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 interaction; population pharmacokinetics; rectal cancer; regorafenib

Developing a Nationwide Infrastructure for Therapeutic Drug Monitoring of Targeted Oral Anticancer Drugs: The ON-TARGET Study Protocol

Exposure-efficacy and/or exposure-toxicity relationships have been identified for up to 80% of oral anticancer drugs (OADs). Usually, OADs are administered at fixed doses despite their high interindividual pharmacokinetic variability resulting in large differences in drug exposure. Consequently, a substantial proportion of patients receive a suboptimal dose. Therapeutic Drug Monitoring (TDM), i.e., dosing based on measured drug concentrations, may be used to improve treatment outcomes. The prospective, multicenter, non-interventional ON-TARGET study (DRKS00025325) aims to investigate the potential of routine TDM to reduce adverse drug reactions in renal cell carcinoma patients receiving axitinib or cabozantinib. Furthermore, the feasibility of using volumetric absorptive microsampling (VAMS), a minimally invasive and easy to handle blood sampling technique, for sample collection is examined. During routine visits, blood samples are collected and sent to bioanalytical laboratories. Venous and VAMS blood samples are collected in the first study phase to facilitate home-based capillary blood sampling in the second study phase. Within one week, the drug plasma concentrations are measured, interpreted, and reported back to the physician. Patients report their drug intake and toxicity using PRO-CTCAE-based questionnaires in dedicated diaries. Ultimately, the ON-TARGET study aims to develop a nationwide infrastructure for TDM for oral anticancer drugs

Evaluation of patient-reported severity of hand–foot syndrome under capecitabine using a Markov modeling approach

Purpose!#!The inclusion of the patient's perspective has become increasingly important when reporting adverse events and may assist in management of toxicity. The relationship between drug exposure and toxicity can be quantified by combining Markov elements with pharmacometric models. A minimal continuous-time Markov model (mCTMM) was applied to patient-reported outcomes using hand-foot syndrome (HFS) induced by capecitabine anti-cancer therapy as an example.!##!Methods!#!Patient-reported HFS grades over time of 150 patients from two observational studies treated with oral capecitabine were analyzed using a mCTMM approach. Grading of HFS severity was based on the Common Terminology Criteria for Adverse Events. The model was evaluated by visual predictive checks (VPC). Furthermore, a simulation study of the probability of HFS severity over time was performed in which the standard dosing regimen and dose adjustments according to HFS severity were investigated.!##!Results!#!The VPC of the developed dose-toxicity model indicated an accurate description of HFS severity over time. Individual absolute daily dose was found to be a predictor for HFS. The simulation study demonstrated a reduction of severe HFS using the recommended dose adjustment strategy.!##!Conclusion!#!A minimal continuous-time Markov model was developed based on patient-reported severity of hand-foot syndrome under capecitabine. Thus, a modeling framework for patient-reported outcomes was created which may assist in the optimization of dosage regimens and adjustment strategies aiming at minimizing symptom burden during anti-cancer drug therapy

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

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

Developing a Nationwide Infrastructure for Therapeutic Drug Monitoring of Targeted Oral Anticancer Drugs: The ON-TARGET Study Protocol

Simple Summary Relationships between drug concentrations in blood and efficacy and/or toxicity have been reported for up to 80% of oral anticancer drugs (OADs). Most OADs exhibit highly variable drug concentrations at the approved dose. This may result in a significant proportion of patients with suboptimal drug concentrations. Therapeutic Drug Monitoring (TDM), which is dose optimization based on measured drug concentrations, can be used to personalize drug dosing with the overall goal to improve the benefit-risk ratio of anticancer drug treatment. The ON-TARGET study aims to investigate the feasibility of TDM in patients receiving either axitinib or cabozantinib for the treatment of renal-cell carcinoma with the main objective to improve severe tyrosine kinase inhibitor associated toxicity. Additionally, the feasibility of volumetric absorptive microsampling (VAMS), a novel minimally invasive and easy to handle blood sampling technique, for TDM sample collection is investigated. Exposure-efficacy and/or exposure-toxicity relationships have been identified for up to 80% of oral anticancer drugs (OADs). Usually, OADs are administered at fixed doses despite their high interindividual pharmacokinetic variability resulting in large differences in drug exposure. Consequently, a substantial proportion of patients receive a suboptimal dose. Therapeutic Drug Monitoring (TDM), i.e., dosing based on measured drug concentrations, may be used to improve treatment outcomes. The prospective, multicenter, non-interventional ON-TARGET study (DRKS00025325) aims to investigate the potential of routine TDM to reduce adverse drug reactions in renal cell carcinoma patients receiving axitinib or cabozantinib. Furthermore, the feasibility of using volumetric absorptive microsampling (VAMS), a minimally invasive and easy to handle blood sampling technique, for sample collection is examined. During routine visits, blood samples are collected and sent to bioanalytical laboratories. Venous and VAMS blood samples are collected in the first study phase to facilitate home-based capillary blood sampling in the second study phase. Within one week, the drug plasma concentrations are measured, interpreted, and reported back to the physician. Patients report their drug intake and toxicity using PRO-CTCAE-based questionnaires in dedicated diaries. Ultimately, the ON-TARGET study aims to develop a nationwide infrastructure for TDM for oral anticancer drugs