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Gisela Velez, MD, MPH; Peng Yuan, PhD; Cynthia Sung, PhD; Ginger Tansey, DVM; George F. Reed, PhD; Chi-Chao Chan, MD; Robert B. Nussenblatt, MD; Michael R. Robinson, MD

Arch Ophthalmol. 2001;119:1518-1524.

Objective  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, first-order 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 (>0.5µM) 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.

From the Laboratory of Immunology, National Eye Institute (Drs Velez, Chan, and Nussenblatt), Pharmacy Department, Clinical Center (Dr Yuan), Bioengineering and Physical Sciences Program, Office of the Director (Dr Sung), Veterinary Research and Resources Section, National Eye Institute (Dr Tansey), and Division of Epidemiology and Clinical Research, National Eye Institute (Drs Reed and Robinson), National Institutes of Health, Bethesda, Md. Dr Velez is now with the Massachusetts Eye and Ear Infirmary, Boston, and Retina Specialists of Boston.

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