Abstract 3367: Massbalance, excretion and metabolism of [14C]-Pralatrexate (PDX) incancer patients in a phase I trial.

Abstract

Abstract Background: PDX is a novel 10-deaza-aminopterin analogue of methotrex[[Unsupported Character - Codename ­]]ate consisting of a mixture of R- and S-diastereomeric folate derivatives. PDX inhibits folate metabolism by binding to and inhibiting the enzyme dihydrofolate reductase (DHFR). PDX is the first drug approved by the US Food and Drug Admin[[Unsupported Character - Codename ­]]istration (FDA) specifically for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma. Mass balance studies in animals and humans with radiolabeled compounds represent a standard part of the development process for new drugs. Isotopically labeled analogs of a drug or its metabolites play an important role in understanding the absorption, distribution, metabolism and excretion profiles of a compound. The objectives of this study were to determine the pharmacokinetics (PK), metabolism and routes of excretion of [14C]-PDX and to characterize its metabolites in human plasma and urine. Methods: Four patients were administered intravenously with a mixture of 50 μCi of [14C]-PDX (0.5 mg) and 224.5 mg of non radioactive PDX over a 3-5 minute infusion. Serial blood and plasma samples were drawn at: 0 (before PDX infusion), and up to 144 h after the start of infusion. Urine and fecal samples were collected for up to 168 h after the start of infusion. Expired air samples were collected up to 24 hours after administration. The radioactivity measurement in biological fluids was performed using liquid scintillation counting. Results: Mass balance was achieved with a mean recovery radioactivity in excreta= 82.9 % ± 20.0 % for the four patients. The mean recovery of radioactivity in urine, feces, and expired air were 34.1%, 38.7% and 10.1%, respectively, indicating renal and fecal excretions were the major route of elimination of [14C]-PDX. A three-compartment open model adequately described [14C]-PDX time radioactivity-concentration courses. The AUC0-∞, and clearance values for total radioactivity in plasma were 18.1 nCi.h/mL, and 3.95 L/h, respectively. Metabolite profiling will be performed using HPLC with beta radiation detector. Conclusions: This study quantified the mass balance of PDX and defined its substantial excretion in both urine and feces after IV administration. The PK of [14C]-PDX was best described by a three compartment open model. The metabolite profiling of PDX is ongoing. Citation Format: Elodie Odore, Keyvan Rezaï, Olivier Madar, Sophie Weill, Ahmad Awada, Bert Pronk, Esteban Cvitkovic, Francois Lokiec. Massbalance, excretion and metabolism of [14C]-Pralatrexate (PDX) incancer patients in a phase I trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3367. doi:10.1158/1538-7445.AM2013-3367