Pharmacokinetic behavior of vincristine sulfate following administration of vincristine sulfate liposome injection

Abstract

The pharmacokinetic behavior of vincristine sulfate (VINC) following administration of vincristine sulfate liposome injection (VSLI), 0.16 mg/ml, as an intravenous infusion over 60 min in 24 of 25 patients enrolled in a phase I clinical study of this drug is described. Plasma samples for determination of the pharmacokinetic behavior of VINC were collected during the infusion at 15, 30 and 60 min as well as at 2, 4, 8, 12, 48 and 72 h postinfusion. Total VINC concentration was determined using a validated high-performance liquid chromatographic (HPLC) assay. Patients receiving doses of 0.5 to 1.5 mg/m2 VSLI did not provide useful pharmacokinetic data at late time-points owing to the limit of quantitation of the HPLC assay (28.6 ng/ml). Sufficient concentration-time data were available for seven of the patients receiving doses of VSLI from 2.0 to 2.8 mg/m2 for compartmental modelling. A two-compartment open model (PCNONLIN Model 10) was the best fit for the observed VINC plasma data for these patients. The mean maximum observed concentration values were significantly greater for patients receiving VSLI at 2.8 mg/m2 (2260 +/- 212 ng/ml, n = 2) than for those receiving 2.0 mg/m2 and 2.4 mg/m2 (891 +/- 671 ng/ml, n = 6; 679 +/- 634 ng/ml, n = 6, respectively). No significant differences were observed in maximum concentration values between patients at 2.0 mg/m2 and those at 2.4 mg/m2. A trend towards higher parametric AUC (0 to infinity) values with increasing dose (on a milligram per meter squared basis) was observed but statistical significance was not reached. Comparison of the pharmacokinetic behavior of VSLI observed in this study with nonencapsulated VINC demonstrated that (1) the variability observed for VSLI pharmacokinetic parameters was similar to nonencapsulated VINC, (2) although variability in absolute concentration was observed between patients, the behavior of VSLI in individual patients followed a two- rather than a three-compartment open model, and (3) VINC plasma concentrations were significantly greater following administration of VSLI than described for nonencapsulated VINC. Overall, the results for patients treated with VSLI from 2.0 to 2.8 mg/m2 suggest that this formulation protects VINC from the early phase of rapid elimination seen with nonencapsulated drug, resulting in significantly elevated VINC plasma concentrations over extended periods of time.

Pharmacokinetic characteristics of vincristine sulfate liposomes in patients with advanced solid tumors

“…Vinca alkaloids vincristine (VCR) is a widely used chemotherapeutic agent since the 1960s [1] and its cytotoxic activity is based on its capability to alter the tubulin polymerization equilibrium and arrest cell growth during metaphase [2,3] . VCR has a broad antitumor activity and is an important component of combination chemotherapy regimens for the treatment of childhood and adult acute lymphocytic leukemia, Hodgkin's and non-Hodgkin's lymphoma, rhabdomyosarcoma, neuroblastoma and Wilms' tumor [4,5] .…”

Treating relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia: liposome-encapsulated vincristine

“…77 Pharmacokinetic studies, which measured total plasma (both liposome-entrapped and nonencapsulated) vincristine concentrations, indicated that plasma elimination of vincristine after injection best fits a two-compartment model, suggesting that this formulation protects vincristine from the early phase of rapid elimination seen with the standard nonencapsulated drug formulation. 77,78 In addition, total vincristine plasma concentrations were significantly greater following liposomal administration than described previously following nonencapsulated vincristine injection. 77,78 It should be noted, however, that the plasma concentration of free vincristine released from the liposome into the circulation was too low to be quantified.…”

“…77,78 In addition, total vincristine plasma concentrations were significantly greater following liposomal administration than described previously following nonencapsulated vincristine injection. 77,78 It should be noted, however, that the plasma concentration of free vincristine released from the liposome into the circulation was too low to be quantified.…”

Are PEGylated liposomes better than conventional liposomes? A special case for vincristine

“…Embree et al (1997) conducted the first clinical trial of liposomal vincristine (DSPC/Chol liposomes) to determine the pharmacokinetic behavior of this preparation by intravenous infusion over 1 h. The t 1/2 values of 2.0, 2.4, and 2.8 mg/m 2 were 117 ± 403, 317 ± 472 and 434 ± 286 min, respectively, which were significantly prolonged compared to the vincristine solution. In addition, there was a significant increase (about 45-fold) of vincristine levels in plasma.…”