start of tamoxifen treatment with this POP-PK model can reduce the proportion of patients with subtherapeutic endoxifen levels at steady-state to less than 5 %.",

author = "Agema, {Bram C} and Buijs, {Sanne M} and Sassen, {Sebastiaan D T} and M{\"u}rdter, {Thomas E} and Mathias Schwab and Koch, {Birgit C P} and Agnes Jager and {van Schaik}, {Ron H N} and Mathijssen, {Ron H J} and Koolen, {Stijn L W}",

note = "Funding Information: Funding for the prospective studies are available at the original manuscripts as cited in this paper. M.S., and T.E.M. were supported in part by the Robert Bosch Stiftung (Stuttgart, Germany) and the Federal Ministry of Education and Research (BMBF; 01EK1509A ), Germany. M.S was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany{\textquoteright}s Excellence Strategy —EXC 2180—390900677 ). Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = apr,

doi = "10.1016/j.biopha.2023.114369",

language = "English",

volume = "160",

journal = "Biomedicine and Pharmacotherapy",

issn = "0753-3322",

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TY - JOUR

T1 - Toward model-informed precision dosing for tamoxifen

T2 - A population-pharmacokinetic model with a continuous CYP2D6 activity scale

AU - Agema, Bram C

AU - Buijs, Sanne M

AU - Sassen, Sebastiaan D T

AU - Mürdter, Thomas E

AU - Schwab, Mathias

AU - Koch, Birgit C P

AU - Jager, Agnes

AU - van Schaik, Ron H N

AU - Mathijssen, Ron H J

AU - Koolen, Stijn L W

N1 - Funding Information: Funding for the prospective studies are available at the original manuscripts as cited in this paper. M.S., and T.E.M. were supported in part by the Robert Bosch Stiftung (Stuttgart, Germany) and the Federal Ministry of Education and Research (BMBF; 01EK1509A ), Germany. M.S was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy —EXC 2180—390900677 ). Publisher Copyright: © 2023 The Authors

PY - 2023/4

Y1 - 2023/4

N2 - BACKGROUND: Tamoxifen is important in the adjuvant treatment of breast cancer. A plasma concentration of the active metabolite endoxifen of > 16 nM is associated with a lower risk of breast cancer-recurrence. Since inter-individual variability is high and > 20 % of patients do not reach endoxifen levels > 16 nM with the standard dose tamoxifen, therapeutic drug monitoring is advised. However, ideally, the correct tamoxifen dose should be known prior to start of therapy. Our aim is to develop a population pharmacokinetic (POP-PK) model incorporating a continuous CYP2D6 activity scale to support model informed precision dosing (MIPD) of tamoxifen to determine the optimal tamoxifen starting dose.METHODS: Data from eight different clinical studies were pooled (539 patients, 3661 samples) and used to develop a POP-PK model. In this model, CYP2D6 activity per allele was estimated on a continuous scale. After inclusion of covariates, the model was subsequently validated using an independent external dataset (378 patients). Thereafter, dosing cut-off values for MIPD were determined.RESULTS: A joint tamoxifen/endoxifen POP-PK model was developed describing the endoxifen formation rate. Using a continuous CYP2D6 activity scale, variability in predicting endoxifen levels was decreased by 37 % compared to using standard CYP2D6 genotype predicted phenotyping. After external validation and determination of dosing cut-off points, MIPD could reduce the proportion of patients with subtherapeutic endoxifen levels at from 22.1 % toward 4.8 %.CONCLUSION: Implementing MIPD from the start of tamoxifen treatment with this POP-PK model can reduce the proportion of patients with subtherapeutic endoxifen levels at steady-state to less than 5 %.

AB - BACKGROUND: Tamoxifen is important in the adjuvant treatment of breast cancer. A plasma concentration of the active metabolite endoxifen of > 16 nM is associated with a lower risk of breast cancer-recurrence. Since inter-individual variability is high and > 20 % of patients do not reach endoxifen levels > 16 nM with the standard dose tamoxifen, therapeutic drug monitoring is advised. However, ideally, the correct tamoxifen dose should be known prior to start of therapy. Our aim is to develop a population pharmacokinetic (POP-PK) model incorporating a continuous CYP2D6 activity scale to support model informed precision dosing (MIPD) of tamoxifen to determine the optimal tamoxifen starting dose.METHODS: Data from eight different clinical studies were pooled (539 patients, 3661 samples) and used to develop a POP-PK model. In this model, CYP2D6 activity per allele was estimated on a continuous scale. After inclusion of covariates, the model was subsequently validated using an independent external dataset (378 patients). Thereafter, dosing cut-off values for MIPD were determined.RESULTS: A joint tamoxifen/endoxifen POP-PK model was developed describing the endoxifen formation rate. Using a continuous CYP2D6 activity scale, variability in predicting endoxifen levels was decreased by 37 % compared to using standard CYP2D6 genotype predicted phenotyping. After external validation and determination of dosing cut-off points, MIPD could reduce the proportion of patients with subtherapeutic endoxifen levels at from 22.1 % toward 4.8 %.CONCLUSION: Implementing MIPD from the start of tamoxifen treatment with this POP-PK model can reduce the proportion of patients with subtherapeutic endoxifen levels at steady-state to less than 5 %.

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DO - 10.1016/j.biopha.2023.114369

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SN - 0753-3322

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JO - Biomedicine and Pharmacotherapy

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Toward model-informed precision dosing for tamoxifen: A population-pharmacokinetic model with a continuous CYP2D6 activity scale

Abstract

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