Pharmacokinetics of melphalan after intravitreal injection in a rabbit model.

BUITRAGO E; WINTER U; WILLIAMS G; ASPREA M; CHANTADA G; SCHAIQUEVICH P

JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS

MARY ANN LIEBERT INC

Lugar: New York; Año: 2015

1080-7683

Purpose: AlthoughDespite being widely used for vitreous seeds control in retinoblastoma patients, currently there isare no current data abouton melphalan pharmacokinetics after intravitreal injections. Thereforeus, in this study we characterized the ocular and systemic disposition of melphalan after intravitreal injection in the rabbit eye. Methods: New Zealand rabbits received a single intravitreal injection of 15µg of melphalan. Vitreous, aqueous, retina, and blood samples were collected at different times up to 12 hours after the injection. Melphalan was quantitated in the biological samples using a validated high performance liquid-chromatography technique and pharmacokinetic parameters were calculated by means of compartmental models. Results: Model-predicted melphalan maximum vitreous, aqueous, and retina concentrations were 7.8g/ml, 0.024g/ml, and 9.8g/g tissue, respectively, attained immediately and at 0.8 and 0.25 hours after intravitreal injection. Melphalan vitreous concentrations were higher than 0.3g/ml for 5 hours after dosing. The elimination half-life from the vitreous, and aqueous humor, and retina was 1.0, 0.2, and 1.2 hours, respectively. Aqueous exposure (AUC) was only 0.7% of that of the vitreous AUC. Melphalan concentrations in the retina were still detectable 12 hours after dosing while plasma exposure was under the limit of quantitation. Conclusion: Intravitreal administration of 15 g of melphalan leads to pharmacological vitreous levels with low aqueous exposure. Melphalan concentrations in the retina were measurable up to 12 hours after dosing but we report non-detectable systemic exposure in the rabbit. The results correlate with the clinical features of retinoblastoma patients that show control of vitreous seeds control without systemic toxicityies using intravitreal melphalan.