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

Wettergren Y, Taflin H, Odin E, Kodeda K, Derwinger K - Cancer Chemother. Pharmacol. (2014)

Bottom Line: The results correlated with PK observations.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Institute of Clinical Sciences, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden, yvonne.wettergren@dep-surg.gu.se.

ABSTRACT

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/m². 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/m²) 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/m² and 52 at 60 mg/m²; 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/m²; C(max) ratio 15, AUC(last) ratio 11 at 60 mg/m²).

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.

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Related in: MedlinePlus

Comparison of mean concentrations (including SD) of methyleneTHF, THF, methylTHF, and formylTHF in mucosa and tumor after 60 or 200 mg/m2 Isovorin® or Modufolin® (n = 29, per protocol population)
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Fig2: Comparison of mean concentrations (including SD) of methyleneTHF, THF, methylTHF, and formylTHF in mucosa and tumor after 60 or 200 mg/m2 Isovorin® or Modufolin® (n = 29, per protocol population)

Mentions: The differences in magnitude and significance of the analyzed folate metabolites after Modufolin® and Isovorin® administration, respectively, are shown by drug, dose, and metabolite in Fig. 2 and Supplementary Table 1. Modufolin® administration resulted in significantly higher mucosa concentrations of methyleneTHF (p < 0.01 at both dose levels) and THF (p < 0.05 at 60 mg/m2, p < 0.01 at 200 mg/m2) than did Isovorin®. Higher concentrations of methyleneTHF and THF were also observed in tumor tissue after Modufolin® administration. The concentration difference in tumor was statistically significant in favor for Modufolin® at 200 mg/m2 (p < 0.01 for methyleneTHF and p < 0.05 for THF), while significance was not reached at the lower dose level for methyleneTHF or THF. The methylTHF levels did not differ significantly according to treatment, neither in mucosa nor in tumor tissue. The formylTHF levels, on the other hand, were significantly higher in both mucosa and tumor tissue of patients treated with Isovorin® as compared to Modufolin®, at both doses.Fig. 2


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

Wettergren Y, Taflin H, Odin E, Kodeda K, Derwinger K - Cancer Chemother. Pharmacol. (2014)

Comparison of mean concentrations (including SD) of methyleneTHF, THF, methylTHF, and formylTHF in mucosa and tumor after 60 or 200 mg/m2 Isovorin® or Modufolin® (n = 29, per protocol population)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4281361&req=5

Fig2: Comparison of mean concentrations (including SD) of methyleneTHF, THF, methylTHF, and formylTHF in mucosa and tumor after 60 or 200 mg/m2 Isovorin® or Modufolin® (n = 29, per protocol population)
Mentions: The differences in magnitude and significance of the analyzed folate metabolites after Modufolin® and Isovorin® administration, respectively, are shown by drug, dose, and metabolite in Fig. 2 and Supplementary Table 1. Modufolin® administration resulted in significantly higher mucosa concentrations of methyleneTHF (p < 0.01 at both dose levels) and THF (p < 0.05 at 60 mg/m2, p < 0.01 at 200 mg/m2) than did Isovorin®. Higher concentrations of methyleneTHF and THF were also observed in tumor tissue after Modufolin® administration. The concentration difference in tumor was statistically significant in favor for Modufolin® at 200 mg/m2 (p < 0.01 for methyleneTHF and p < 0.05 for THF), while significance was not reached at the lower dose level for methyleneTHF or THF. The methylTHF levels did not differ significantly according to treatment, neither in mucosa nor in tumor tissue. The formylTHF levels, on the other hand, were significantly higher in both mucosa and tumor tissue of patients treated with Isovorin® as compared to Modufolin®, at both doses.Fig. 2

Bottom Line: The results correlated with PK observations.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Institute of Clinical Sciences, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden, yvonne.wettergren@dep-surg.gu.se.

ABSTRACT

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/m². 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/m²) 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/m² and 52 at 60 mg/m²; 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/m²; C(max) ratio 15, AUC(last) ratio 11 at 60 mg/m²).

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.

Show MeSH
Related in: MedlinePlus