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
5124 - STAR_PAC: Phase I clinical trial repurposing all trans retinoic acid (ATRA) as stromal targeting agent in a novel drug combination for pancreatic cancer.
Presenter: Hemant Kocher
Session: Poster Display session 2
Resources:
Abstract
5257 - Outcomes of First Line FOLFIRINOX (FFX) Versus Gemcitabine and Nab-Paclitaxel (GN) in Patients with Advanced Pancreatic Cancer: Multi-Institutional Canadian Sites Experience
Presenter: Neha Papneja
Session: Poster Display session 2
Resources:
Abstract
1166 - Effect of prior cancer on survival outcomes for patients with pancreatic adenocarcinoma
Presenter: Chaobin He
Session: Poster Display session 2
Resources:
Abstract
1169 - Association of combination of irreversible electroporation ablation and chemotherapy with outcomes of locally advanced pancreatic cancer: a large cohort study
Presenter: Chaobin He
Session: Poster Display session 2
Resources:
Abstract
1222 - Results from phase I study of the oncolytic viral immunotherapy agent Canerpaturev (C-REV) in combination with gemcitabine plus nab-paclitaxel as first-line treatment of unresectable pancreatic cancer
Presenter: Yusuke Hashimoto
Session: Poster Display session 2
Resources:
Abstract
1698 - Multicenter retrospective study of gemcitabine plus nab-paclitaxel for elderly patients with advanced pancreatic cancer
Presenter: Masato Ozaka
Session: Poster Display session 2
Resources:
Abstract
2424 - Irinotecan Combined with Oxaliplatin and S1 in Patients with Metastatic Pancreatic Adenocarcinoma
Presenter: Keke Nie
Session: Poster Display session 2
Resources:
Abstract
2885 - Cancer-associated thrombosis in patients with pancreatic cancer and its correlation with plasma tissue factor level: A Japanese prospective cohort study
Presenter: Satoshi Kobayashi
Session: Poster Display session 2
Resources:
Abstract
3702 - A Phase I/Ib, multi-center trial of ARQ-761 (Beta-Lapachone) with gemcitabine/nab-Paclitaxel in patients with advanced pancreatic cancer
Presenter: Muhammad Beg
Session: Poster Display session 2
Resources:
Abstract
5185 - Systemic administration of the hyaluronidase-expressing oncolytic adenovirus VCN-01 in patients with advanced or metastatic pancreatic cancer: first-in-human clinical trial
Presenter: Rocio Garcia-Carbonero
Session: Poster Display session 2
Resources:
Abstract