Influence of oxaliplatin on 5-fluorouracil plasma clearance and clinical consequences.

The influence of oxaliplatin (OXA) on 5-fluorouracil (5-FU) plasma clearance was investigated. Patients and methods: A group of 29 patients with advanced colorectal cancer refractory to prior weekly 8-h 5-FU infusion plus bolus folinic acid (FA), received the same combination plus OXA at 130 mg/m2 every 3 weeks, OXA plus 5-FU plus FA on day 1, and 5-FU plus FA on days 8 and 15. Steady-state 5-FU concentrations in plasma were measured weekly and 5-FU clearance was calculated. Both before and after the addition of OXA, the 5-FU dose was individually adjusted according to the pharmacokinetic follow-up (target steady-state plasma concentrations 2.5–3 mg/l). Results and discussion: A total of 122 OXA-containing infusions and 338 5-FU plus FA infusions were given and the median number of infusions per patient was 4 (2–9) and 10 (5–28), respectively. 5-FU plasma clearance was significantly decreased on days 8 and 15 when compared with the value on day 1 and with the values before OXA introduction using a direct paired comparison (2.36 and 2.31 l/min, respectively, vs 3.12 and 3.05 l/min; P<10–5). Of 25 evaluable patients, 6 had an objective response after the introduction of OXA (24% objective response rate, 95% confidence interval 9.4–45%). Conclusion: OXA reduces 5-FU plasma clearance for 15 days. This may be a factor in the synergy between the two drugs. It is not linked to dihydropyrimidine dehydrogenase inhibition. Implications for drug schedules in clinical practice are discussed.