title: Plasma and cerebrospinal fluid pharmacokinetics of vincristine and vincristine sulfate liposomes injection (VSLI, marqibo®) after intravenous administration in Non-human primates.
abstract: OBJECTIVE
  Vincristine sulfate liposomes injection (VSLI, Marqibo®) is an FDA approved encapsulated preparation of standard vincristine in sphingomyelin/cholesterol liposomes. Clinical pharmacokinetics show VSLI to be a long-circulating, slow release formulation that is confined to plasma, and prior data on cerebrospinal fluid (CSF) pharmacokinetics are lacking. We report our results comparing CSF and plasma pharmacokinetic parameters of intravenous aqueous vincristine to intravenous VSLI using an established non-human primate (NHP) model.
  
  
  METHODS
  Three adult male rhesus monkeys (Macaca mulatta) were administered 0.1 mg/kg (1.2 mg/m(2) human-equivalent dose) of vincristine or VSLI in a crossover pharmacokinetic study. Serial paired blood and CSF samples were obtained before infusion, at the end of infusion (EOI) and at various time points thereafter.
  
  
  RESULTS
  In contrast to standard vincristine, which had a multi-exponential plasma disappearance curve with a median initial (EOI to 30 min post-infusion) half-life (T1/2) of 4.8 min (range, 4.4-5.0 min) and terminal T1/2 of 24.3 h, a near-monoexponential curve with a median T1/2 of 17.9 h (range, 13.9-21.5 h) hours was calculated with VSLI. The ratios Cl VCR:Cl VSLI for the individual NHP were 300, 463 and 477. Vincristine was not detected in any CSF sample after administration of either formulation.
  
  
  CONCLUSIONS
  In three animals, each serving as their own control, we demonstrate that the pharmacokinetic profile of VSLI shows markedly prolonged clearance (approximately 400-fold lower) of total vincristine in comparison to the standard aqueous formulation, enhancing our understanding of VSLI pharmacokinetics. Several clinical trials incorporating VSLI as substitution for standard vincristine are in progress.
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 1W-3750, 9000, Rockville Pike, Bethesda, MD, 20892-1104, USA. Nirali.Shah@nih.gov.
authors.forename: Nirali N
authors.initials: NN
authors.lastname: Shah
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 1W-3750, 9000, Rockville Pike, Bethesda, MD, 20892-1104, USA.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Cole
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 1W-3750, 9000, Rockville Pike, Bethesda, MD, 20892-1104, USA.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Lester-McCully
authors.affiliation: Children's Center for Cancer and Blood Diseases, Division of Hematology, Oncology and Blood & Marrow Transplantation, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Wayne
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 1W-3750, 9000, Rockville Pike, Bethesda, MD, 20892-1104, USA.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Warren
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 1W-3750, 9000, Rockville Pike, Bethesda, MD, 20892-1104, USA.
authors.forename: Brigitte C
authors.initials: BC
authors.lastname: Widemann
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002784:Cholesterol / Q000737:chemistry; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000737:chemistry*; D006207:Half-Life; D007262:Infusions, Intravenous; D008081:Liposomes; D008253:Macaca mulatta; D008297:Male; D013109:Sphingomyelins / Q000737:chemistry; D014750:Vincristine / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008081:Liposomes; D013109:Sphingomyelins; D014750:Vincristine; D002784:Cholesterol
keywords: Cerebrospinal fluid; Non-human primate model; Pharmacokinetics; Vincristine sulfate liposomes injection