Back to Search
Start Over
Population pharmacokinetic analyses of regorafenib and capecitabine in patients with locally advanced rectal cancer (SAKK 41/16 RECAP)
- Source :
- Schmulenson, Eduard; Bovet, Cédric; Theurillat, Regula; Decosterd, Laurent Arthur; Largiadèr, Carlo R; Prost, Jean-Christophe; Csajka, Chantal; Bärtschi, Daniela; Guckenberger, Matthias; von Moos, Roger; Bastian, Sara; Joerger, Markus; Jaehde, Ulrich (2022). Population pharmacokinetic analyses of regorafenib and capecitabine in patients with locally advanced rectal cancer (SAKK 41/16 RECAP). British Journal of Clinical Pharmacology, 88(12):5336-5347.
- Publication Year :
- 2022
-
Abstract
- Aims: 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 of studying potential DDI with new anticancer drug combinations. Keywords: capecitabine; drug-drug inte
Details
- Database :
- OAIster
- Journal :
- Schmulenson, Eduard; Bovet, Cédric; Theurillat, Regula; Decosterd, Laurent Arthur; Largiadèr, Carlo R; Prost, Jean-Christophe; Csajka, Chantal; Bärtschi, Daniela; Guckenberger, Matthias; von Moos, Roger; Bastian, Sara; Joerger, Markus; Jaehde, Ulrich (2022). Population pharmacokinetic analyses of regorafenib and capecitabine in patients with locally advanced rectal cancer (SAKK 41/16 RECAP). British Journal of Clinical Pharmacology, 88(12):5336-5347.
- Notes :
- application/pdf, info:doi/10.5167/uzh-220949, English
- Publication Type :
- Electronic Resource
- Accession number :
- edsoai.on1443046823
- Document Type :
- Electronic Resource