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
2670 - Molecular subtypes of metastatic(met) gastric cancer(GC) (MoTriGastric): new biomarkers closer to the clinics
Presenter: Maria Alsina Maqueda
Session: Poster Display session 2
Resources:
Abstract
3797 - Exploring candidate signal transduction pathways for targeted therapy in esophageal cancer
Presenter: Aafke Creemers
Session: Poster Display session 2
Resources:
Abstract
5485 - Clinical implication of CLDN18, RhoGAP, and E-cadherin in gastric signet ring cell carcinoma
Presenter: Hyunho Kim
Session: Poster Display session 2
Resources:
Abstract
1970 - Identification of a spectrum of germline mutations for hereditary diffuse gastric cancer in the Russian population by next-generation sequencing.
Presenter: IRINA EFIMOVA
Session: Poster Display session 2
Resources:
Abstract
4989 - The molecular profiling and prognostic value of Chinese gastric signet ring cell carcinoma patients
Presenter: Jia Wei
Session: Poster Display session 2
Resources:
Abstract
7145 - A phase 2 basket study of MCLA-128, a bispecific antibody targeting the HER3 pathway, in NRG1 fusion-positive advanced solid tumors
Presenter: Alison Schram
Session: Poster Display session 2
Resources:
Abstract
1406 - Simultaneous Resection of Pancreatic Cancer and Liver Oligometastases After Induction Chemotherapy in Stage IV Patients:an Open-Label Prospective Randomized Multicenter phase 3 trial(CSPAC-1)
Presenter: Miaoyan Wei
Session: Poster Display session 2
Resources:
Abstract
1530 - Multicenter randomized phase II trial of 5-Fluorouracil/leucovorin (5-FU/LV) with or without liposomal irinotecan (nal-IRI) in metastatic biliary tract cancer (BTC) as second-line therapy after progression on gemcitabine plus cisplatin (GemCis): NIFTY trial
Presenter: Changhoon Yoo
Session: Poster Display session 2
Resources:
Abstract
1563 - A randomized phase II study of Maintenance therapy with multiepitope vaccine Tedopi (OSE2101) ± nivolumab or FOLFIRI after induction chemotherapy (CT) with FOLFIRINOX in patients (Pts) with advanced Pancreatic ductal adenocarcinoma (aPDAC) (TEDOPaM – PRODIGE 63 GERCOR study)
Presenter: Cindy Neuzillet
Session: Poster Display session 2
Resources:
Abstract
2780 - A phase 3, randomized, double-blind, placebo-controlled, international study of durvalumab in combination with gemcitabine plus cisplatin for patients with advanced biliary tract cancers: TOPAZ-1
Presenter: Do-Youn Oh
Session: Poster Display session 2
Resources:
Abstract