Abstract 2642
Background
About 20% of breast cancer (BC) patients do not attain tamoxifen’s (TAM) active metabolite endoxifen (ENDX) target concentrations when receiving 20 mg TAM once daily (q.d.). Thus, individualised dosing of up to 120 mg TAM q.d. for ENDX target attainment (TA) has been proposed. Combining concentrations and antiestrogenic activities of ENDX and its 3 precursors, the antiestrogenic activity score (AAS) has been developed as alternative TA metric. We aimed to integrate experimental and clinical data from diverse sources in an innovative modelling approach to identify patient groups at risk of treatment failure and to assess whether ENDX- or AAS-guided dosing would be more favourable for TA applying in silico simulation.
Methods
In vitro data from enzyme kinetic experiments, pharmacokinetic (PK) parameters from previous clinical studies and in vivo data from three clinical trials were synthesised into a minimal nonlinear mixed-effects physiologically-based pharmacokinetic (NLME-PBPK) model. Using simulation, lowest doses needed for TA, applying either the ENDX (≥5.97 ng/mL) or the AAS (≥1798) threshold, were investigated in a representative virtual BC population with various CYP2D6 activity scores (AS) and age.
Results
The developed NLME-PBPK model captured individual TAM and 3 metabolite concentration profiles from 406 BC patients well. Bioactivation to ENDX was 4.5-fold higher in CYP2D6 normal (NM) than in poor metabolisers (PM). Patients with low CYP2D6 activity and young age showed highest risks for ENDX non-TA. Among all patients, 76% received the same dose irrespective of the TA metric used. For the remaining 23% with different dose selections, applying the AAS instead of the ENDX target, TA increased in NM and intermediate metabolisers (IM) (+21.7% and +6.9%, respectively), while TA decreased in PM (-11.7%).
Conclusions
Our modelling approach combined pharmacogenetic factors, physiological changes and variability on PK parameters in a quantitative manner and allowed to translate PK information on TAM and its three major metabolites into individualised dosing. While ENDX-guided dosing was preferable for PM in our simulation, AAS-guided dosing was superior for NM and IM.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
L. Klopp-Schulze: Full / Part-time employment: Merck Healthcare KGaA. S.L. Koolen: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Roche; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Cristal Therapeutics; Travel / Accommodation / Expenses: Ipsen. R.H.J. Mathijssen: Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Cristal Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pamgene; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: Servier. C. Kloft: Research grant / Funding (institution), Grants received outside the submitted work: DDMoRe; Research grant / Funding (institution), Grants received outside the submitted work: Industry consortium (AbbVie Deutschland GmbH & Co. KG, Boehringer Ingelheim Pharma GmbH & Co. KG, Gruenenthal GmbH, F. Hoffmann-La Roche Ltd., Merck KGaA and SANOFI); Research grant / Funding (institution), Grants received outside the submitted work: Federal Ministry of Education and Research; Research grant / Funding (institution), Grants received outside the submitted work: Diurnal Ltd. All other authors have declared no conflicts of interest.
Resources from the same session
733 - Clinical experience: ramucirumab with FOLFIRI/XELIRI as a second line for patients with metastatic gastric cancer
Presenter: Tatiana Titova
Session: Poster Display session 2
Resources:
Abstract
2186 - Efficacy and safety of apatinib for the treatment of AFP-producing gastric cancer
Presenter: Ningning Li
Session: Poster Display session 2
Resources:
Abstract
3172 - Apatinib in combination with docetaxol and S1 chemotherapy in the first line treatment of metastatic gastric cancer
Presenter: Ling Xia
Session: Poster Display session 2
Resources:
Abstract
3982 - Parameters of local cellular immunity in metastatic gastric cancer
Presenter: Aleksandr Sagakyants
Session: Poster Display session 2
Resources:
Abstract
5102 - Germline pathogenic mutations in Chinese patients with gastric cancer identified by next-generation sequencing (NGS)
Presenter: Xiaotian Zhang
Session: Poster Display session 2
Resources:
Abstract
5012 - Inhibition of the PI3K pathway in HER2-positive gastric cancer
Presenter: Sinead Toomey
Session: Poster Display session 2
Resources:
Abstract
4803 - Investigation on gastric cancer susceptibility genes in Chinese early-onset diffuse gastric cancer
Presenter: Yi Feng
Session: Poster Display session 2
Resources:
Abstract
4778 - A correlation analysis between survival rate and the characteristic gene of gastric cancer based on bioinformatics analysis
Presenter: Yi-wen Zhang
Session: Poster Display session 2
Resources:
Abstract
4805 - Phase I study of apatinib combined with POF (paclitaxel plus FOLFOX) in patients (pts) with treatment-naïve advanced gastric cancer (TNAGC)
Presenter: Rongbo LIN
Session: Poster Display session 2
Resources:
Abstract
3248 - Second-line palliative systemic treatment for synchronous metastatic esophagogastric cancer: a population-based study
Presenter: Willemieke Dijksterhuis
Session: Poster Display session 2
Resources:
Abstract