PRECLINICAL PHARMACOLOGY, TOXICOLOGY AND EFFICACY OF SPHINGOMYELIN CHOLESTEROL LIPOSOMAL VINCRISTINE FOR THERAPEUTIC TREATMENT OF CANCER/

Purpose: To establish the pharmacodynamic relationships between drug b iodistribution and drug toxicity/efficacy, a comprehensive preclinical evaluation of sphingomyelin/cholesterol (SM/chol) liposomal vincristi ne and unencapsulated vincristine in mice was undertaken. Methods: Pha rmaceutically acceptable formulations of unencapsulated vincristine an d liposomal vincristine at drug/lipid ratios of 0.05 or 0.10 (wt/wt) w ere evaluated for toxicity, antitumor activity and pharmacokinetics fo llowing intravenous administration. Results: Mice given liposomal vinc ristine at 2 mg/kg vincristine had concentrations of vincristine in bl ood and plasma at least two orders of magnitude greater then those ach ieved after an identical dose of unencapsulated drug. One day after ad ministration of the liposomal vincristine, there were at least tenfold greater drug quantities, relative to unencapsulated vincristine, in t he axillary lymph nodes, heart, inguinal lymph nodes, kidney, liver? s kin, small intestines and spleen. Increased plasma and tissue exposure to vincristine as a result of encapsulation in SM/chol liposomes was not associated with increased drug toxicities. Treatment of the murine P388 ascitic tumor with a single intravenous dose of unencapsulated d rug at 2, 3 and 4 mg/kg, initiated 1 day after tumor cell inoculation, resulted in a 33 to 38% increase in lifespan. In contrast, long-term survival rates of 50% or more were achieved in all groups treated with the SM/chol liposomal vincristine formulations at doses of 2, 3 and 4 mg/kg. At the 4 mg/kg dose, eight of ten and nine of ten animals surv ived past day 60 when treated with SM/chol liposomal vincristine prepa red at the 0.05 and 0.1 drug/lipid ratios, respectively. Conclusions: Overall, increased and prolonged plasma concentrations of vincristine achieved by liposomal encapsulation were correlated with dramatically increased antitumor activity in comparison with the unencapsulated dru g, but no correlations could be established between pharmacokinetic pa rameters and toxicity.