A phase I and pharmacology study of continuous-infusion low-dose methotrexate administration

Lokich, Jacob J.; Curt, Gregory A.

doi:10.1002/1097-0142(19851115)56:10<2391::aid-cncr2820561008>3.0.co;2-w

Cited by 9 publications

References 9 publications

(2 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

Pharmacokinetics and Toxicity of Intravitreal Chemotherapy for Primary Intraocular Lymphoma

Velez

Yuan²,

Sung³

et al. 2001

Arch Ophthalmol

View full text Add to dashboard Cite

To investigate the pharmacokinetics and toxicity of intravitreal chemotherapeutic agents in the rabbit eye for the potential treatment of primary intraocular lymphoma and other intraocular malignancies. Methods:The ocular pharmacokinetics of intravitreal methotrexate sodium (400 µg) was studied in 10 New Zealand white rabbits, and a single-compartment, firstorder elimination model was used to calculate the drug half-life. With the use of these data, a treatment schedule using serial injections of intravitreal methotrexate and single injections of fluorouracil and dexamethasone sodium phosphate was developed. This schedule was studied in 4 New Zealand white rabbits to explore the combined toxicity of these agents.Results: Methotrexate vitreous levels, following a 400-µg intravitreal injection, remained therapeutic (Ͼ0.5µM) in the rabbit eye for 48 to 72 hours. Intravitreal methotrexate, combined with fluorouracil and dexamethasone, showed no evidence of drug toxicity as determined by electroretinography and histopathologic examination.Conclusions: A treatment schedule for primary intraocular lymphoma consisting of methotrexate intravitreal injections every 48 to 72 hours provides therapeutic drug concentrations in the vitreous and, in combination with fluorouracil and dexamethasone, appears to be safe in the rabbit eye.Clinical Relevance: Although responsive to conventional chemotherapy or radiotherapy, recurrence of ocular involvement with primary central nervous system lymphoma occurs in more than 50% of treated cases. Anecdotal reports of the use of intravitreal chemotherapy for primary intraocular lymphoma have been encouraging. However, animal data on the pharmacokinetics and toxicity of combined intravitreal agents for the treatment of this disease are lacking.

show abstract

Pharmacokinetics and Toxicity of Intravitreal Chemotherapy for Primary Intraocular Lymphoma

Velez

Yuan²,

Sung³

et al. 2001

Arch Ophthalmol

View full text Add to dashboard Cite

show abstract

5-fluorouracil and methotrexate administered simultaneously as a continuous infusion. A phase I study

Lokich

Phillips

Green

et al. 1985

Cancer

Self Cite

View full text Add to dashboard Cite

Infusion delivery systems have been evaluated for administration of many individual chemotherapeutic agents including 5-fluorouracil (5-FU) and methotrexate (MTX). This study combined the two drugs as an admixture, and in a Phase I trial design established a useful dose schedule for each of the component drugs. 5-FU at a fixed dose rate of 300 mg/M2/day was delivered with methotrexate (MTX) at four different dose rates (0.75, 1.0, 1.5, or 2.0 mg/M2/day, respectively). The drug solution was delivered via a subclavian venous access with a portable infusion pump in an ambulatory setting. Twenty-nine patients received a total of 38 courses of the two-drug infusion: 21 courses were delivered with the two agents admixed constantly throughout treatment (Schedule A) and 17 were administered the treatment with 5-FU delivered continuously and MTX added to the 5-FU for alternate 14-day cycles (Schedule B). For the former schedule, dose-rate-limiting toxicity was related to MTX and included stomatitis developing at days 8 to 14 (median, day 8) with the higher dose rates (1.5-2.0 mg/M2/day) and thrombocytopenia developing at days 11 to 56 (median, day 14) at the lowest dose rates (1.0 mg/M2/day). For Schedule B, dose-rate-limiting toxicity was similarly due to the MTX with thrombocytopenia and/or chemical hepatitis developing in six of seven courses of MTX at 1.0 mg/M2/day and in five of ten courses delivered at 0.75 mg/M2/day. On Schedule B the MTX-associated toxicities were reversed when the MTX administration was interrupted and in the face of continued 5-FU infusion. A reasonable dose rate and schedule for continuous infusion of 5-FU combined with MTX is: 5-FU 300 mg/M2/day X 28 days and MTX 0.75 mg/M2/day for days 1 to 14, with cycles administered consecutively each 28 days.

show abstract

Cyclophosphamide, methotrexate, and 5-fluorouracil in a three-drug admixture. Phase I trial of 14-day continuous ambulatory infusion

Lokich

Bern

Anderson

et al. 1989

Cancer

View full text Add to dashboard Cite

The compatibility and stability at room temperature for up to 7 days of a three-drug admixture of cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) (CMF) was established permitting the practical delivery of the combination as an infusion in an ambulatory setting. Fourteen patients received 20 courses of CMF administered on a continuous infusion schedule for 14 days of a 28-day cycle. The dose rates were fixed for 5-FU (300 mg/M2/day) and methotrexate (0.75 mg/M2/day). The cyclophosphamide dose was escalated from 25 to 50, 75, and 100 mg/M2/d. Leukopenia and thrombocytopenia were observed in two of five patients receiving the maximal dose of cyclophosphamide. No other toxicities were observed including alopecia, stomatitis or liver function abnormalities. This Phase I trial suggests that the cumulative doses of cyclophosphamide, methotrexate, and 5-FU are comparable to the maximum doses delivered as single agent infusions. Furthermore, when the infusion CMF is compared to the "standard" bolus schedule for CMF, the infusion schedule delivers 116%, 8%, and 350% of the respective three component drugs (cyclophosphamide, methotrexate, and 5-FU).

show abstract

A phase I and pharmacology study of continuous-infusion low-dose methotrexate administration

Cited by 9 publications

References 9 publications

Pharmacokinetics and Toxicity of Intravitreal Chemotherapy for Primary Intraocular Lymphoma

Pharmacokinetics and Toxicity of Intravitreal Chemotherapy for Primary Intraocular Lymphoma

5-fluorouracil and methotrexate administered simultaneously as a continuous infusion. A phase I study

Cyclophosphamide, methotrexate, and 5-fluorouracil in a three-drug admixture. Phase I trial of 14-day continuous ambulatory infusion

Contact Info

Product

Resources

About