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

Abstract

Abstract 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.