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Plasma and cerebrospinal fluid pharmacokinetics of vincristine and vincristine sulfate liposomes injection (VSLI, marqibo®) after intravenous administration in Non-human primates.

Abstract：

PURPOSE: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.

journal_name

Invest New Drugs

journal_title

Investigational new drugs

authors

Shah NN,Cole DE,Lester-McCully CM,Wayne AS,Warren KE,Widemann BC

doi

10.1007/s10637-015-0311-x

subject

Has Abstract

pub_date

2016-02-01 00:00:00

pages

61-5

issue

eissn

0167-6997

issn

1573-0646

pii

10.1007/s10637-015-0311-x

journal_volume

pub_type

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Plasma and cerebrospinal fluid pharmacokinetics of vincristine and vincristine sulfate liposomes injection (VSLI, marqibo®) after intravenous administration in Non-human primates.