Abstract
Purpose: :
There are several recent reports of efficacious intravitreal methotrexate (IVMTX) use in a variety of retinal diseases successfully including uveitic cystoid macula edema, proliferative diabetic retinopathy and age-related macula degeneration refractory to anti-VEGF therapy. We use the neurooncological intrathecal methorexate (ITMTX) literature to inform use of IVMTX and offer novel ideas for dose, toxicity and adjuvant therapy.
Methods: :
ITMTX is standardly dosed based on body surface area to avoid toxicity, as an indirect measure of volume of CNS distribution. We apply a similar formula to the eye using the frequently published dose of intravitreal MTX (400ug) and the range of human retinal surface area (RSA). The mean RSA in humans, is 1204 mm2 (+/- 184) with a range of 681 to 1636 mm2. The dose can be calculated as .337 ug/mm2 (95% CI: 0.207 to 0.467 ug/mm2) and from this we can extrapolate the amount of MTX needed to generate the same dose for various RSAs. Also, concomitant medicines that act within folate metabolism in ITMTX have been reported to decrease and increase the therapeutic index. Likewise, concomitant systemic MTX or disruptions in the blood-brain barrier may alter the toxicity profile.
Results: :
The average dose, based on the mean RSA is .337ug/mm2 (95% CI: 0.207 to 0.467). The dose for the smallest human adult RSA (681 mm2) is calculated as 229.4 ug (95% CI: 142.2 to 316.6 ug), and for the largest RSA (1636mm2) is calculated as 552.0 ug (95% CI: 339.9 to 764.1 ug). This results in a difference in dose of 322.6 ug (two-tailed P value = .0038, 95% CI: 174.6 to 470.6 ug) over the range of human adult RSA. Commonly used inhibitors of folate synthesis such as sulfadiazine and inhibitors of dihydrofolate reductase metabolism such as pyrimethamine and trimethoprim should likely be avoided in IVMTX because of toxicity reported in ITMTX. In addition, because of reports of toxicity in ITMTX intravitreal folinic acid should be avoided and intravenous administration further explored. Lastly, as suggested by ITMTX outcomes, concomitant systemic MTX, previous external beam radiation exposure or diseases conferring a disruption in the blood-retinal barrier may be more susceptible to MTX toxicity.
Conclusions: :
IVMTX has been generating much recent interest. Outcomes gleaned from ITMTX reports can usefully inform IVMTX. ITMTX offers important correlates for IVMTX dosing methods and adjuvant therapies for potentiation or protection/reversal of toxicity.
Keywords: uveitis-clinical/animal model • drug toxicity/drug effects • macula/fovea