Pharmacology and toxicity of nicotinamide combined with domperidone during fractionated radiotherapy.

摘要

BACKGROUND AND PURPOSE: Treatment of head and neck tumors by the ARCON regimen has yielded high local control rates. As a result of this treatment intensification there was some increase in mainly acute toxicity of radiotherapy, but nicotinamide by itself has specific side effects such as nausea and vomiting. Due to these side effects and with the initial dose of 80 mg/kg, 31% of the patients discontinued nicotinamide intake. The aim of the study was to investigate the effect of a dose reduction to 60 mg/kg, and the addition of domperidone on the side effects of nicotinamide and its pharmacokinetic profile. PATIENTS AND METHODS: In 22 patients blood plasma nicotinamide levels were determined after intake of 60 mg/kg nicotinamide. A next group of 87 patients received 60 mg/kg nicotinamide in combination with domperidone. In ten of these patients blood plasma nicotinamide levels were also determined. A full pharmacokinetic profile was constructed over the first 24 h after intake of the first drug dose. Furthermore, daily plasma levels at 1 h after nicotinamide intake was determined in the first and last weeks of radiotherapy. All patients were treated according to the ARCON schedule. RESULTS AND DISCUSSION: The mean maximum plasma nicotinamide concentration was 793 nmol/ml without domperidone and 776 nmol/ml with domperidone. The median time at which the maximum concentration occurred was not significantly different for 60 mg/kg nicotinamide without or with domperidone (0.46 versus 0.54 h). The side effects were drastically reduced if nicotinamide was accompanied by domperidone. The percentage of patients that stopped nicotinamide intake was reduced from 32% without domperidone to 14% with domperidone. No correlation was found between the plasma peak concentrations of nicotinamide and the severity of side effects. CONCLUSION: The currently used dose of 60 mg/kg nicotinamide results in a 30% reduction in peak plasma concentrations compared with 80 mg/kg nicotinamide. If nicotinamide was given in combination with domperidone, 86% of the patients continued the nicotinamide medication until the end of the treatment period.