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Toward model-informed precision dosing for tamoxifen:A population-pharmacokinetic model with a continuous CYP2D6 activity scale
- Source :
- 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 , vol. 160 , 114369 .
- Publication Year :
- 2023
-
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 %.
Details
- Database :
- OAIster
- Journal :
- 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 , vol. 160 , 114369 .
- Notes :
- application/pdf, English
- Publication Type :
- Electronic Resource
- Accession number :
- edsoai.on1376784864
- Document Type :
- Electronic Resource