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

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