Abstract 3356: Comparative plasma and cerebrospinal (CSF) pharmacokinetics (PK) of vincristine sulfate standard preparation (VCR) and vincristine sulfate liposomes injection (VSLI) in a non-human primate (NHP) model.

Abstract Background: Vincristine has been used as standard therapy for adult and pediatric malignancies for 50 years. Cumulative neurotoxicity often requires capping the maximum single and cumulative VCR dose. VSLI is a novel preparation of VCR encapsulated in sphingomyelin/cholesterol liposomes. Following clinical trials that demonstrated safety, tolerability and efficacy in adults with relapsed/refractory acute lymphoblastic leukemia, VSLI has been granted FDA accelerated approval at a dose of 2.25 mg/m2given once weekly for that population. A pediatric Phase I trial is ongoing. We evaluated plasma and CSF PK of intravenously (IV) administered VCR and total VSLI (liposomal encapsulated and non-encapsulated) in our NHP model. Methods: 0.1 mg/kg (1.2 mg/m2 human-equivalent dose) VCR over 1 minute or VSLI over 15 minutes was administered on separate occasions to each of 3 adult rhesus monkeys (Macaca mulatta). Serial paired plasma and CSF samples were collected for up to 48 hrs. Drug concentrations were quantified using HPLC/tandem mass spectrometry assays. For plasma samples, VCR standard curves were linear over a range of .0025-10.0 μg/ml (lower limit of quantification, .0025 μg/ml). Lower limit of detection for VCR in NHP CSF was .001 μg/ml. PK parameters were estimated using non-compartmental methods. Results: Plasma PK parameters (median and range) for VCR and VSLI Cmax (μg/ml) AUC0-infinity (μg*hr/ml) Cl (ml/min) Terminal T1/2 (hours) VCR 1.07 (0.99–2.1) 0.614 (0.336–0.676) 33.8 (29.6–54) 24.3 (14.2–54.4) VSLI 4.8 (3.7–7.3) 195 (163–312) 0.089 (0.073–0.113) 17.9 (13.9–21.5) Cmax = maximal concentration, AUC = area under the concentration x time curve, Cl = clearance, T1/2 = half life VCR demonstrated a multi-exponential and VSLI a near-monoexponential plasma concentration versus time curve. The ratios ClVCR: ClVSLI for the individual NHP were 300, 463 and 477. Vincristine was not detected in any CSF sample. Conclusions: The NHP model allowed for a direct comparison of VCR and VSLI PK. VCR Cl exceeds that of VSLI by approximately 400-fold. No penetration into the CSF was observed for either preparation. Citation Format: Diane E. Cole, Cynthia M. Lester-McCully, Nirali N. Shah, Katherine E. Warren, Alan S. Wayne, Brigitte C. Widemann. Comparative plasma and cerebrospinal (CSF) pharmacokinetics (PK) of vincristine sulfate standard preparation (VCR) and vincristine sulfate liposomes injection (VSLI) in a non-human primate (NHP) model. [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 3356. doi:10.1158/1538-7445.AM2013-3356