Clinical Pharmacokinetics of Intra-arterial Melphalan and Topotecan Combination in Patients with Retinoblastoma.

TAICH P; CECILIANO A; BUITRAGO E; SAMPOR C; FANDIÑO A; VILLASANTE F; LUCENA; ROMERO; CHANTADA G; SCHAIQUEVICH P

OPHTHALMOLOGY

ELSEVIER SCIENCE INC

Lugar: Amsterdam; Año: 2014 vol. 121 p. 889 - 897

0161-6420

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