Pharmacokinetic and pharmacodynamic comparison of two doses of calcium folinate combined with continuous fluorouracil infusion in patients with advanced colorectal cancer

Abstract

The optimum dose of calcium folinate (leucovorin) as modulator of fluorouracil has not been defined yet. We conducted a randomized trial to compare the pharmacokinetics/pharmacodynamics of two doses of calcium folinate. 16 patients with advanced colorectal cancer were treated with 650 mg/m2/d fluorouracil as 5 day continuous infusion and randomized to receive either 20 mg/m2 or 100 mg/m2 calcium folinate as short infusion twice daily. The two diastereoisomers of calcium folinate were analyzed separately by chiral HPLC to account for differences in their pharmacokinetics. The pharmacokinetics of fluorouracil was not affected by folinate dosing. Total clearance of the active (6S)-diastereoisomer was found to be lower after the higher dose of folinate which can be explained by nonlinear metabolism. The incidence of treatment-induced mucositis significantly increased with (6S)-folinate exposure, whereas fluorouracil exposure was not related to this type of toxicity. In conclusion, exposure to folinate is more important for toxicity in this regimen than fluorouracil pharmacokinetics. Therefore, monitoring of fluorouracil plasma levels is not useful in this combination. Our results show that folinate dose should be carefully selected. Lower doses of folinate might be preferred because of less toxicity compared to higher doses.