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Pharmacokinetics and Urinary Excretion of Vincristine Sulfate Liposomes Injection in Metastatic Melanoma Patients

From the Department of Melanoma Medical Oncology, the University of Texas, M. D. Anderson Cancer Center, Houston, Texas (Dr Bedikian, Ms Vardeleon, Ms Smith) and Inex Pharmaceuticals Corporation, Burnaby, British Columbia, Canada (Ms Campbell, Dr Namdari).

Vincristine sulfate liposomes injection (VSLI) is a liposomal formulation of vincristine encapsulated in sphingosomes composed of sphinogomyelin and cholesterol (58/42; mol/mol). The pharmacokinetics and urinary excretion of VSLI were evaluated in 12 patients with metastatic melanoma after single-dose (2.0 mg/m² every 2 weeks = 1 cycle) and multiple-dose (cycle 3, pharmacokinetics only) administrations (intravenous infusion over 1 hour). After VSLI infusion, total (released and encapsulated) vincristine concentrations in plasma remained relatively constant for 3 to 12 hours and thereafter declined, with interpatient variability seen in the rate of decline resulting in monoexponential or biexponential profiles. The area under the plasma concentration-time curve from time zero to infinity of total vincristine in plasma ranged from 4933 to 40495 h·ng/mL and total clearance ranged from 131 to 445 mL/h. The volume of distribution at steady state was 2650 ± 731 mL, indicating VSLI was mainly confined within the plasma. The released vincristine concentrations in plasma were below the level of quantitation in 95% of samples. The pharmacokinetic parameters were similar between cycles 1 and 3, and trough plasma levels of total vincristine were below the level of quantitation of 1 ng/mL. Approximately 8% of the injected dose was excreted in the urine as unchanged vincristine (7%) or N-desformylvincristine (0.8%). Overall, VSLI exhibited a longer circulation half-life and higher area under the plasma concentration-time curve compared to conventional vincristine, whereas its route of elimination remained unchanged.

Key Words: Liposomes • drug delivery • pharmacokinetics • urinary excretion • vincristine

Address for reprints: Agop Y. Bedikian, MD, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 430, Houston, TX 77030; e-mail: abedikia{at}mdanderson.org.

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