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The Annals of Pharmacotherapy Oct 2012To comprehensively review the literature regarding the efficacy, safety, and costs associated with the use of levoleucovorin in cancer treatment and to assess whether... (Review)
Review
OBJECTIVE
To comprehensively review the literature regarding the efficacy, safety, and costs associated with the use of levoleucovorin in cancer treatment and to assess whether levoleucovorin would be a reasonable alternative to the use of racemic leucovorin.
DATA SOURCES
A MEDLINE search was conducted for English-language human studies published between January 1980 and April 2012 using the terms l-LV, levoleucovorin, d,l-LV, leucovorin, folinic acid, folinate, 5-formyltetrahydrofolate, folic acid, folates, methotrexate, 5-fluorouracil, and clinical trials.
STUDY SELECTION AND DATA EXTRACTION
Articles pertinent to clinical trials (Phase 1, 2, 3) related to evaluating the efficacy, interchangeability, and safety of levoleucovorin were collected and their contents reviewed.
DATA SYNTHESIS
From these pharmacokinetics and clinical studies, information on the use of levoleucovorin as a modulator of fluorouracil as well as when combined with other antitumor agents were scrutinized and extracted for comparison with leucovorin whenever possible. Two randomized Phase 3 clinical studies comparing the efficacy and adverse effect profiles of leucovorin and levoleucovorin demonstrated that levoleucovorin is as effective as leucovorin in terms of response, toxicity, and survival. Six randomized Phase 3 clinical studies demonstrated the safety and efficacy of levoleucovorin as a modulator of fluorouracil in combination with/without other antitumor agents in colorectal cancer patients. Levoleucovorin has been studied in other cancers. These clinical Phase 1/2/3 studies demonstrated efficacy and safety of levoleucovorin in combination chemotherapeutic regimens comprising fluorouracil and other antitumor agents.
CONCLUSIONS
The results of the clinical studies suggest that levoleucovorin is efficacious and can be used safely in combination with fluorouracil and other antitumor agents. Levoleucovorin can be used interchangeably with leucovorin for modulating fluorouracil. The current shortage of the supply of leucovorin centered in North America renders levoleucovorin a reasonable alternative in terms of efficacy and toxicity profile, but from the perspective of cost, leucovorin remains the drug of choice.
Topics: Antineoplastic Agents; Drug Interactions; Humans; Levoleucovorin; Neoplasms
PubMed: 23032661
DOI: 10.1345/aph.1Q677 -
Clinical Colorectal Cancer Oct 2009Our purpose is to perform a comprehensive literature review of the use of levoleucovorin in gastrointestinal malignancies and to assess whether levoleucovorin is a... (Review)
Review
PURPOSE
Our purpose is to perform a comprehensive literature review of the use of levoleucovorin in gastrointestinal malignancies and to assess whether levoleucovorin is a reasonable alternative to racemic leucovorin.
DESIGN
This is an extensive literature review of levoleucovorin use in patients with gastrointestinal tract malignancies. Our review revealed 125 citations with abstracts in the English language, including 16 randomized, controlled trials; 40 case studies; and 69 nonrandomized, controlled trials that included 6 pharmacokinetic (PK)/pharmacodynamic studies with 1 population PK study.
RESULTS
Upon our review, there were 2 randomized controlled trials that directly compared racemic leucovorin with levoleucovorin. Goldberg et al noted that there was no statistically significant difference between time to progression (P = .78) and time to death (P = .57). Furthermore, Scheithauer et al again noted no significant difference in terms of response rates (25% vs. 32%; P = .25), median survival time (15 months vs. 14.5 months; P = .28), overall survival at 1 year (58.3% vs. 60.6%; P = .72), and probability of survival at 2 years (15.3% vs. 23%; P = .16). In addition, multiple other studies, including randomized, controlled; nonrandomized, controlled; and case studies, demonstrate similar efficacy and tolerability between the use of racemic leucovorin or levoleucovorin as a modulator of 5-FU.
CONCLUSION
In many studies of patients with gastrointestinal malignancies, levoleucovorin has been used interchangeably and solely for racemic leucovorin for 5-FU modulation. Our literature review demonstrates that levoleucovorin has similar efficacy and tolerability when compared with racemic leucovorin, whether used in combination with other chemotherapeutic agents or alone.
Topics: Antimetabolites, Antineoplastic; Fluorouracil; Gastrointestinal Neoplasms; Humans; Leucovorin; Stereoisomerism
PubMed: 19822510
DOI: 10.3816/CCC.2009.n.034 -
Oncology (Williston Park, N.Y.) Jul 2008
Topics: Antineoplastic Agents; Cytoprotection; Humans; Leucovorin; Methotrexate; Osteosarcoma; Vitamin B Complex
PubMed: 19856573
DOI: No ID Found -
American Journal of Health-system... Apr 1995The physical compatibility of fluorouracil mixed with leucovorin calcium or levoleucovorin calcium, undiluted and modestly diluted with 5% dextrose injection, was... (Review)
Review
The physical compatibility of fluorouracil mixed with leucovorin calcium or levoleucovorin calcium, undiluted and modestly diluted with 5% dextrose injection, was evaluated. Fluorouracil 50 mg/mL was combined in duplicate with leucovorin or levoleucovorin 20 mg/mL (as the calcium salt) in 250-mL polyvinyl chloride (PVC) portable-pump reservoirs in six volume ratios, either undiluted or diluted with 5% dextrose injection (to a final volume 25% greater than the drug volume). Duplicate reservoirs of each combination were stored for seven days at 4, 23, or 32 degrees C. Samples were evaluated visually with a high-intensity monodirectional light beam to observe development of particulates. Turbidimetry and light-obscuration particle counting and sizing also were used to evaluate compatibility. Small amounts of tiny crystalline particles developed in most of the combinations, usually by four days. In some cases, the particles could be seen in normal diffuse room light. Particle content was greater with higher leucovorin concentrations and over longer storage periods. Storage temperature did not play a consistent role in particle development. Fluorouracil and leucovorin calcium or levoleucovorin calcium were not compatible when stored in PVC reservoirs at 4, 23, or 32 degrees C.
Topics: Chemical Precipitation; Drug Incompatibility; Fluorouracil; Humans; Leucovorin; Nephelometry and Turbidimetry
PubMed: 7627739
DOI: 10.1093/ajhp/52.7.710 -
Journal of Biomolecular Structure &... Jul 2024Lysyl oxidase like-2 (LOXL2) belongs to copper dependent amine oxidase from the lysyl oxidase family and is associated with breast cancer metastasis This study used...
Lysyl oxidase like-2 (LOXL2) belongs to copper dependent amine oxidase from the lysyl oxidase family and is associated with breast cancer metastasis This study used multi-stage computational screening and in vitro validations to repurpose FDA approved drugs targeting LOXL2 to control breast cancer progression.Molecular modeling techniques and high-throughput virtual-screening technique was employed to screen FDA-approved drug library for its avid binding to LOXL2.hLOXL2, MDA-MB231 and MCF 7 cells were used for in vitro.Collectively, this repurposing study identified levoleucovorin to bind the active site of LOXL2 protein to inhibit its activity. Further validation of levoleucovorin against LOXL2 activity is warranted toward repurposing levoleucovorin as a therapeutic agent for treating breast cancer patients. validations.Computational modeling of LOXL2 identified putative druggable region at the active site of LOXL2 protein. High-throughput virtual screening predicted levoleucovorin as a best lead drug candidate to have a favorable binding affinity for LOXL2 at its active site. Molecular dynamic simulation predicts levoleucovorin to bind stably and avidly to LOXL2 with favorable interactions. In vitro validations show levoleucovorin significantly inhibited hLOXL2 with and IC50 value of 68.81 μM. Levoleucovorin controlled cell proliferations in MDM-MB 231 and MCF-7 cells with GI50 values of 55.91 μM and 79.20 μM respectively. Further, a dose dependent inhibition of cancer cell migration was noted along with apoptosis induction in these cells with levoleucovorin treatment.Communicated by Ramaswamy H. Sarma.
Topics: Humans; Breast Neoplasms; Amino Acid Oxidoreductases; Cell Proliferation; Female; Molecular Dynamics Simulation; Molecular Docking Simulation; Drug Repositioning; Cell Line, Tumor; Protein Binding; Antineoplastic Agents; MCF-7 Cells; Catalytic Domain; Enzyme Inhibitors
PubMed: 37340696
DOI: 10.1080/07391102.2023.2224894 -
American Journal of Health-system... Apr 2008
Topics: Drug Approval; Humans; Leucovorin; United States; United States Food and Drug Administration
PubMed: 18387890
DOI: 10.2146/news080030 -
Clinical Pharmacy Apr 1993The bioequivalence and bioavailability of oral and intravenous formulations of levoleucovorin and leucovorin were studied, and the absolute bioavailabilities of... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The bioequivalence and bioavailability of oral and intravenous formulations of levoleucovorin and leucovorin were studied, and the absolute bioavailabilities of levoleucovorin and leucovorin tablet formulations were determined. Healthy male volunteers participated in two randomized, single-dose, four-way crossover studies. The treatment groups were as follows: A = five 2.5-mg levoleucovorin tablets, B = five 5-mg leucovorin tablets, C = one 12.5-mg levoleucovorin tablet, D = one 25-mg leucovorin tablet, in study 1; A = 15-mg levoleucovorin injection, B = two 7.5-mg levoleucovorin tablets, C = 30-mg leucovorin injection, D = two 15-mg leucovorin tablets, in study 2. Serum concentrations of N-5-methyltetrahydrofolate (the primary metabolite and circulating form of reduced folate after leucovorin administration) and total tetrahydrofolate were measured over 24 hours after dose administration. Pharmacokinetic values were calculated for N-5-methyltetrahydrofolate and total tetrahydrofolates; values were compared for A versus B, C versus D, A versus C, and B versus D in study 1 and A versus C and B versus D in study 2. Results from 35 men in study 1 and 33 in study 2 showed that 12.5-mg oral doses and 15-mg intravenous doses of levoleucovorin are bioequivalent to 25-mg oral doses and 30-mg intravenous doses of leucovorin, respectively. Equivalence was observed after oral and intravenous administration. The absolute bioavailability of levoleucovorin (74%) was not significantly different from that of leucovorin (65%).(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Administration, Oral; Adult; Biological Availability; Humans; Injections; Leucovorin; Male; Stereoisomerism; Tetrahydrofolates; Therapeutic Equivalency
PubMed: 8458180
DOI: No ID Found -
European Journal of Clinical... 1993The pharmacokinetic values of d,l-leucovorin and l-leucovorin were compared in eight healthy volunteers following oral administration of 25 mg d,l-leucovorin and 12.5 mg... (Comparative Study)
Comparative Study
The pharmacokinetic values of d,l-leucovorin and l-leucovorin were compared in eight healthy volunteers following oral administration of 25 mg d,l-leucovorin and 12.5 mg l-leucovorin. Serum levels of l-5-formyltetrahydrofolate, l-5-methyltetrahydrofolate, and total reduced folates were measured by an established microbiological method. Pharmacokinetic data for both preparations were consistent with those previously reported for d,l-leucovorin, with essentially complete first pass metabolism to l-5-methyltetrahydrofolate, the active metabolite. No differences were found between the two preparations in serum concentrations of active folate fractions, AUC, or Cmax, or in clearance and volume of distribution estimates. These data suggest that after administration of 25 mg of d,l-leucovorin, the d-diastereoisomer has no significant effect on the standard pharmacokinetic measurements of the active l-folates.
Topics: Adolescent; Adult; Humans; Leucovorin; Male; Middle Aged; Stereoisomerism; Tetrahydrofolates
PubMed: 8405015
DOI: 10.1007/BF02440861 -
Clinical Drug Investigation 2010Combined therapy with irinotecan/fluorouracil/levoleucovorin (calcium levofolinate) [IFL] has lost its position as the standard regimen for metastatic colorectal cancer...
BACKGROUND
Combined therapy with irinotecan/fluorouracil/levoleucovorin (calcium levofolinate) [IFL] has lost its position as the standard regimen for metastatic colorectal cancer because its toxicity and effectiveness have become controversial.
OBJECTIVE
To (i) identify the optimal regimen for IFL therapy in terms of irinotecan dosage, and (ii) determine the maximum tolerated dose and efficacy of the modified-IFL regimen in patients with histologically confirmed advanced colorectal cancer.
METHODS
In a phase I study, nine patients with advanced colorectal cancer received IFL treatment modified such that irinotecan was administered every 2 weeks, as opposed to the more toxic once-weekly administration. The study evaluated three escalating dose levels of irinotecan (100, 125 and 150 mg/m(2)). Each treatment cycle consisted of irinotecan on days 1 and 15; fluorouracil 600 mg/m(2) on days 1, 8, 15 and 22; and levoleucovorin 250 mg/m(2) on days 1, 8, 15 and 22. Data from the phase I study were used to determine the recommended dose of irinotecan for the phase II study. The latter study evaluated the effectiveness (overall response rate, median time to disease progression and median survival time) and tolerability of this modified-IFL therapy as ambulatory treatment in 22 patients with advanced colorectal cancer.
RESULTS
The dose-limiting toxicity of irinotecan was grade 3 neutropenia, which occurred in three patients at dose level 2 (125 mg/m(2)); furthermore, a fourth patient developed grade 4 neutropenia at this dose level. Therefore, 125 mg/m(2) was considered to be the maximum tolerated dose, and the dose of irinotecan for the phase II study was set at 100 mg/m(2). Fourteen patients achieved partial response using this modified-IFL regimen, and the overall response rate was 63.6% (95% CI 43.5, 83.7). The median time to progression was 197 days (range 111-283 days) and the median survival time was 414 days (95% CI 116, 712). Toxicities were acceptable and manageable.
CONCLUSIONS
Modified-IFL therapy is a practical, effective and tolerable option for ambulatory treatment of advanced colorectal cancer.
Topics: Adolescent; Adult; Aged; Ambulatory Care; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Survival Rate; Treatment Outcome; Young Adult
PubMed: 20225907
DOI: 10.2165/11534470-000000000-00000