Clinical Pharmacokinetics of Melphalan After Super-Selective Ophthalmic Artery Infusion in Retinoblastoma Patients

SCHAIQUEVICH P; TAICH P; BUITRAGO E; CECILIANO A; VILLASANTE F; FANDIÑO A; CHANTADA G; SCHAIQUEVICH P

Congreso; XXII Congress of the Theapeutic Drug Monitoring and Clinical Toxicology society; 2013

Background: In few years, superselective ophthalmic artery infusion (SSOAI) of chemotherapeutic agents has become an established therapy for advanced intraocular retinoblastoma. Melphalan is the main drug used SSOAI based on its in vitro activity and eye preservation rate. The dose of melphalan is chosen empirically based upon patient?s characteristics and response to previous treatment. However, scarce data was previously available about melphalan pharmacokinetics after SSOAI. Thus, we aimed to characterize melphalan pharmacokinetics in retinoblastoma patients after SSOAI as a sin-gle agent or concomitant to topotecan and to correlate with hematopoietic toxicity to implement a rational dosage design to optimize chemotherapy treatment. Methods: The study included children with relapsed/refractory or naïve stage IV intraocular retinoblastoma with SSOAI indication. IRB approval was obtained. According to the age, patients received 3?6 mg of melphalan per eye and bilateral infusions (tandem therapy) received ,0.5 mg/kg. Serial blood samples were obtained and melphalan was quantitated by HPLC. Hematological toxicities were graded according to the CTCAEv4.0. Melpha-lan population pharmacokinetic analysis was performed by means of NLME modeling implemented in Monolix 3.2. Statistical analysis was performed to study relationships between pharmacokinetic parameters and hematological adverse events. Results: A total of 66 cycles of chemotherapy from 34 patients were evalu-ated. A 2-compartment model fitted adequately the data. Inter-individual variability in clearance (CL, 52%) and volume of distribution of the central compartment (Vc, 74%) was largely explained by body weight (P , 0.001). The fi nal population model was CL: 0.48 L $h2 1 $ kg21 ; Vc: 0.18 L/kg. A linear relationship between melphalan systemic exposure and dosage (mg/kg) was observed (P , 0.05). Few adverse events were recorded including (cycles) neutropenia G3 (10) and G4 (2) mainly observed in tandem therapy (7). G3/4 neutropenia was observed in 58% of the cycles where patients received . 0.48 mg/kg and 9% with lower dosages. Concomitant topotecan administration did not affect melphalan pharmacokinetics (P . 0.05). Conclusions: This is the first time melphalan pharmacokinetics is character-ized after SSOAI. Dosages of melphalan after SSOAI greater than 0.48 mg/kg were associated with higher systemic exposure and increased risk of neutro-penia. Combinations of chemotherapy agents and maximum melphalan dos-age should be considered in particular for tandem therapy.