Pharmacokinetic Analysis of Melphalan after Superselective Ophthalmic Artery Infusion in Preclinical Models and Retinoblastoma Patients

Abstract

Potentially active levels of melphalan after SSOAI were achieved in the vitreous of animals. Low systemic exposure was found in animals and children. Doses greater than 0.48 mg/kg, given for bilateral tandem infusions, were associated with significantly higher plasma levels and increased risk of neutropenia. Synergistic in vitro cytotoxicity between melphalan and topotecan favors combination treatment.

Chemoreduction of Orbital Recurrence of Uveal Melanoma by Intra-Arterial Melphalan

“…Or it could be used to reduce large uveal melanomas to a size that could appropriately receive definitive treatment with plaque brachytherapy. In support of this, it is known from the retinoblastoma literature that intra-arterial melphalan results in a substantial dose of drug to the choroid [23]. Or perhaps it could be used in the management of other ocular melanomas, such as refractory conjunctival melanomas with orbital extension.…”

Secondary and tertiary intra-arterial chemotherapy for massive persistent or recurrent subretinal retinoblastoma seeds following previous chemotherapy exposure: long-term tumor control and globe salvage in 30 eyes

“…15 These levels are beyond the 50% minimum inhibitory concentration in vitro for melphalan to achieve control of retinoblastoma tumor with only minimal (57 ng/ml) concentrations in the plasma after direct ophthalmic artery infusion. 15 The RPE choroid to vitreous ratio of melphalan also indicates limited trans-retina diffusion of melphalan, which has been attributed to its poor affinity to the L-type amino acid transporter (LAT1) along the bloodretina barrier, an important pharmacokinetic property with significant clinical implications. 16 Topotecan exhibits a similar high ratio of vitreous to plasma concentration in animal studies after ophthalmic artery infusion that is well over the 50% minimum inhibitory concentration; however, studies on relative RPE choroid to vitreous concentration after ophthalmic artery infusion are not to our knowledge, available.…”

“…14 The rationale for using melphalan in IAC is to minimize its systemic toxicity through direct intra-arterial intraocular infusion. [14][15] In animal studies, the concentration of melphalan after a single ophthalmic artery infusion in the retinal pigment epithelium (RPE) choroid is 295.2 ng/g of tissue compared to 170.1 ng/g of vitreous humor, assuming a normal vitreous density of 1 g/ml. 15 These levels are beyond the 50% minimum inhibitory concentration in vitro for melphalan to achieve control of retinoblastoma tumor with only minimal (57 ng/ml) concentrations in the plasma after direct ophthalmic artery infusion.…”

“…[14][15] In animal studies, the concentration of melphalan after a single ophthalmic artery infusion in the retinal pigment epithelium (RPE) choroid is 295.2 ng/g of tissue compared to 170.1 ng/g of vitreous humor, assuming a normal vitreous density of 1 g/ml. 15 These levels are beyond the 50% minimum inhibitory concentration in vitro for melphalan to achieve control of retinoblastoma tumor with only minimal (57 ng/ml) concentrations in the plasma after direct ophthalmic artery infusion. 15 The RPE choroid to vitreous ratio of melphalan also indicates limited trans-retina diffusion of melphalan, which has been attributed to its poor affinity to the L-type amino acid transporter (LAT1) along the bloodretina barrier, an important pharmacokinetic property with significant clinical implications.…”

“…Also, infusion of both melphalan and topotecan does not affect each drug's penetration, and there is in vitro evidence of synergistic cytotoxicity of the two drugs that favors combination therapy when higher doses of melphalan are necessary for advanced disease. 15,19 The pharmacokinetic properties of melphalan delivered by ophthalmic artery infusion are reflected in its clinical activity toward control of solid tumor and SRS relative to VS. In a series of 70 eyes treated with IAC, Shields and associates reported complete solid tumor regression in 94%, SRS regression in 95%, and VS regression in 87% after a mean 3 cycles of IAC.…”