Pharmacokinetic study of oxaliplatin iv chronomodulated infusion combined with 5-fluorouracil iv continuous infusion in the treatment of advanced colorectal cancer

We investigated the pharmacokinetics (PK), preliminary clinical results and toxicity of chronomodulated oxaliplatin (OHP) plus 5-fluorouracil (5-FU) without folinic acid (FA) in 13 patients with metastatic colorectal cancer. 5-FU (200 mg/m2/day as 14-day continuous iv infusion for six cycles) plus OHP at increasing doses (25-30-35 mg/m2/day, as 12 h chronomodulated iv infusion on days 1-2-3-4, every 14 days for six cycles) were administered to reach maximum tolerated dose (MTD). At MTD (30 mg/m2/day), a PK study of 5-FU and OHP (in total and ultrafiltered-UF plasma) was performed. 5-FU plasma levels were fairly stable, below that reported in similar studies and closely related to the lack of the most typical 5-FU toxicities. OHP Cmax occurred 7 h after infusion start; a progressive accumulation of free Pt and ultrafiltered Pt (UF-OHP) through cycles 1-6 was noted. A marked difference between total plasma and UF Pt was seen in the elimination phase. OHP plasma clearance decrease was related to Vz (volume of distribution of late elimination phase), whereas in UF-OHP was due to a change in Ke or t1/2. In conclusion, the association of 5-FU with chronomodulated OHP do not seem to influence PK parameters of either drugs. Toxicity was modest/acceptable and clinical efficacy good: preliminary data showed a threshold neurotoxicity at total plasma Pt concentrations >1500 ng/ml and UF plasma Pt concentrations >150 ng/ml.