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Review
. 2013 Mar;71(3):555-64.
doi: 10.1007/s00280-012-2042-4. Epub 2012 Dec 5.

Marqibo® (vincristine sulfate liposome injection) improves the pharmacokinetics and pharmacodynamics of vincristine

Jeffrey A Silverman  1 , Steven R Deitcher
Affiliations
Review

Marqibo® (vincristine sulfate liposome injection) improves the pharmacokinetics and pharmacodynamics of vincristine

Jeffrey A Silverman et al. Cancer Chemother Pharmacol. 2013 Mar.

Abstract

Vincristine (VCR) is a mainstay of treatment of hematologic malignancies and solid tumors due to its well-defined mechanism of action, demonstrated anticancer activity and its ability to be combined with other agents. VCR is an M-phase cell cycle-specific anticancer drug with activity that is concentration and exposure duration dependent. The pharmacokinetic profile of standard VCR is described by a bi-exponential elimination pattern with a very fast initial distribution half-life followed by a longer elimination half-life. VCR also has a large volume of distribution, suggesting diffuse distribution and tissue binding. These properties may limit optimal drug exposure and delivery to target tissues as well as clinical utility as a single agent or as an effective component of multi-agent regimens. Vincristine sulfate liposome injection (VSLI), Marqibo(®), is a sphingomyelin and cholesterol-based nanoparticle formulation of VCR that was designed to overcome the dosing and pharmacokinetic limitations of standard VCR. VSLI was developed to increase the circulation time, optimize delivery to target tissues and facilitate dose intensification without increasing toxicity. In xenograft studies in mice, VSLI had a higher maximum tolerated dose, superior antitumor activity and delivered higher amounts of active drug to target tissues compared to standard VCR. VSLI recently received accelerated FDA approval for use in adults with advanced, relapsed and refractory Philadelphia chromosome-negative ALL and is in development for untreated adult ALL, pediatric ALL and untreated aggressive NHL. Here, we summarize the nonclinical data for VSLI that support its continued clinical development and recent approval for use in adult ALL.

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Figures

Fig. 1
Fig. 1
Plasma vincristine concentration following administration of 2 mg/m2 of VCR (dashed lines) or VSLI (solid lines) to rats. Vincristine drug concentrations were measured in plasma from Sprague–Dawley rats (N = 3/sex, except at 120 h, N = 5) at the indicated timepoints post-dose of 2 mg/m2 VSLI (solid lines) or vincristine (dashed lines). Symbols indicate the following: Male VCR (open circle), Female VCR (open square), Male VSLI (filled circle), Female VSLI (filled square)
Fig. 2
Fig. 2
Plasma vincristine concentration following administration of 0.8 mg/m2 VCR or VSLI to dogs. Vincristine drug concentrations were measured in plasma from dogs at the indicated timepoints post-dose of VSLI or vincristine. Symbols indicate the following: VSLI Monoexponential (N = 12, closed diamond), VSLI Bi-exponential (N = 2, filled square), VCR (N = 14, filled triangle)
Fig. 3
Fig. 3
Tissue total vincristine concentration following administration of VSLI (a) or VCR (b) to rats. Rats were administered a single bolus dose of 2.0 mg/m2 of either [3H]Vincristine or VSLI that had [3H]Vincristine encapsulated into the liposome. Tissue drug levels were measured up to 72 h post-dose by liquid scintillation counting of tissue samples. The bars represent samples taken at the following times: 4 h (open bars), 12 h (black bars), 24 h (gray bars)
Fig. 4
Fig. 4
VSLI and VCR antitumor activity in Namawala (a) and LX-1 (b) tumor bearing mice. Namawala (human lymphoma model) or LX-1 (human SCLC model) tumor cells were implanted subcutaneously into SCID mice. Mice received vehicle (dotted line), VCR (dashed lines), or VSLI (solid lines) on days 11, 18 and 25 post-implantation. Data represent mean ± SD, N = 5–10. The symbols indicate the following treatments: Vehicle-treated control (−), vincristine 0.5 mg/kg (+), 1.0 mg/kg (open circle), 1.5 mg/kg (open square); VSLI 1.0 mg/kg (filled circle), 1.5 mg/kg (filled square), 2.5 mg/kg (filled diamond)
Fig. 5
Fig. 5
Mean plasma concentration–time profile of total VCR in humans following IV administration of VSLI at 2.25 mg/m2. Plasma was collected from adult Ph-chromosome-negative relapsed/refractory patients, N = 12. Total VCR concentrations were measured at the indicated times post-dose of VSLI using a validated LC/MS–MS method. The lower limit of quantitation (LLOQ) for vincristine sulfate was 1.00 ng/mL. Pharmacokinetic parameters for total VCR concentrations (encapsulated and free) in plasma were calculated from the plasma concentration–time data using a noncompartmental analysis (NCA) method (WinNonlin Professional Network Edition, Version 5.2, Pharsight Corp, Palo Alto, CA, USA)
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