Pharmacokinetics and toxicity of intravitreal chemotherapy for primary intraocular lymphoma

Objective: To investigate the pharmacokinetics and toxicity of intravitreal chemotherapeutic agents in the rabbit eye for the potential treatment of p rimary intraocular lymphoma and other intraocular malignancies. Methods: The ocular pharmacokinetics of intravitreal methotrexate sodium (4 00 mug) was studied in 10 New Zealand white rabbits, and a single-compartme nt, first-order elimination model was used to calculate the drug half-life. With the use of these data, a treatment schedule using serial injections o f intravitreal methotrexate and single injections of fluorouracil and dexam ethasone 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-mug intravitreal inj ection, remained therapeutic (> 0.5 muM) in the rabbit eye for 48 to 72 hou rs. 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 consisti ng of methotrexate intravitreal injections every 48 to 72 hours provides th erapeutic drug concentrations in the vitreous and, in combination with fluo rouracil and dexamethasone, appears to be safe in the rabbit eye. Clinical Relevance: Although responsive to conventional chemotherapy or rad iotherapy, recurrence of ocular involvement with primary central nervous sy stem lymphoma occurs in more than 50% of treated cases. Anecdotal reports o f the use of intravitreal chemotherapy for primary intraocular lymphoma hav e been encouraging. However, animal data on the pharmacokinetics and toxici ty of combined intravitreal agents for the treatment of this disease are la cking.