SPONTANEOUS OR IMPOSED CIRCADIAN CHANGES IN PLASMA-CONCENTRATIONS OF 5-FLUOROURACIL COADMINISTERED WITH FOLINIC ACID AND OXALIPLATIN - RELATIONSHIP WITH MUCOSAL TOXICITY IN PATIENTS WITH CANCER

Pharmacokinetics of total platinum, 5-fluorouracil, l-folinic and d-folinic acid, and 5-methyltetrahydrofolate were studied in plasma from nine patients with advanced colorectal cancer treated with oxaliplatin (20 mg/m(2)/day), 5-fluorouracil (600 mg/m(2)/day), and folinic acid (300 mg/m(2)/day). Drugs were administered with a programmable-in-time pump by continuous infusion for 5 days. We compared two drug delivery schedules: constant rate versus chronomodulated rate with peak of oxaliplatin at 4 PM and peak of 5-fluorouracil and folinic acid at 4 AM. In the chronomodulated schedule, plasma concentrations of the drugs paralleled the pump functioning: maximum platinum concentration near 4 PM, and maximum 5-fluorouracil and folate concentrations near 4 AM. When drugs were administered at a constant rate, mean plasma concentration of 5-fluorouracil varied in a circadian manner each treatment day, that is, a peak at 4 AM (approximate to 800 ng/ml) and a trough at 1 PM (approximate to 100 ng/ml). Mean plasma levels of total platinum and folate compounds increased over the first 24 hours. Total platinum mean level and that of the inactive d-folinic acid isomer reached a constant plasma concentration, whereas biologically active folates exhibited circadian variation in their plasma concentrations (peak around 7 AM, trough near 6 PM, and amplitude approximate to 10%). Severe mucositis was exhibited by all four patients on the flat schedule, but only by one on the chronomodulated schedule (p < 0.008). Individual pharmacokinetic and toxicity data showed that patients with circadian rhythms in 5-fluorouracil concentrations were least sensitive to 5-fluorouracil-related toxicity. Thus amplification or induction of such rhythm in 5-fluorouracil exposure may permit dose escalation.