Pharmacokinetic-Pharmacodynamic Model of Paclitaxel-Induced Peripheral Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a common neurological toxicity of paclitaxel treatment in patients with cancer that can cause irreversible reductions in function and quality of life. CIPN risk is higher in patients with greater systemic paclitaxel exposure, including the maximum concentration at the end of infusion (C_max). The objective of this study is to build a paclitaxel pharmacokinetic-pharmacodynamic (PK-PD) model of CIPN that could inform personalized dosing strategies. Data was obtained from the UMCC2014.002 clinical study of patients with breast cancer receiving weekly 1-h infusion of 80 mg/m² paclitaxel for 12 weeks. The PK model, built using paclitaxel C_max and 16-24 h samples was combined with weekly a CIPN20 questionnaire to build the model. Model performance was explored by simulating CIPN resulting from a standard (80 mg/m² × 12 weekly doses) and enhanced (100 mg/m² × 6 + 80 mg/m² × 6) dosing regimen and compared with the actual CIPN from patients receiving these regimens within the CALGB C9840 clinical trial. A two-compartment PK model and a turnover PD model incorporating an effect compartment and threshold structure best described the data. The PK-PD model adequately captures CIPN from patients in UMCC2014.002. Simulations recapitulate CIPN from standard (18% simulated vs. 21% actual) and enhanced (35% simulated vs. 30% actual) paclitaxel regimens from CALGB C9840. A novel PK-PD model adequately describes CIPN from weekly paclitaxel. This CIPN PK-PD model may be able to inform personalized dosing strategies that reduce CIPN and improve treatment outcomes in paclitaxel-treated patients.