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

Eduard Schmulenson; Cédric Bovet; Regula Theurillat; Laurent Arthur Decosterd; Carlo R Largiadèr; Jean-Christophe Prost; Chantal Csajka; Daniela Bärtschi; Matthias Guckenberger; Roger von Moos; Sara Bastian; Markus Joerger; Ulrich Jaehde

doi:10.1111/bcp.15461

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

Br J Clin Pharmacol. 2022 Dec;88(12):5336-5347. doi: 10.1111/bcp.15461. Epub 2022 Jul 23.

Affiliations

¹ Institute of Pharmacy, Department of Clinical Pharmacy, University of Bonn, Bonn, Germany.
² Department of Clinical Chemistry, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
³ Laboratory of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
⁴ Clinical Pharmaceutical Sciences, Lausanne University, Lausanne, Switzerland.
⁵ SAKK Coordinating Center, Bern, Switzerland.
⁶ Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
⁷ Cantonal Hospital Graubünden, Chur, Switzerland.
⁸ Department of Medical Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.

PMID: 35831229
DOI: 10.1111/bcp.15461

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 interaction; population pharmacokinetics; rectal cancer; regorafenib.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Capecitabine
Fluorouracil / therapeutic use
Humans
Phenylurea Compounds*
Pyridines
Rectal Neoplasms* / chemically induced
Rectal Neoplasms* / drug therapy

Substances

Capecitabine
Fluorouracil
Phenylurea Compounds
Pyridines
regorafenib