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
2860 - Prognostic value of metabolic response assessed by 18FDG-PET after induction chemotherapy and after chemoradiotherapy (CRT) in localized esophageal squamous cell carcinoma (ESCC) patients (pts) receiving definite CRT (dCRT)
Presenter: Yeonghak Bang
Session: Poster Display session 2
Resources:
Abstract
3881 - Comprehensive genomic profiling of early-stage esophageal squamous cell carcinoma
Presenter: Jing Zuo
Session: Poster Display session 2
Resources:
Abstract
3944 - A novel nomogram and risk classification system predicting radiation pneumonitis in patients with esophageal cancer receiving radiotherapy
Presenter: Lu Wang
Session: Poster Display session 2
Resources:
Abstract
1956 - Drinking alcohol, smoking, multiple dysplastic lesions and the risk of field cancerization of squamous cell carcinoma in the esophagus and head and neck region
Presenter: Chikatoshi Katada
Session: Poster Display session 2
Resources:
Abstract
2144 - Neoadjuvant chemotherapy can eliminate the negative impact of postoperative infectious complications on recurrence in patients with esophageal cancer
Presenter: Kazuki Kano
Session: Poster Display session 2
Resources:
Abstract
2403 - Comparison of chemoradiotherapy (CRT) followed by consolidation with cisplatin and 5-fluorouracil (CF) versus definitive CRT with carboplatin and paclitaxel (CP) in esophageal cancer
Presenter: Marcelle Cesca
Session: Poster Display session 2
Resources:
Abstract
3247 - Paclitaxel in Combination with Cisplatin and 5-fluorouracil(TPF) Induction Chemotherapy for Locally Advanced Borderline-resectable Esophageal Squamous cell Carcinoma: A Phase II Clinical Trial
Presenter: Yuhong Li
Session: Poster Display session 2
Resources:
Abstract
4293 - Prognosis of esophageal squamous cell carcinoma based on local immunity evaluation
Presenter: Elena Zlatnik
Session: Poster Display session 2
Resources:
Abstract
5419 - Impact of Sarcopenia and adiposity in survival of metastatic esophageal cancer (MEC)
Presenter: Aline Fares
Session: Poster Display session 2
Resources:
Abstract
2083 - PALAESTRA - A phase II trial with short-course radiotherapy followed by chemotherapy as palliative treatment in esophageal adenocarcinoma
Presenter: David Borg
Session: Poster Display session 2
Resources:
Abstract