title: Clinical pharmacokinetics of intra-arterial melphalan and topotecan combination in patients with retinoblastoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Single-center, prospective, clinical pharmacokinetic study.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Unidad de Farmacocinética Clínica, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina.
authors.forename: Paula
authors.initials: P
authors.lastname: Taich
authors.affiliation: Servicio de Cardiología-Intervencionismo, Maternidad Suizo Argentina, Buenos Aires, Argentina.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Ceciliano
authors.affiliation: Unidad de Farmacocinética Clínica, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Buitrago
authors.affiliation: Servicios de Hematología-Oncología, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sampor
authors.affiliation: Servicios de Oftalmología, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina.
authors.forename: Adriana
authors.initials: A
authors.lastname: Fandino
authors.affiliation: Servicio de Cardiología-Intervencionismo, Maternidad Suizo Argentina, Buenos Aires, Argentina.
authors.forename: Francisco
authors.initials: F
authors.lastname: Villasante
authors.affiliation: Instituto Nacional de Cancer, Rio de Janeiro, Brazil.
authors.forename: Evandro
authors.initials: E
authors.lastname: Lucena
authors.affiliation: Unidad de Oncologia Ocular Hospital Oncologico Luis Razzetti, Caracas, Venezuela.
authors.forename: Livia
authors.initials: L
authors.lastname: Romero
authors.affiliation: Servicios de Hematología-Oncología, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina.
authors.forename: Guillermo L
authors.initials: GL
authors.lastname: Chantada
authors.affiliation: Unidad de Farmacocinética Clínica, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Cientificas y Tecnicas, CONICET, Buenos Aires, Argentina. Electronic address: paula.schaiquevich@gmail.com.
authors.forename: Paula
authors.initials: P
authors.lastname: Schaiquevich
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D007223:Infant; D007261:Infusions, Intra-Arterial; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000493:pharmacokinetics; D009880:Ophthalmic Artery / Q000187:drug effects; D011446:Prospective Studies; D019572:Retinal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D012175:Retinoblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019772:Topotecan / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D019772:Topotecan; D008558:Melphalan