Nontoxic suramin as a chemosensitizer in patients: dosing nomogram development.

摘要

PURPOSE: We reported that suramin produced chemosensitization at nontoxic doses. This benefit was lost at the approximately 10-fold higher, maximally tolerated doses (MTD). The aim of the current study was to identify in patients the chemosensitizing suramin dose that delivers 10-50 microM plasma concentrations over 48 h. METHODS: Nonsmall cell lung cancer patients were given suramin, paclitaxel, and carboplatin, every 3 weeks. The starting chemosensitizing suramin dose was estimated based on previous results on MTD suramin in patients, and adjusted by using real-time pharmacokinetic monitoring. A dosing nomogram was developed by using population-based pharmacokinetic analysis of phase I results (15 patients, 85 treatment cycles), and evaluated in phase II patients (19 females, 28 males, 196 treatment cycles). RESULTS: The chemosensitizing suramin dose showed a terminal half-life of 202 h and a total body clearance of 0.029 L h(-1) m(-2) (higher than the 0.013 L h(-1) m(-2) value for MTD of suramin). The dosing nomogram, incorporating body surface area as the major covariate of intersubject variability and the time elapsed since the previous dose (to account for the residual concentrations due to the slow elimination), delivered the target concentrations in >95% of treatments. CONCLUSIONS: The present study identified and validated a dosing nomogram and schedule to deliver low and nontoxic suramin concentrations that produce chemosensitization in preclinical models.