Clinical and Preclinical Pharmacology of Liposomal Vincristine

Abstract

Vincristine is one of the most commonly administered anticancer drugs and is active in a wide range of indications including non-Hodgkin's lymphomas, acute lymphocytic leukemias and lung cancer. Administration of vincristine in long-circulating liposomes may be expected to result in increased accumulation of drug at tumor sites due to “passive targeting” or “disease-site targeting” effects arising from the more permeable vasculature in these regions. Further, for liposomes with appropriate drug release characteristics, extended exposure of tumor cells to vincristine would result from liposomal delivery. The combination of increased drug delivery and extended duration of drug exposure may be expected to result in increased efficacy, particularly because vincristine is a cell-cycle specific drug. It is shown that vincristine can be encapsulated in large unilamellar vesicles (diameter β 100 nm) using a pH gradient (interior acidic) approach. Further, the efficacy of liposomal formulations of vincristine in animal models is highly sensitive to the drug release rate in vivo. A liposomal formulation with drug retention characteristics such that more than 50% of the vincristine is retained in the carrier 24 h following i.v. injection exhibits significantly improved antitumor efficacy in A431 xenograft and P388 murine tumor models in comparison to either free drug or leakier liposomal formulations. The clinical activity of liposomal vincristine has been investigated in relapsed or refractory non-Hodgkin's lymphoma patients at a dose level of 2 mg/m2 every two weeks. Of 83 registered patients, there were 24 responses in 68 evaluable patients. The responses according to histology are: Indolent-13%; Transformed-42%; Aggressive-45%. There were no serious cases of myelosuppression or any toxic deaths. It is concluded that liposomal vincristine can be given at high doses, is active and well tolerated and is rarely neurotoxic or myelosuppressive in these heavily pretreated patients. It appears that the benefits of low toxicity and enhanced efficacy noted in the tumor models are also observed in the clinical setting. A multicenter pivotal Phase II trial of liposomal vincristine in relapsed and refractory non-Hodgkin's lymphoma has been approved by the US FDA and is ongoing.