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Dan Douer - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of Vincristine sulfate liposome injection in the treatment of adult acute lymphocytic leukemia
Oncologist, 2016Co-Authors: Dan DouerAbstract:UNLABELLED : Acute lymphoblastic leukemia (ALL) is a heterogeneous group of hematologic malignancies that arise from clonal proliferation of immature lymphoid cells in the bone marrow, peripheral blood, and other organs. The vinca alkaloid Vincristine is a standard component of chemotherapy regimens used to treat ALL, because of its well-defined mechanism of action, demonstrated anticancer activity, and ability to be combined with other agents. However, the dosage of Vincristine is frequently capped because of neurotoxicity concerns, and patients with large body surface areas are, therefore, almost always underdosed. Liposomal formulations have the ability to "passively" accumulate at sites of increased vasculature permeability and reduce the adverse effects of encapsulated relative to free drug. Vincristine sulfate liposome injection (VSLI) is a sphingomyelin/cholesterol-based liposome-encapsulated formulation that is delivered weekly in a 1-hour infusion. Based on the pharmacokinetics of the liposomal delivery system, Vincristine is slowly released from the liposome and delivered into the tissues more efficiently than with the standard preparation, allowing a higher dose. This increase in therapeutic index from reduced toxicity is a valuable difference between the two formulations. VSLI is indicated for the treatment of adults with second or greater relapse and clinically advanced Philadelphia chromosome-negative ALL. For the first time, studies will be able to exploit the delivery of higher and uncapped doses of Vincristine in randomized studies comparing first-line chemotherapy with standard Vincristine versus VSLI in both ALL and lymphoma to determine whether VSLI is superior to conventional Vincristine. IMPLICATIONS FOR PRACTICE This review summarizes the development of Vincristine sulfate liposome injection, a new formulation of Vincristine. The pharmacokinetics of liposomal drug delivery are examined, the limitations and advantages of conventional and liposomal Vincristine are compared, and the use of Vincristine sulfate liposome injection in clinical trials and case studies is included. Clinicians will be informed of a new chemotherapy agent that is indicated for the treatment of adults with Philadelphia chromosome-negative acute lymphoblastic leukemia, whose disease has relapsed two or more times or whose leukemia has progressed after two or more regimens of antileukemia therapy.
Brigitte C Widemann - One of the best experts on this subject based on the ideXlab platform.
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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
Investigational New Drugs, 2016Co-Authors: Nirali N Shah, Diane E Cole, Katherine E Warren, Alan S Wayne, Cynthia M. Lester-mccully, Brigitte C WidemannAbstract: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 (T_1/2) of 4.8 min (range, 4.4–5.0 min) and terminal T_1/2 of 24.3 h, a near-monoexponential curve with a median T_1/2 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.
Rostam Namdari - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics and urinary excretion of Vincristine sulfate liposomes injection in metastatic melanoma patients
The Journal of Clinical Pharmacology, 2006Co-Authors: Agop Y Bedikian, Anna Vardeleon, T Smith, Susan Campbell, Rostam NamdariAbstract: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.
Nirali N Shah - One of the best experts on this subject based on the ideXlab platform.
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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
Investigational New Drugs, 2016Co-Authors: Nirali N Shah, Diane E Cole, Katherine E Warren, Alan S Wayne, Cynthia M. Lester-mccully, Brigitte C WidemannAbstract: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 (T_1/2) of 4.8 min (range, 4.4–5.0 min) and terminal T_1/2 of 24.3 h, a near-monoexponential curve with a median T_1/2 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.
Joyce A Deleo - One of the best experts on this subject based on the ideXlab platform.
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propentofylline attenuates Vincristine induced peripheral neuropathy in the rat
Neuroscience Letters, 2006Co-Authors: Sarah M Sweitzer, Joyce A Deleo, Janice L PahlAbstract:Abstract The development of painful peripheral neuropathy is a dose-limiting side effect of numerous cancer chemotherapeutic agents. The present study utilized a rodent model of Vincristine-induced neuropathy to determine whether a glial modulating agent, propentofylline, could attenuate Vincristine-induced mechanical allodynia. Intravenous Vincristine administered on days 1 through 5 and days 8 through 11 produced mechanical allodynia using 2 and 12 g von Frey filaments. Lumbar spinal cord from animals on day 15 expressed mild bilateral microglial and astrocytic activation as compared to saline-treated animals. Daily intraperitoneal propentofylline at 10 mg/kg attenuated mechanical allodynia induced by Vincristine administration. In addition, propentofylline was found to decrease spinal microglial and astrocytic activation on day 15. These data suggest that central glial cells may play an important role in the development of painful neuropathy following Vincristine administration.
