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

• Published in: Clinical pharmacology and therapeutics Vol. 56; no. 2; p. 190
• Main Authors: Metzger, G, Massari, C, Etienne, M C, Comisso, M, Brienza, S, Touitou, Y, Milano, G, Bastian, G, Misset, J L, Lévi, F
• Format: Journal Article
• Language: English
• Published: United States 01.08.1994
• Subjects: Adult; Aged; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - blood; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Circadian Rhythm; Colorectal Neoplasms - blood; Colorectal Neoplasms - drug therapy; Female; Fluorouracil - administration & dosage; Fluorouracil - blood; Fluorouracil - pharmacokinetics; Fluorouracil - therapeutic use; Folic Acid - blood; Humans; Infusion Pumps; Leucovorin - administration & dosage; Leucovorin - blood; Leucovorin - pharmacokinetics; Leucovorin - therapeutic use; Male; Middle Aged; Mouth Mucosa - drug effects; Organoplatinum Compounds - administration & dosage; Organoplatinum Compounds - blood; Organoplatinum Compounds - pharmacokinetics; Organoplatinum Compounds - therapeutic use; Oxaliplatin; Stereoisomerism; Stomatitis - chemically induced; Tetrahydrofolates - blood
• ISSN: 0009-9236
• DOI: 10.1038/clpt.1994.123

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/m2/day), 5-fluorouracil (600 mg/m2/day), and folinic acid (300 mg/m2/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 (approximately 800 ng/ml) and a trough at 1 pm (approximately 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 approximately 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.