Topotecan pharmacokinetics after periocular or intravitreous administration: an alternative for retinoblastoma chemotherapy

BRAMUGLIA GF; BUITRAGO E; MONTERO CARCABOSO A; ABRAMSON DH; SCHAIQUEVICH; CHANTADA G

Canadá

Congreso; IATDMCT; 2009

Introduction: Topotecan (TPT) is effective for retinoblastoma and was shown to have good vitreous penetration when given intravenously. The local route (periocular or intravitreous) may be preferable due to its favorable toxicity profile.  Methods:  Single intravitreous TPT (IVT) dose (5 ug) was administered in rabbits and vitreous and blood samples were obtained until 16 hs. A phase I dose-escalating study of periocular TPT (POT) was performed in patients with relapsed-resistant intraocular retinoblastoma facing imminent enucleation. Plasmatic or vitreous levels of TPT were measured by HPLC.  Results: In previous studies we observed that periocular injection of TPT (1 mg) in rabbits reached potentially active vitreous levels, although systemic absorption was detected . After IVT administration in rabbits, TPT vitreous levels were observed until 16 hs (mean: 25.0 ng/ml). TPT was not detected in blood after IVT route. The clinical assay included 5 patients that received 14 applications of POT. Only mild orbital edema occurred and grade 1 vomiting developed in the first patient. TPT was detected in plasma (mean AUC 50.4 ng/ml*h; 4 mg/m2 dose). Even though the study was not designed to assess response, we were able to observe that one eye had a partial response, 4 had stable disease and 1 had progressive disease after the second cycle.    Conclusions: POT (2mg) is a safe treatment option for retinoblastoma and its activity should be explored in phase 2-3 studies. Previous studies in children receiving intravenous topotecan with TDM guided  administration have shown that a median dose of 2.7 mg/m2 was necessary to reach the target AUC of 80 to 120 ng/ml*h, suggesting that therapeutic ranges/TDM strategies  should be re-defined when local treatments are used.  IVT administration in rabbits showed high concentrations of vitreous TPT that maintained for 16 hs and could be an alternative for TPT systemic treatment that should be study in future clinical trials.