Pharmacokinetics of Melphalan After Intravitreal Injection in a Rabbit Model

Buitrago, Emiliano; Winter, Ursula; Williams, Gustavo; Asprea, Marcelo; Chantada, Guillermo; Schaiquevich, Paula

doi:10.1089/jop.2015.0088

Cited by 23 publications

(13 citation statements)

References 20 publications

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“…Aqueous seeding has remained an intractable form of retinoblastoma due to a sanctuary effect linked to insufficient drug bioavailability in the AC, despite direct ophthalmic artery or intravitreal delivery, to achieve an antitumor effect [11]. …”

Section: Discussionmentioning

confidence: 99%

Intracameral Chemotherapy (Melphalan) for Aqueous Seeding in Retinoblastoma: Bicameral Injection Technique and Related Toxicity in a Pilot Case Study

et al. 2016

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Background: The anterior chamber has been shown by pharmacokinetic studies to represent a sanctuary never achieving a tumoricidal dose with the present administration routes, such as systemic, intra-arterial, or intravitreal injections. Method: A novel intracameral chemotherapy technique is described to control aqueous seeding in a pilot unilateral group E retinoblastoma case with primary aqueous seeding. Anterior segment toxicity was carefully monitored. Results: Control of the retinal tumor and vitreous seeding was achieved by intra-arterial and intravitreal chemotherapies. Sterilization of the aqueous was achieved after a first cycle of 7 melphalan injections in the anterior chamber, but relapse was noted 3.5 months later. This relapse was finally controlled with a second cycle of 6 intracameral injections targeting the posterior chamber. Corneal endothelial cell density remained stable over the injection period. Heterochromia and a progressive cataract developed, which required cataract surgery. At 5 years' follow-up, the patient is tumor free with normal vision (20/20 in both eyes), full binocularity, and no metastasis. Conclusions: The present bicameral injection technique appears to be safe and effective with limited toxicity. Melphalan-induced side effects were noted on the iris and lens but with no impact on the final visual function.

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Section: Discussionmentioning

confidence: 99%

Intracameral Chemotherapy (Melphalan) for Aqueous Seeding in Retinoblastoma: Bicameral Injection Technique and Related Toxicity in a Pilot Case Study

et al. 2016

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“…By localizing the chemotherapy, P-IVitC restricts the effective V d , as melphalan can only diffuse so far before rendered inactive by its short 1-h half-life [15]. Willekens et al [16] investigated intravitreal dispersion of iomeprol, a water-soluble contrast agent.…”

Section: Discussionmentioning

confidence: 99%

“…Assuming comparable melphalan diffusion, a P-IVitC dose of just 3.5 µg melphalan could theoretically reach the 4.0 μg/mL tumoricidal concentration around target vitreous seed(s) (0.9 mL accessible vitreous × 4.0 μg/mL tumoricidal concentration = 3.5 µg dose). The effects of diffusion past 1 h could be clinically insignificant, owing to the short 1-h half-life of melphalan and increase in globe movements as the child awakens from anesthesia [15]. A 75% dose reduction to 3.5 µg would likely reduce retinal toxicity, but its effectiveness in seed control would need to be tested.…”

Section: Discussionmentioning

confidence: 99%

Precision Intravitreal Chemotherapy for Localized Vitreous Seeding of Retinoblastoma

Dalvin

Welch

et al. 2018

Ocul Oncol Pathol

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Purpose: To describe and evaluate the effectivity of a novel precision intravitreal injection technique for select cases of localized vitreous seeding in retinoblastoma. Methods: Patients with localized vitreous seeds from retinoblastoma received intravitreal chemotherapy via a precision injection technique (P-IVitC) intended to optimize local delivery of melphalan to target seeds. The needle was inserted trans-pars plana and chemotherapy deposited within 3 mm of the target seed(s) under indirect ophthalmoscopic guidance. Without subsequent globe manipulation, the head was then positioned to promote gravity-dependent settling of chemotherapy. Results: There were 8 eyes of 8 patients treated with P-IVitC for active vitreous seeds following adequate solid tumor control with intravenous chemotherapy (n = 3, 38%) or intra-arterial chemotherapy (n = 5, 63%). Viable vitreous seeds were primarily solitary spheres (n = 6, 75%) and measured an average of 2.7 mm in diameter. Vitreous seed resolution (n = 8, 100%) was noted after a mean of 2.6 injections (median 2; range 1–3) of 20 μg melphalan. There was no recurrence at a mean follow-up of 10.0 months. Only 1 eye had an associated complication (focal retinal pigment epithelial mottling, n = 1, 13%). Conclusions: With direct delivery of chemotherapy to within 3–4 mm of vitreous seed activity, P-IVitC provided complete control of localized vitreous seeds with minimal toxicity.

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“…Recently, IVT injection of melphalan or topotecan has also shown promise as a means of eradicating vitreous seeding of retinoblastoma with acceptable side effects [8]. A recent paper demonstrated that after an IVT injection of melphalan in a rabbit eye, the concentrations of the drug in the vitreous and anterior chamber were, respectively, 7.8 and 0.024 µg/mL, with a rapid clearance of the drug in the anterior chamber [9]. This pharmacokinetic study showed that in case of anterior chamber involvement, IVT injection alone is probably not sufficient.…”

Section: Discussionmentioning

confidence: 99%

Eye Salvage with Combination of Intravitreal and Intracameral Melphalan Injection for Recurrent Retinoblastoma with Anterior Chamber Involvement: Report of a Case

Cassoux¹,

Aerts²,

Rouic³

et al. 2016

Ocul Oncol Pathol

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Aims: Herein we report successful eye salvage following combined intravitreal and intracameral administration of melphalan for anterior chamber recurrence of retinoblastoma. Methods: A 12-month-old boy was referred with a sporadic bilateral retinoblastoma staged as group D and V in the right eye and group E and V in the left eye. Treatment initially involved 6 cycles of 3 drugs followed by focal treatments. The left eye was enucleated. Three months after the end of systemic chemotherapy, multiple recurrent lesions were noted in the ciliary body and the anterior chamber. A series of intravitreal (IVT) and intracameral (IC) injections of melphalan combined with a 7th cycle of systemic chemotherapy was performed. The therapeutic schedule alternated: week A an IVT of melphalan (30 μg/0.1 mL) for a total of 4 versus week B IC injections of melphalan (15 μg/0.05 mL) 4 IC in total. Each injection was preceded by an anterior chamber. Cryotherapy to the injection punctures was systematically performed. Results: Rapidly, iris and ciliary body nodules regressed completely based on clinical and ultrasound biomicroscopic examinations. After 3 years of follow-up, the patient has shown no evidence of recurrence. Conclusion: In our patient, combined IVT and IC administration of melphalan proved highly efficacious in eradicating the ciliary body and anterior chamber disease and salvage of his one remaining functional eye.

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Pharmacokinetics of Melphalan After Intravitreal Injection in a Rabbit Model

Cited by 23 publications

References 20 publications

Intracameral Chemotherapy (Melphalan) for Aqueous Seeding in Retinoblastoma: Bicameral Injection Technique and Related Toxicity in a Pilot Case Study

Intracameral Chemotherapy (Melphalan) for Aqueous Seeding in Retinoblastoma: Bicameral Injection Technique and Related Toxicity in a Pilot Case Study

Precision Intravitreal Chemotherapy for Localized Vitreous Seeding of Retinoblastoma

Eye Salvage with Combination of Intravitreal and Intracameral Melphalan Injection for Recurrent Retinoblastoma with Anterior Chamber Involvement: Report of a Case

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