Pharmacokinetics and Toxicity of Intravitreal Chemotherapy for Primary Intraocular Lymphoma

Abstract

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.

Retinal and Ocular Toxicity in Ocular Application of Drugs and Chemicals – Part II: Retinal Toxicity of Current and New Drugs

“…Velez et al [65] showed no ERG abnormalities after intravitreal injection of 2 g/0.1 ml. On the other hand, 4 g/0.1 ml caused a decrease of 34.5% in the b-wave, and with 8 g/0.1 ml, the b-wave was absent.…”

“…MTX affects cells in the S phase of the cell cycle [69] , and it is most effective against rapidly proliferating cells. MTX is mostly used in combination with other antineoplastic agents in the treatment of the ocular neoplasias [65,69,70] .…”

“…Velez et al [65] evaluated the ocular toxicity of intravitreal combination chemotherapy, composed of 3 cycles of serial injections of MTX (400 g on days 1, 4 and 6), a single injection of 5-FU (500 g on day 2) and dexamethasone (500 g on day 7). The investigation was performed in New Zealand white rabbits, and fluctuations in the aand b-wave amplitudes in both the experimental (right) and control (left) eyes were observed.…”

Retinal toxicity after repeated intravitreal carboplatin injection into rabbit eyes

“…Some are too complex for clinical practice or vitreous concentrations of chemo therapeutic do not reach effective levels and are unstable 1 . Another described treatment is intravitreal transscleral injection of chemotherapeutic agent 4,5 . No serious com plications have been found to date but tumor dissemi nation in human retinoblastoma was demonstrated by subsequent fine needle biopsy or pars plana vitrectomy 6 .…”

Experimental models of autoimmune inflammatory ocular diseases

“…The use of experimental models is important as there are many difficulties involved in getting intraocular tissue from patients' eyes, including technical and ethical issues. Experimental models are important for the development of new therapeutic agents as they are useful to evaluate the efficacy and toxicity of systemic and intravitreous drug delivery, such as antibiotics (3)(4)(5) , corticosteroids (6,7) , immunosuppressive drugs (8,9) , and more recently anti-VEGF (10,11) , and biological agents (e.g., tacrolimus, sirolimus, etanercept, infliximab, adalimumab, and rituximab) (12)(13)(14)(15)(16)(17)(18)(19) . The aim of this paper is to review the most used experimental autoimmune ocular inflammatory diseases models used in Ophthalmology and their most important aspects.…”