RESUMO
PURPOSE: To review preclinical and clinical pharmacokinetic studies of the three most important chemotherapy drugs used for intraocular retinoblastoma and the contribution of the reported results to optimize treatment. METHODS: Systemic review of pharmacokinetic studies identified by a literature search at Pubmed using the keywords carboplatin, melphalan, topotecan, intravitreal, ophthalmic artery chemosurgery, pharmacokinetics, and retinoblastoma. RESULTS: A total of 21 studies were reviewed for assessing the preclinical and clinical pharmacokinetics of carboplatin, topotecan, and melphalan delivered by intravenous, periocular, ophthalmic artery, and intravitreal routes. Some preclinical studies were done before translation to the clinics. Others, despite encouraging preclinical data as reported for periocular topotecan did not correlate with clinical use. In addition, as was the case for melphalan after ophthalmic artery chemosurgery and despite nonfavorable preclinical information, some routes of drug delivery are clinically effective. Besides topotecan, complete knowledge of the pharmacokinetics of melphalan and carboplatin is still lacking. CONCLUSION: Pharmacokinetic knowledge of chemotherapy may aid to guide retinoblastoma treatment in favor of safety and efficacy. Nonetheless, results obtained in preclinical models should be translated with care to the clinics.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatina/farmacocinética , Melfalan/uso terapêutico , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Topotecan/farmacocinética , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carboplatina/uso terapêutico , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Infusões Intra-Arteriais , Injeções Intraoculares , Melfalan/administração & dosagem , Melfalan/farmacocinética , Topotecan/administração & dosagem , Topotecan/uso terapêuticoRESUMO
PURPOSE: Although widely used for vitreous seed control in retinoblastoma patients, currently there are no data on melphalan pharmacokinetics after intravitreal injections. Therefore, 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 15 µg of melphalan. Vitreous, aqueous, retina, and blood samples were collected at different times up to 12 h 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 µg/mL, 0.024 µg/mL, and 9.8 µg/g tissue, respectively, attained immediately and at 0.8 and 0.25 h after intravitreal injection. Melphalan vitreous concentrations were higher than 0.3 µg/mL for 5 h after dosing. The elimination half-life from the vitreous, aqueous humor, and retina was 1.0, 0.2, and 1.2 h, respectively. Aqueous exposure [area under the curve (AUC)] was only 0.7% of that of the vitreous AUC. Melphalan concentrations in the retina were still detectable 12 h after dosing, while plasma exposure was under the limit of quantitation. CONCLUSION: Intravitreal administration of 15 µg melphalan leads to pharmacological vitreous levels with low aqueous exposure. Melphalan concentrations in the retina were measurable up to 12 h after dosing, but we report nondetectable systemic exposure in the rabbit. The results correlate with the clinical features of retinoblastoma patients that show control of vitreous seeds without systemic toxicity using intravitreal melphalan.
Assuntos
Melfalan/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Injeções Intravítreas , Melfalan/administração & dosagem , Melfalan/análise , Coelhos , Retina/química , Retina/metabolismo , Distribuição TecidualRESUMO
PURPOSE: To assess the antitumor activity, toxicity, and plasma pharmacokinetics of the combination of melphalan and topotecan for superselective ophthalmic artery infusion (SSOAI) treatment of children with retinoblastoma. DESIGN: Single-center, prospective, clinical pharmacokinetic study. PARTICIPANTS: Twenty-six patients (27 eyes) with intraocular retinoblastoma. METHODS: Patients with an indication for SSOAI received melphalan (3-6 mg) and topotecan (0.5-1 mg; doses calculated by age and weight). Plasma samples were obtained for pharmacokinetic studies, and a population approach via nonlinear mixed effects modeling was used. Safety and efficacy were assessed and compared with historical cohorts of patients treated with melphalan single-agent SSOAI. MAIN OUTCOME MEASURES: Melphalan and topotecan pharmacokinetic parameters and efficacy and safety parameters. RESULTS: Twenty-seven eyes from 26 consecutive patients received 66 cycles of SSOAI melphalan and topotecan in combination. All 5 eyes treated as primary therapy responded to the combination chemotherapy and were preserved. Sixteen of the 22 eyes with relapsed or resistant tumors responded, but 3 of them ultimately underwent enucleation at a median of 8 months (range, 7.9-9.1 months). The incidence of grade III and IV neutropenia was 10.6% and 1.5%, respectively, which was comparable with historical controls of single-agent SSOAI melphalan. No episode of fever neutropenia was observed, and no patient required transfusion of blood products. The large variability in melphalan pharmacokinetics was explained by body weight (P <0.05). Concomitant topotecan administration did not influence melphalan pharmacokinetic parameters. There was no effect of the sequence of melphalan and topotecan administration in plasma pharmacokinetics. CONCLUSIONS: A regimen combining melphalan and topotecan for SSOAI treatment of retinoblastoma is active and well tolerated. This combination chemotherapy previously showed synergistic pharmacologic activity, and we herein provide evidence of not increasing the hematologic toxicity compared with single-agent melphalan.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias da Retina/metabolismo , Retinoblastoma/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Lactente , Infusões Intra-Arteriais , Masculino , Melfalan/administração & dosagem , Melfalan/farmacocinética , Artéria Oftálmica/efeitos dos fármacos , Estudos Prospectivos , Neoplasias da Retina/tratamento farmacológico , Neoplasias da Retina/patologia , Retinoblastoma/tratamento farmacológico , Retinoblastoma/patologia , Topotecan/administração & dosagem , Topotecan/farmacocinéticaRESUMO
PURPOSE: To characterize melphalan pharmacokinetics after superselective ophthalmic artery infusion (SSOAI) in animals and children with retinoblastoma. METHODS: Vitreous and plasma samples of five Landrace pigs were obtained over a 4-hour period after SSOAI of melphalan (7 mg). Melphalan cytotoxicity was evaluated in retinoblastoma cell lines with and without topotecan. Plasma samples were obtained from 17 retinoblastoma patients after SSOAI of 3 to 6 mg of melphalan to one (n=14) or two eyes (n=3). Correlation between plasma pharmacokinetics and age, dosage, and systemic toxicity was studied in patients. RESULTS: In animals, melphalan peak vitreous levels were greater than its IC50 and resulted in 3-fold vitreous-to-plasma exposure. In patients, a large variability in pharmacokinetic parameters was observed and it was explained mainly by body weight (P<0.05). A significantly higher systemic area under the curve was obtained in children receiving more than 0.48 mg/kg for bilateral tandem infusions (P<0.05). These children had 50% probability of grades 3-4 neutropenia. Plasma concentrations after 2 and 4 hours of SSOAI were significantly higher in these children (P<0.05). A synergistic cytotoxic effect of melphalan and topotecan was evident in cell lines. CONCLUSIONS: 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.