In:
British Journal of Clinical Pharmacology, Wiley, Vol. 88, No. 12 ( 2022-12), p. 5336-5347
Kurzfassung:
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/m 2 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.
Materialart:
Online-Ressource
ISSN:
0306-5251
,
1365-2125
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2022
ZDB Id:
1498142-7
SSG:
15,3
