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

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).MethodsThirty-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.ResultsMethyleneTHF 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®Cmax ratio for methyleneTHF was 113 at 200 mg/m2 and 52 at 60 mg/m2; the AUClast ratios were 17 and 9, respectively. The THF plasma concentrations were also higher after Modufolin® administration (Cmax ratio 23, AUClast ratio 13 at 200 mg/m2; Cmax ratio 15, AUClast ratio 11 at 60 mg/m2).ConclusionModufolin® 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 materialThe online version of this article (doi:10.1007/s00280-014-2611-9) contains supplementary material, which is available to authorized users.

Phase 1 dose de-escalation trial of the endogenous folate [6R]-5,10-methylene tetrahydrofolate in combination with fixed-dose pemetrexed as neoadjuvant therapy in patients with resectable rectal cancer

“…However, this was a phase 1 study, and larger phase 2/3 studies will provide a more rigorous evaluation of the safety and tolerability of [6R]-MTHF plus pemetrexed combination therapy. With regard to SAEs, none were considered to be related to [6R]-MTHF, corroborating the toxicity findings of Wettergren et al [ 42 ], who reported that no AEs/SAEs were related to [6R]-MTHF treatment.…”

Phase 1 dose de-escalation trial of the endogenous folate [6R]-5,10-methylene tetrahydrofolate in combination with fixed-dose pemetrexed as neoadjuvant therapy in patients with resectable rectal cancer

“…However, this was a phase 1 study, and larger phase 2/3 studies will provide a more rigorous evaluation of the safety and tolerability of [6R]-MTHF plus pemetrexed combination therapy. With regard to SAEs, none were considered to be related to [6R]-MTHF, corroborating the toxicity findings of Wettergren et al [ 42 ], who reported that no AEs/SAEs were related to [6R]-MTHF treatment.…”

Metastatic colorectal cancer: Advances in the folate-fluoropyrimidine chemotherapy backbone

“…Following administration of a dose of 200 mg/m 2 , arfolitixorin resulted in significantly higher plasma C max and AUC last of methylene-THF than the same dose of leucovorin. At the same dose, intratumoural and intramucosal concentrations of methylene-THF and THF were also significantly higher after treatment with arfolitixorin versus leucovorin [74]. This may, in turn, translate to more effective ternary complex formation.…”

Folate‐Associated Gene Expression in Primary Tumors Is Associated With Tumor Response and Progression‐Free Survival of Patients With Metastatic Colorectal Cancer Undergoing 5‐ FU /Leucovorin‐Based Combination Chemotherapy

“…At the same time, however, high concentrations of 5,10‐MeTHF are needed for maximal inhibition of TYMS. Modulation of the folate pool towards high levels of 5,10‐MeTHF may be accomplished by replacing LV with the novel folate arfolitixorin ([6‐R] 5,10‐MeTHF), which is given as a bolus injection in FLV‐based combination chemotherapy [ 1 , 11 ].…”

Phase 1 dose de-escalation trial of the endogenous folate [6R]-5,10-methylene tetrahydrofolate in combination with fixed-dose pemetrexed as neoadjuvant therapy in patients with resectable rectal cancer

“…However, this was a phase 1 study, and larger phase 2/3 studies will provide a more rigorous evaluation of the safety and tolerability of [6R]-MTHF plus pemetrexed combination therapy. With regard to SAEs, none were considered to be related to [6R]-MTHF, corroborating the toxicity findings of Wettergren et al [ 42 ], who reported that no AEs/SAEs were related to [6R]-MTHF treatment.…”

Metastatic colorectal cancer: Advances in the folate-fluoropyrimidine chemotherapy backbone

“…Following administration of a dose of 200 mg/m 2 , arfolitixorin resulted in significantly higher plasma C max and AUC last of methylene-THF than the same dose of leucovorin. At the same dose, intratumoural and intramucosal concentrations of methylene-THF and THF were also significantly higher after treatment with arfolitixorin versus leucovorin [74]. This may, in turn, translate to more effective ternary complex formation.…”

Folate‐Associated Gene Expression in Primary Tumors Is Associated With Tumor Response and Progression‐Free Survival of Patients With Metastatic Colorectal Cancer Undergoing 5‐ FU /Leucovorin‐Based Combination Chemotherapy

“…At the same time, however, high concentrations of 5,10‐MeTHF are needed for maximal inhibition of TYMS. Modulation of the folate pool towards high levels of 5,10‐MeTHF may be accomplished by replacing LV with the novel folate arfolitixorin ([6‐R] 5,10‐MeTHF), which is given as a bolus injection in FLV‐based combination chemotherapy [ 1 , 11 ].…”

Phase 1 dose de-escalation trial of the endogenous folate [6R]-5,10-methylene tetrahydrofolate in combination with fixed-dose pemetrexed as neoadjuvant therapy in patients with resectable rectal cancer

“…However, this was a phase 1 study, and larger phase 2/3 studies will provide a more rigorous evaluation of the safety and tolerability of [6R]-MTHF plus pemetrexed combination therapy. With regard to SAEs, none were considered to be related to [6R]-MTHF, corroborating the toxicity findings of Wettergren et al [ 42 ], who reported that no AEs/SAEs were related to [6R]-MTHF treatment.…”

Metastatic colorectal cancer: Advances in the folate-fluoropyrimidine chemotherapy backbone

“…Following administration of a dose of 200 mg/m 2 , arfolitixorin resulted in significantly higher plasma C max and AUC last of methylene-THF than the same dose of leucovorin. At the same dose, intratumoural and intramucosal concentrations of methylene-THF and THF were also significantly higher after treatment with arfolitixorin versus leucovorin [74]. This may, in turn, translate to more effective ternary complex formation.…”

Folate‐Associated Gene Expression in Primary Tumors Is Associated With Tumor Response and Progression‐Free Survival of Patients With Metastatic Colorectal Cancer Undergoing 5‐ FU /Leucovorin‐Based Combination Chemotherapy

“…At the same time, however, high concentrations of 5,10‐MeTHF are needed for maximal inhibition of TYMS. Modulation of the folate pool towards high levels of 5,10‐MeTHF may be accomplished by replacing LV with the novel folate arfolitixorin ([6‐R] 5,10‐MeTHF), which is given as a bolus injection in FLV‐based combination chemotherapy [ 1 , 11 ].…”