A pharmacokinetic and pharmacodynamic investigation of Modufolin(®) compared to Isovorin(®) after single dose intravenous administration to patients with colon cancer: a randomized study

PURPOSE: Leucovorin is commonly used as folate supplement in 5-fluorouracil-based chemotherapy, but needs to be converted to active 5,10-methylenetetrahydrofolate (methyleneTHF) intracellularly. This provides for interindividual differences. MethyleneTHF has recently been developed into the stable, distributable drug, Modufolin(®). The aim was to compare the concentration of folate metabolites in tumor, mucosa, and plasma of patients with colon cancer after administration of Modufolin(®) or Isovorin(®) (levo-leucovorin). METHODS: Thirty-two patients scheduled for colon resection were randomized to receive Modufolin(®) or Isovorin(®) at dosage of 60 or 200 mg/m(2). The study drug was given as one i.v. bolus injection after anesthesia. Plasma was collected for pharmacokinetic (PK) analysis before, during, and after surgery. Tissue biopsies were collected at surgery. Folate metabolites were analyzed by LC-MS/MS. RESULTS: MethyleneTHF and THF concentrations were significantly higher in mucosa (p < 0.01, both dosages) and tumors (p < 0.01, 200 mg/m(2)) after Modufolin(®) as compared to Isovorin(®) administration. The results correlated with PK observations. The Modufolin(®) to Isovorin(®) C (max) ratio for methyleneTHF was 113 at 200 mg/m(2) and 52 at 60 mg/m(2); the AUC(last) ratios were 17 and 9, respectively. The THF plasma concentrations were also higher after Modufolin(®) administration (C (max) ratio 23, AUC(last) ratio 13 at 200 mg/m(2); C (max) ratio 15, AUC(last) ratio 11 at 60 mg/m(2)). CONCLUSION: Modufolin(®) administration resulted in significantly higher methyleneTHF levels than Isovorin(®) and may potentially increase the efficacy of 5-fluorouracil-based chemotherapy. The results encourage further evaluation of Modufolin(®) as a substitute to Isovorin(®) including the potential clinical benefits. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00280-014-2611-9) contains supplementary material, which is available to authorized users.