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.
Similar content being viewed by others
References
Moran RG, Scanlon KL. Schedule-dependent enhancement of the cytotoxicity of fluoropyrimidines to human carcinoma cells in the presence of folinic acid. Cancer Res 1991;51: 4618-23.
Kreuser ED, Küchler T, Zwingers T, Matthias M, Ridwelski K, Ehrich PM et al. A multicenter prospective randomized trial with assessment of quality of life in patients with metastatic colorectal carcinoma comparing interferon α-2b and folinic acid as modulators of 5-fluorouracil. Oncology 1994;17:78-84.
Cohen AM, Minsky BD, Schilsky RL. Colon cancer. In: De Vita VT, Hellman S, Rosenberg SA (eds) Cancer. Principles & Practice of Oncology. J.B. Lippincott Co., Philadelphia, 1993:929-77.
Leichman CG, Leichman L, Spears CP, Rosen PJ, Jeffers S, Groshen S. Prolonged continuous infusion of fluorouracil with weekly bolus leucovorin: A phase II study in patients with disseminated colorectal cancer. J Natl Cancer Inst 1993;85:41-4.
Ardalan B, Chua L, Tian E, Reddy R, Sridhar K, Benedetto P, Richman S, Legaspi A, Waldman S, Morrell L, Feun L, Savaraj N, Livingstone A. A phase II study of weekly 24-hour infusion with high-dose fluorouracil with leucovorin in colorectal carcinoma. J Clin Oncol 1991;9:625-30.
Petrelli NJ, Rustum YM, Bruckner H, Stablein D. The Roswell Park Memorial Institute and Gastrointestinal Tumor Study Group phase III experience with the modulation of 5-fluorouracil by leucovorin in metastatic colorectal adenocarcinoma. Adv Exp Med Biol 1988;244:143-55.
Petrelli, N, Douglass Jr. HO, Herrera L, Russell D, Stablein DM, Bruckner HW et al. The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. J Clin Oncol 1989;7:1419-26.
Jäger E, Heike M, Bernhard H, Klein O, Bernhard G, Lautz D, Michaelis J, Meyer zum Büschenfelde KH, Knuth A. Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: Results of a randomized multicenter trial. J Clin Oncol 1996;14:2274-9.
O´Connell MJ. A phase III trial of 5-fluorouracil and leucovorin in the treatment of advanced colorectal cancer. A Mayo Clinic/North Central Cancer Treatment Group study. Cancer 1989;63(Suppl 6):1026-30.
Schalhorn A, Kühl M. Clinical pharmacokinetics of fluorouracil and folinic acid. Semin Oncol 1992;19(Suppl. 3):82-92.
Sips JHM, Van Tellingen O, Nooijen WJ, Rodenhuis S, Ten Bokkel Huinink WW, Beijnen JH. The pharmacokinetics of reduced folates after intraperitoneal and intravenous administration of racemic [6S,R]-folinic acid. Cancer Chemother Pharmacol 1994;35:144-8.
Straw JA, Szapary D, Wynn WT. Pharmacokinetics of the diastereomers of leucovorin after intravenous and oral administration to normal subjects. Cancer Res 1984;44:3114-9.
Mader RM, Steger GG, Rizovski B, Sieder AE, Locker G, Gnant MFX, Jakesz R, Rainer H. Pharmacokinetics of rac-leucovorin vs [S]-leucovorin in patients with advanced gastrointestinal cancer. Br J Clin Pharmacol 1994;37:243-8.
Zittoun J. Pharmacokinetics and in vitro studies of l-leucovorin. Comparison with the d and d,l-leucovorin. Ann Oncol 1993;4(Suppl 2):S1-S5
Streit M, Jaehde U, Stremetzne S, Ridwelski K, Kerz H, Strohbach F, Hohenberger P, Zwiebel FM, Hebart H, Böthig R, Kairies M, Zillig D, Schuchmann S, Warnecke S, Thiel E, Kreuser ED. Five-day continuous infusion of 5-fluorouracil and pulsed folinic acid in patients with metastatic colorectal carcinoma: an effective second-line regimen. Ann Oncol 1997;8:1163-5
Christophidis N, Mihaly G, Vajda F, Louis W. Comparison of liquid-and gas-liquid chromatographic assays of 5-fluorouracil in plasma. Clin Chem 1979;25:83-86.
Quebbeman EJ, Hoffman NE, Hamid AAR, Ausman RK. An HPLC method for measuring 5-fluorouracil in plasma. J Liq Chromatogr 1984;7:1489-94.
Wainer IW, Stiffin RM. Direct resolution of the stereoisomers of leucovorin and 5-methyltetrahydrofolate using a bovine serum albumin high-performance liquid chromatographic chiral stationary phase coupled to an achiral phenyl column. J Chromatogr Biomed Appl 1988;424:158-62.
Comandone A, Bretti S, La Grotta G, Manzoni S, Bonardi G, Berardo R, Bumma C. Palmar-plantar erythrodystesthasia syndrome associated with 5-fluorouracil treatment. Anticancer Res 1993;13:1781-4.
Harris BE, Song R, Soong S, Diasio RB. Relationship between dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadiane variation of enzyme activity and plasma drug levels in cancer patients receiving 5-fluorouracil by protracted continuous infusion. Cancer Res 1990;50:197-201.
Metzger G, Massari C, Etienne MC, Comisso M, Brienza S, Toitou Y, Milano G, Bastian G, Misset JL, Levi F. 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. Clin Pharmacol Ther 1994;56:190-201.
Bertrand R, Jolivet J. Lack of interference by the unnatural isomer of 5-formyltetrahydrofolate with the effects of the natural isomer in leucovorin preparations. J Natl Cancer Inst 1989;81:1175-78.
Newman EM, Akman SA, Harrison JS, Leong LA, Margolin KA, Morgan RJ, Raschko JW, Somlo G, Ahn CW, Doroshow JH. Pharmacokinetics and toxicity of continuous infusion (6S)-folinic acid and bolus 5-fluorouracil in patients with advanced cancer. Cancer Res 1992;52:2408-12.
Schilsky RL, Ratain MJ. Clinical pharmacokinetics of high-dose leucovorin calcium after intravenous and oral administration. J Natl Cancer Inst 1990;82:1411-5.
Seifert P, Baker LH, Reed ML, Vaitkevicius VK. Comparison of continuously infused 5-fluorouracil with bolus injection in treatment of patients with colorectal adenocarcinoma. Cancer 1975;36:123-8.
Poorter RL, Bakker PJM, Veenhof CHN. Continuous infusion of chemotherapy: focus on 5-fluorouracil and fluorodeoxyuridine. Pharm World Sci 1998;20(2):45-59.
Thyss A, Milano G, Renée N, Vallicioni J, Schneider M, Demard F. Clinical pharmacokinetic study of 5-FU in continuous 5-day infusion for head and neck cancer. Clin Pharmacol Ther 1986;16:64-66.
Rights and permissions
About this article
Cite this article
Stremetzne, S., Schunack, W., Jaehde, U. et al. Pharmacokinetic and pharmacodynamic comparison of two doses of calcium folinate combined with continuous fluorouracil infusion in patients with advanced colorectal cancer. Pharm World Sci 21, 184–189 (1999). https://doi.org/10.1023/A:1008671129128
Issue Date:
DOI: https://doi.org/10.1023/A:1008671129128