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Mechanism Of Action
Levoleucovorin effects during high-dose methotrexate therapy
Levoleucovorin is the pharmacologically active isomer of 5-formyl tetrahydrofolic acid. Levoleucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “onecarbon” moieties. Administration of levoleucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase.
Levoleucovorin effects in combination with 5-fluorouracil
Levoleucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy such as 5-fluorouracil. 5-fluorouracil is metabolized to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), which binds to and inhibits thymidylate synthase (an enzyme important in DNA repair and replication). Levoleucovorin is readily converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of FdUMP to thymidylate synthase and thereby enhances the inhibition of this enzyme.
Levoleucovorin is actively and passively transported across cell membranes. In vivo, levoleucovorin is converted to 5-methyltetrahydrofolic acid (5-methyl-THF), the primary circulating form of active reduced folate. Levoleucovorin and 5-methyl-THF are polyglutamated intracellularly by the enzyme folylpolyglutamate synthetase. Folylpolyglutamates are active and participate in biochemical pathways that require reduced folate.
The pharmacokinetics of levoleucovorin after intravenous administration of a 15 mg dose was studied in healthy male volunteers. After rapid intravenous administration, serum total tetrahydrofolate (total-THF) concentrations reached a mean peak of 1722 ng/mL. Serum (6S)-5-methyl-5,6,7,8-tetrahydrofolate concentrations reached a mean peak of 275 ng/mL and the mean time to peak was 0.9 hours. The mean terminal half-life for total-THF and (6S)-5-methyl-5,6,7,8tetrahydrofolate was 5.1 and 6.8 hours, respectively.
A pharmacokinetic study was conducted in 40 healthy subjects who received a single intravenous dose of either Fusilev (200 mg/m² ) or racemic d,l-leucovorin (400 mg/m²), each administered as a 2-hour infusion in a crossover design. Results indicate that the 90% confidence interval for the geometric mean ratios for both AUC0-inf and Cmax were within the standard limit of 80-125% for both l-leucovorin and l-5-methyl-THF. Therefore, the exposure to l-leucovorin and 5-methyl-THF (AUC0-inf and Cmax) was comparable whether it was administered as Fusilev or as d,l-leucovorin. The geometric mean AUC0-inf values for levoleucovorin were 30719 ng•h/mL and 31296 ng.h/mL for Fusilev and d,l-leucovorin, respectively. The geometric mean Cmax values for levoleucovorin were 10895 ng/mL and 11301 ng/ mL for Fusilev and d,l-leucovorin, respectively. The geometric mean AUC0-inf values for 5-methyl-THF were 52105 ng.h/mL and 50137 ng.h/mL for Fusilev and d,l-leucovorin, respectively. The geometric mean Cmax values for 5-methyl-THF were 4930 ng/mL and 4658 ng/mL for Fusilev and d,l-leucovorin, respectively.
Use of Levoleucovorin in combination with 5-fluorouracil
A published cross study comparison showed that the mean dose-normalized steady-state plasma concentrations for both levoleucovorin and 5-methyl-THF were comparable whether 5-FU (370 mg/m²/day IV bolus) was given in combination with levoleucovorin (250 mg/m² and 1000 mg/m² as a continuous IV infusion for 5.5 days, N=9) or in combination with d,l-leucovorin (500 mg/m² as a continuous IV infusion for 5.5 days, N=6).
Animal Toxicology And/Or Pharmacology
The acute intravenous LD50 values in adult mice and rats were 575 mg/kg (1725 mg/m²) and 378 mg/kg (2268 mg/m²), respectively. Signs of sedation, tremors, reduced motor activity, prostration, labored breathing, and/or convulsion were observed in these studies. Anticipated human dose for each administration is approximately 5 mg/m² for high-dose methotrexate therapy which represents a 3-log safety margin.
High-Dose Methotrexate Therapy
The safety and efficacy of Fusilev rescue following high-dose methotrexate were evaluated in 16 patients age 6-21 who received 58 courses of therapy for osteogenic sarcoma. High-dose methotrexate was one component of several different combination chemotherapy regimens evaluated across several trials. Methotrexate 12 g/m² IV over 4 hours was administered to 13 patients, who received Fusilev 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate. Three patients received methotrexate 12.5 g/m² IV over 6 hours, followed by Fusilev 7.5 mg every 3 hours for 18 doses beginning 12 hours after completion of methotrexate. The mean number of Fusilev doses per course was 18.2 and the mean total dose per course was 350 mg. The efficacy of Fusilev rescue following high-dose methotrexate was based on the adverse reaction profile. [See ADVERSE REACTIONS]
Combination with 5-FU in Colorectal Cancer
In a randomized clinical study conducted by the Mayo Clinic and the North Central Cancer Treatment Group (Mayo/NCCTG) in patients with advanced metastatic colorectal cancer, three treatment regimens were compared: d,l-leucovorin (LV) 200 mg/m² and 5-fluorouracil (5-FU) 370 mg/m² versus LV 20 mg/m² and 5-FU 425 mg/m² versus 5-FU 500 mg/m². All drugs were administered by slow intravenous infusion daily for 5 days repeated every 28 to 35 days. Response rates were 26% (p=0.04 versus 5-FU alone), 43% (p=0.001 versus 5-FU alone) and 10% for the high dose leucovorin, low dose leucovorin and 5-FU alone groups, respectively. Respective median survival times were 12.2 months (p=0.037), 12 months (p=0.050), and 7.7 months. The low dose LV regimen gave a statistically significant improvement in weight gain of more than 5%, relief of symptoms, and improvement in performance status. The high dose LV regimen gave a statistically significant improvement in performance status and trended toward improvement in weight gain and in relief of symptoms but these were not statistically significant.
In a second Mayo/NCCTG randomized clinical study the 5-FU alone arm was replaced by a regimen of sequentially administered methotrexate (MTX), 5-FU, and LV. Response rates with LV 200 mg/m² and 5-FU 370 mg/m² versus LV 20 mg/m² and 5-FU 425 mg/m² versus sequential MTX and 5-FU and LV were respectively 31% (p ≤ 0.01), 42% (p ≤ 0.01), and 14%. Respective median survival times were 12.7 months (p ≤ 0.04), 12.7 months (p ≤ 0.01), and 8.4 months. No statistically significant difference in weight gain of more than 5% or in improvement in performance status was seen between the treatment arms.
A randomized controlled trial conducted by the NCCTG in patients with advanced metastatic colorectal cancer failed to show superiority of a regimen of 5-FU + levoleucovorin to 5-FU + d,l-leucovorin in overall survival. Patients were randomized to 5-FU 370 mg/m² intravenously and levoleucovorin 100 mg/m² intravenously, both daily for 5 days, or with 5-FU 370 mg/m² intravenously and d,l-leucovorin 200 mg/m² intravenously, both daily for 5 days. Treatment was repeated week 4 and week 8, and then every 5 weeks until disease progression or unacceptable toxicity.
Fusilev is dosed at one-half the usual dose of racemic d,l-leucovorin.
Last reviewed on RxList: 6/6/2011
This monograph has been modified to include the generic and brand name in many instances.
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