Population pharmacokinetic analyses of regorafenib and capecitabine in patients with locally advanced rectal cancer (SAKK 41/16 RECAP).
Publisher DOI
PubMed ID
35831229
Abstract
AIM
Locally advanced rectal cancer (LARC) is an area of unmet medical need with one third of patients dying from their disease. With response to neoadjuvant chemo-radiotherapy being a major prognostic factor, trial SAKK 41/16 assessed potential benefits of adding regorafenib to capecitabine-amplified neoadjuvant radiotherapy in LARC patients.
METHODS
Patients received regorafenib at three dose levels (40/80/120 mg once daily) combined with capecitabine 825 mg/m2 bidaily and local radiotherapy. We developed population pharmacokinetic models from plasma concentrations of capecitabine and its metabolites 5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluorouridine as well as regorafenib and its metabolites M-2 and M-5 as implemented into SAKK 41/16 to assess potential drug-drug interactions (DDI). After establishing parent-metabolite base models, drug exposure parameters were tested as covariates within the respective models to investigate for potential DDI. Simulation analyses were conducted to quantify their impact.
RESULTS
Plasma concentrations of capecitabine, regorafenib and metabolites were characterized by one- and two compartment models and absorption was described by parallel first- and zero-order processes and transit compartments, respectively. Apparent capecitabine clearance was 286 L/h (relative standard error [RSE] 14.9%, interindividual variability [IIV] 40.1%) and was reduced by regorafenib cumulative area under the plasma-concentration curve (median reduction of 45.6%) as exponential covariate (estimate -4.10×10-4 , RSE 17.8%). Apparent regorafenib clearance was 1.94 L/h (RSE 12.1%, IIV 38.1%). Simulation analyses revealed significantly negative associations between capecitabine clearance and regorafenib exposure.
CONCLUSIONS
This work informs the clinical development of regorafenib and capecitabine combination treatment and underlines the importance to study potential DDI with new anticancer drug combinations.
Locally advanced rectal cancer (LARC) is an area of unmet medical need with one third of patients dying from their disease. With response to neoadjuvant chemo-radiotherapy being a major prognostic factor, trial SAKK 41/16 assessed potential benefits of adding regorafenib to capecitabine-amplified neoadjuvant radiotherapy in LARC patients.
METHODS
Patients received regorafenib at three dose levels (40/80/120 mg once daily) combined with capecitabine 825 mg/m2 bidaily and local radiotherapy. We developed population pharmacokinetic models from plasma concentrations of capecitabine and its metabolites 5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluorouridine as well as regorafenib and its metabolites M-2 and M-5 as implemented into SAKK 41/16 to assess potential drug-drug interactions (DDI). After establishing parent-metabolite base models, drug exposure parameters were tested as covariates within the respective models to investigate for potential DDI. Simulation analyses were conducted to quantify their impact.
RESULTS
Plasma concentrations of capecitabine, regorafenib and metabolites were characterized by one- and two compartment models and absorption was described by parallel first- and zero-order processes and transit compartments, respectively. Apparent capecitabine clearance was 286 L/h (relative standard error [RSE] 14.9%, interindividual variability [IIV] 40.1%) and was reduced by regorafenib cumulative area under the plasma-concentration curve (median reduction of 45.6%) as exponential covariate (estimate -4.10×10-4 , RSE 17.8%). Apparent regorafenib clearance was 1.94 L/h (RSE 12.1%, IIV 38.1%). Simulation analyses revealed significantly negative associations between capecitabine clearance and regorafenib exposure.
CONCLUSIONS
This work informs the clinical development of regorafenib and capecitabine combination treatment and underlines the importance to study potential DDI with new anticancer drug combinations.
Date Issued
2022-12
Publication Type
Article
Subject(s)
Subjects
Capecitabine Drug-Drug Interaction Population Pharmacokinetics Rectal Cancer Regorafenib
Language(s)
en
Author(s)
Schmulenson, Eduard | |
Theurillat, Regula | |
Decosterd, Laurent Arthur | |
Csajka, Chantal | |
Bärtschi, Daniela | |
Guckenberger, Matthias | |
von Moos, Roger | |
Bastian, Sara | |
Joerger, Markus | |
Jaehde, Ulrich |
Additional Credits
Journal
British journal of clinical pharmacology
Publisher
Wiley-Blackwell
ISSN
0306-5251
Access(Rights)
Unknown