PHARMACOKINETIC BEHAVIOR OF VINCRISTINE SULFATE FOLLOWING ADMINISTRATION OF VINCRISTINE SULFATE LIPOSOME INJECTION

The pharmacokinetic behavior of vincristine sulfate (VINC) following a dministration of vincristine sulfate liposome injection (VSLI), 0.16 m g/ml, as an intravenous infusion over 60 min in 24 of 25 patients enro lled in a phase I clinical study of this drug is described. Plasma sam ples for determination of the pharmacokinetic behavior of VINC were co llected 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 determine d using a validated high-performance liquid chromatographic (HPLC) ass ay. Patients receiving doses of 0.5 to 1.5 mg/m(2) VSLI did not provid e useful pharmacokinetic data at late time-points owing to the limit o f quantitation of the HPLC assay (28.6 ng/ml). Sufficient concentratio n-time data were available for seven of the patients receiving doses o f VSLI from 2.0 to 2.8 mg/m(2) for compartmental modelling. A two-comp artment open model (PCNONLIN Model 10) was the best fit for the observ ed VINC plasma data for these patients. The mean maximum observed conc entration values were significantly greater for patients receiving VSL I at 2.8 mg/m(2)(2260 +/- 212 ng/ml, n = 2) than for those receiving 2 .0 mg/m(2) and 2.4 mg/m(2) (891 +/- 671 ng/ml, n = 6; 679 +/- 634 ng/m l, n = 6, respectively). No significant differences were observed in m aximum concentration values between patients at 2.0 mg/m(2) and those at 2.4 mg/m(2). A trend towards higher parametric AUC (0 to infinity) values with increasing dose (on a milligram per meter squared basis) w as observed but statistical significance was not reached. Comparison o f the pharmacokinetic behavior of VSLI observed in this study with non encapsulated VINC demonstrated that (1) the variability observed for V SLI 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-r ather than a three-compartment open model, and (3) VINC plasma concent rations were significantly greater following administration of VSLI th an described for nonencapsulated VINC. Overall, the results for patien ts treated with VSLI from 2.0 to 2.8 mg/m(2) suggest that this formula tion 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.