"The U.S. Food and Drug Administration today expanded the approved use of Imbruvica (ibrutinib) for chronic lymphocytic leukemia (CLL) patients who have received at least one previous therapy.
CLL is a rare blood and bone marrow disease"...
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.
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 Marqiboa
|aDose was administered as a 1-hour infusion.|
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.
Animal Toxicology and/or Pharmacology
In a repeat-dose comparative toxicology study in rats, vincristine sulfate liposome injection or non-liposomal vincristine sulfate was administered to animals intravenously once per week for 6 weeks. Clinical signs of toxicity consistent with neurotoxicity were greater with vincristine sulfate liposome injection than with non-liposomal vincristine sulfate at equal vincristine sulfate doses of 2 mg/m²/week and included uncoordinated movements, weakness, reduced muscle tone, and limited usage of the limbs. Neurological testing indicated drug-induced peripheral neurotoxicity with both drugs. Based on the histopathology examination after 6 weekly doses, vincristine sulfate liposome injection induced greater peripheral neurotoxicity (nerve fiber degeneration) and secondary skeletal muscle atrophy than the equal dose of non-liposomal vincristine sulfate. In a separate tissue distribution study in rats, administration of 2 mg/m² of intravenous liposomal or non-liposomal vincristine sulfate showed greater accumulation of vincristine sulfate in sciatic and tibial nerves (as well as the lymph nodes, spleen, and bone marrow) of the animals following vincristine sulfate liposome injection.
Acute Lymphoblastic Leukemia
Marqibo was studied in an international, open-label, multi-center, single-arm trial (Study 1). Eligible patients were 18 years of age or older with Philadelphia chromosome negative ALL in second or greater relapse or whose disease progressed after two or greater treatment lines of anti-leukemia therapy. Patients had to have achieved a complete remission (CR) to at least one prior anti-leukemia chemotherapy, defined by a leukemia-free interval of equal or more than 90 days. Patients were not eligible for immediate hematopoietic stem cell transplantation (HSCT) at the time of screening and enrollment.
Patients received intravenous Marqibo monotherapy at 2.25 mg/m² over 60 minutes every 7 days. Concomitant corticosteroids were not permitted beyond Day 5.
The treated population included 65 patients who received at least 1 dose of Marqibo. All of the treated patients had received prior vincristine sulfate and 80% had evidence of residual neuropathy at study baseline. Among treated patients, 51% were male, 86% were white, 45% were under 30 years of age, 11% were age 65 or older, 48% had undergone prior HSCT, 51% had received 3 or more prior therapies, and 45% were refractory to their immediate prior therapy. Disease characteristics were 85% precursor B-cell ALL and 15% precursor T-cell ALL. In addition, 22 of 65 (34%) treated patients did not receive asparaginase products prior to enrollment. Efficacy results are shown in Table 4.
Table 4: Study 1 Results
|Complete remission (CR)||3 (4.6)|
|CR with incomplete blood count recovery (CRi)||7 (10.8)|
|CR + CRi||10 (15.4)|
|(95% CIa)||(7.6 - 26.5)|
|MEDIAN DURATION of CR or CRi:||Days (95% CI)|
|Based on the first date of CR or CRi to the date of the last available histologic assessment of the same response (n=8)||28 (7, 36)|
|Based on the first date of CR or CRi to date of documented relapse, death, or subsequent chemotherapies including hematopoietic stem cell transplant (HSCT) (n=10)||56 (9, 65)|
|aCI = Confidence interval (Clopper-Pearson).|
Last reviewed on RxList: 8/17/2012
This monograph has been modified to include the generic and brand name in many instances.
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