Population pharmacokinetic analyses of regorafenib and capecitabine in patients with locally advanced rectal cancer (SAKK 41/16 RECAP).

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), pp. 5336-5347. Wiley-Blackwell 10.1111/bcp.15461

Preview

Text Brit_J_Clinical_Pharma_-_2022_-_Schmulenson_-_Population_pharmacokinetic_analyses_of_regorafenib_and_capecitabine_in.pdf - Accepted Version Available under License Publisher holds Copyright. Download (1MB) | Preview

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.

Interest & Impact

Downloads

2 since deposited on 19 Jul 2022
2 in the past 12 months

Citations

5 Citations in Web of Science ®
6 Citations in Scopus

Search

in Google Scholar™

Services

Actions (login required)

Edit item

Actions (login required)

Edit item