Several clinical trials have demonstrated that the three-
drug combination of
oxaliplatin,
5-fluorouracil (5-FU) and
leucovorin (LV) administered chronomodulated improved antitumour efficacy in the treatment of metastatic
colorectal cancer and was better tolerated than constant-rate infusion. However, only a few pharmacokinetic data of
5-FU during chronomodulated infusion are available but up to now not for
oxaliplatin. In this pilot study, the
platinum levels of plasma ultrafiltrate (PUF) and total plasma were monitored during chronomodulated infusion of
oxaliplatin,
5-FU and LV in 7 patients with metastatic
gastrointestinal cancer. A cycle of the 4-day chemotherapeutic regimen consisted of 12-h infusions with sinusoidal
drug delivery rate of:
oxaliplatin (25 mg/m2/d, peak at 16:00 hours),
5-FU and LV (750 mg/m2/d and 150 mg/m2/d, respectively, peak at 4:00 hours), the same scheme was reinitiated on day 15. Blood samples were collected on day 1 and day 4 during different cycles. Concentration-time profiles of ultrafilterable and total
platinum in plasma during chronomodulated infusion were characterised. As expected, we found residual
platinum levels in total plasma but not in PUF prior next cycle. Comparing day 1 with day 4, Cmax of
platinum in PUF was significantly increased (84 +/- 13 ng/ml vs. 131 +/- 22 ng/ml, P = 0.012) as well as AUC0-24h of
platinum in PUF (0.97 +/- 0.29 microg x h/ml vs. 1.90 +/- 0.44 microg x h/ml, P = 0.018). The same effect was observed for total plasma
platinum suggesting an accumulation within the cycle. The observed interindividual variability of Cmax, tmax, AUC0-24h, t1/2 was moderate. Because of the small sample size in this pilot investigation, the findings need to be confirmed in larger pharmacokinetic studies. In a next step individual pharmacokinetic parameters should be associated with patient specific parameters and treatment-induced toxicity.