Preclinical toxicity and pharmacology of liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II)

Abstract

Liposome-entrapped cis-bis-neodecanoate-trans-R,R-1,2-diaminocylohexane platinum(II) (L-NDDP) is a new lipophilic cisplatin derivative formulated in a liposomal carrier currently in phase I clinical trials. The preclinical toxicity and pharmacology of L-NDDP were studied in mice and dogs. At the LD₅₀ dose (i.v. bolus) in mice (60.5 mg/kg or 181.5 mg/m²), a tenfold decrease in the granulocyte and platelet counts was observed in the absence of renal toxic effects. In dogs, the maximum tolerated dose (MTD) of L-NDDP given i.v. over a period of 45–60 min was 150 mg/m². This dose produced significant vomiting (6–18 episodes), minimal renal dysfunction, a maximal decrease in granulocyte and platelet counts of from 30% to 70%, and acute and transient elevation of liver enzymes. Higher doses (225 and 300 mg/m²) resulted in severe gastrointestinal (GI) toxicity in one animal and the death of two others within 48 h. Autopsy results showed multifocal hemorrhages in the lungs, GI tract, kidney, and liver. Three dogs were treated monthly with the MTD up to a cumulative dose of 637.5–712.5 mg/m² with excellent tolerance. No cumulative myelosuppression or liver dysfunction was observed, whereas a slight increase in the creatinine baseline level was detected in all three animals. Autopsy results at the end of the study showed mild changes limited to the liver, kidney, and GI tract. Pharmacologic studies showed that the drug was cleared, fitting a two-compartment model with a mean t_1/2α of 7.1 min and a t_1/2β of 87.8 h. These studies show that L-NDDP can safely be given at therapeutic doses to animals and that the dose-limiting toxic effects consists of myelosuppression in mice and a multiorgan hemorrhagic syndrome related to vascular injury in dogs.