Pharmacokinetic Analysis of Topotecan After Superselective Ophthalmic Artery Infusion and Periocular Administration in a Porcine Model

Schaiquevich, Paula; Buitrago, Emiliano; Ceciliano, Alejandro; Fandiño, Adriana; Asprea, Marcelo; Sierre, Sergio; Abramson, David H.; Bramuglia, Guillermo F.; Chantada, Guillermo

doi:10.1097/iae.0b013e31821e9f8a

Cited by 33 publications

(45 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pharmacokinetic studies show poor vitreous levels of drugs administered by either IVC or IAC. 132 The highest drug bioavailability in the vitreous is achieved by intravitreal chemotherapy using a safety-enhanced injection technique in carefully selected eligible eyes. 133 Following control of the source of seeds, intravitreal chemotherapy achieved two-year 98.5% control of target seeds and 90.4% event-free ocular survival.…”

Section: Managementmentioning

confidence: 99%

Retinoblastoma

Dimaras

Corson

Cobrinik

et al. 2015

Nat Rev Dis Primers

Self Cite

424

390

View full text Add to dashboard Cite

Retinoblastoma is a rare cancer of the infant retina, which forms when both RB1 alleles mutate in a susceptible retinal cell, likely a cone photoreceptor precursor. Loss of the tumour suppressor functions of the retinoblastoma protein, pRB, leads to uncontrolled cell division and recurrent genomic changes during tumour progression. Although pRB is expressed in virtually all tissues, cone precursors have biochemical and molecular features that may sensitize to RB1 loss to enable tumourigenesis. Retinoblastoma is diagnosed in ~8,000 children each year worldwide. Patient survival is >95% in high-income countries, but <30% globally. However, outcomes are improving through increasing awareness for earlier diagnosis, new guidelines and sharing of expertise. Intra-arterial and intravitreal chemotherapy have emerged as promising methods to salvage eyes. Ongoing international collaborations will replace the multiple different classifications of eye involvement with standardized definitions to consistently assess eligibility, efficacy and safety of treatment options. Life-long follow-up is warranted since survivors of heritable retinoblastoma are at risk for developing second cancers. Defining the molecular consequences of RB1 loss in diverse tissues may open new avenues for treatment and prevention of retinoblastoma as well as second cancers in patients with germline RB1 mutations.

show abstract

Section: Managementmentioning

confidence: 99%

Retinoblastoma

Dimaras

Corson

Cobrinik

et al. 2015

Nat Rev Dis Primers

Self Cite

424

390

View full text Add to dashboard Cite

show abstract

“…The combination of melphalan and topotecan for IAC of retinoblastoma was effective and well tolerated without increased hematologic toxicity with respect to melphalan administered as a single drug 117,118. Topotecan showed a preferential passage to the vitreous humor, where it stayed for at least 4 hours more than its calculated IC 50 (50% inhibitory concentration) 119…”

Section: Clinical Management Of Retinoblastomamentioning

confidence: 98%

Risk definition and management strategies in retinoblastoma: current perspectives

Ghassemi

Khodabande

2015

OPTH

View full text Add to dashboard Cite

This manuscript focuses on high-risk factors of metastatic disease in retinoblastoma and evaluation of the current treatments of retinoblastoma. Presence of histopathologic high-risk factors is associated with a higher risk of local recurrence and systemic metastasis. Currently, globe-sparing therapies, including systemic chemotherapy, intra-arterial chemoreduction, intravitreal chemotherapy, focal consolidation, and combination therapies, are being used and investigated actively. Major advances are being made in the diagnosis and management of retinoblastoma that will lead to improved morbidity and mortality rates in patients with retinoblastoma. By saving the globes, fronting with some high-risk factors for metastasis would be inevitable. International multi-institutional prospective studies could resolve current uncertainties regarding the main tumor treatment regimens for each patient and indications for chemoprophylaxis for high-risk-factor-bearing retinoblastoma cases.

show abstract

“…Although others have used a porcine model, the marked vascular and ocular anatomical differences favor an NHP model. 16,17 Our studies were exploratory in nature and as such are subject to limitations. Our NHP cohort was limited to six animals.…”

Section: Discussionmentioning

confidence: 99%

Intra-Ophthalmic Artery Chemotherapy Triggers Vascular Toxicity through Endothelial Cell Inflammation and Leukostasis

Steinle

Zhang

Thompson

et al. 2012

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

1,6,9 PURPOSE. Super-selective intra-ophthalmic artery chemotherapy (SSIOAC) is an eye-targeted drug-delivery strategy to treat retinoblastoma, the most prevalent primary ocular malignancy in children. Unfortunately, recent clinical reports associate adverse vascular toxicities with SSIOAC using melphalan, the most commonly used chemotherapeutic. METHODS.To explore reasons for the unexpected vascular toxicities, we examined the effects of melphalan, as well as carboplatin (another chemotherapeutic used with retinoblastoma), in vitro using primary human retinal endothelial cells, and in vivo using a non-human primate model, which allowed us to monitor the retina in real time during SSIOAC.RESULTS. Both melphalan and carboplatin triggered human retinal endothelial cell migration, proliferation, apoptosis, and increased expression of adhesion proteins intracellullar adhesion molecule-1 [ICAM-1] and soluble chemotactic factors (IL-8). Melphalan increased monocytic adhesion to human retinal endothelial cells. Consistent with these in vitro findings, histopathology showed vessel wall endothelial cell changes, leukostasis, and vessel occlusion. CONCLUSIONS.These results reflect a direct interaction of chemotherapeutic drugs with both the vascular endothelium and monocytes. The vascular toxicity may be related to the pH, the pulsatile delivery, or the chemotherapeutic drugs used. Our long-term goal is to determine if changes in the drug of choice and/or delivery procedures will decrease vascular toxicity and lead to better eye-targeted treatment strategies. (Invest Ophthalmol Vis Sci.

show abstract

Pharmacokinetic Analysis of Topotecan After Superselective Ophthalmic Artery Infusion and Periocular Administration in a Porcine Model

Abstract: Superselective OAI resulted in significantly higher vitreous concentrations and exposure and a trend toward lower systemic exposure than POI.

Cited by 33 publications

References 26 publications

Retinoblastoma

Retinoblastoma

Risk definition and management strategies in retinoblastoma: current perspectives

Intra-Ophthalmic Artery Chemotherapy Triggers Vascular Toxicity through Endothelial Cell Inflammation and Leukostasis

Contact Info

Product

Resources

About