L). Each Sphingomyelin/Cholesterol Liposome Injection vial consists of 73.5 mg/mL sphingomyelin, 29.5 mg/mL cholesterol, 33.6 mg/mL citric acid, 35.4 mg/mL sodium citrate, and not more than 0.1% ethanol.
•Sodium Phosphate Injection (355 mg/25 mL). Each Sodium Phosphate Injection vial consists of 355 mg/25 mL dibasic sodium phosphate and 225 mg/25 mL sodium chloride.
Marqibo - Clinical Pharmacology
Mechanism of Action
Marqibo is a sphingomyelin/cholesterol liposome-encapsulated formulation of vincristine sulfate. Non-liposomal vincristine sulfate binds to tubulin, altering the tubulin polymerization equilibrium, resulting in altered microtubule structure and function. Non-liposomal vincristine sulfate stabilizes the spindle apparatus, preventing chromosome segregation, triggering metaphase arrest and inhibition of mitosis.
Pharmacokinetics
The plasma pharmacokinetics of Marqibo was investigated in 13 adult patients with relapsed ALL who received a Marqibo dose of 2.25 mg/m2 administered as a 1-hour intravenous infusion. The calculated pharmacokinetic parameters for total plasma vincristine sulfate are given in Table 3. The vincristine sulfate levels reported in Table 3 reflect liposome-encapsulated drug that may not be immediately bioavailable and may not be directly comparable to plasma levels of vincristine sulfate after administration of non-liposomal vincristine sulfate, which is immediately bioavailable.
Table 3. Pharmacokinetic Parameters from Patients with Acute Lymphoblastic Leukemia Treated with 2.25 mg/m2 Marqibo* Variable N Mean SE Median Range
*
Dose was administered as a 1-hour infusion.
AUC∞ (h∙ng/mL) 13 14566 1766 13680 7036-26074
CL (mL/h) 12 345 100 302 148-783
Cmax (ng/mL) 13 1220 64 1230 919-1720
The plasma clearance (CL) of Marqibo is slow, 345 mL/h, at a dose of 2.25 mg/m2. This is in comparison to the rapid clearance of non-liposomal vincristine sulfate at 189 mL/min/m2 (11,340 mL/h). The slow clearance of Marqibo contributes to a much higher AUC for Marqibo relative to non-liposomal vincristine sulfate.
Following intravenous administration of Marqibo, urinary excretion was a minor route of elimination for vincristine sulfate and its metabolite. Less than 8% of the administered Marqibo dose was eliminated in urine over a 96-hour observation period, which is similar to the urinary excretion of non-liposomal vincristine sulfate. Following non-liposomal vincristine sulfate infusion, the main route of vincristine sulfate excretion was the fecal route, accounting for 69% of the administered dose over 72 hours.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenicity studies have been conducted with Marqibo or non-liposomal vincristine sulfate. Based on the mechanism of action and genotoxicity findings in nonclinical studies conducted with non-liposomal vincristine sulfate, Marqibo may be carcinogenic.
No genotoxicity studies have been conducted with Marqibo. Non-liposomal vincristine was genotoxic in some in vitro and in vivo studies.
The single- and repeat-dose animal toxicology study results indicate that Marqibo can impair male fertility, consistent with the literature on non-liposomal vincristine sulfate. Administration of vincristine liposome injection causes testicular degeneration and atrophy, and epididymal aspermia in rats.
Gonadal dysfunction ha
