Pharmacokinetics of L-671,329 in rhesus monkeys and DBA/2 mice

Abstract

The time course of plasma drug levels and urinary recovery for two lipopeptide antifungal antibiotics, L-671,329 and cilofungin, were measured in male rhesus monkeys (Macaca mulatta) and in female DBA/2 mice. The antibiotics were administered intravenously at 10 mg/kg of body weight in phosphate-buffered saline-26% polyethylene glycol for the rhesus monkeys and in 5% dimethyl sulfoxide for the mice. Plasma and urine drug concentrations were determined by high-pressure liquid chromatography and/or a microbiological assay versus AspergiUlus niger, and pharmacokinetic parameters were determined for both species. In each of the two rhesus crossover tests as well as in the mouse studies, the pharmacokinetics of the two compounds were similar; however, a marked difference was evident between species. The half-lives of L-671,329 and cilofungin in plasma were 39 and 34 min in the mice and averaged 1.8 and 2 h in the rhesus monkeys, respectively. In mice and rhesus monkeys, urinary recovery was <4% for both compounds.In the search for new therapeutic agents, animal models of disease states have been an indispensable tool for the prediction of efficacy in humans. For any number of reasons, a therapeutic advantage of one agent over another demonstrated in an animal model may not translate analogously to humans. Thus, it behooves an investigator to be critical of the models he relies on and to develop additional experimental procedures to confirm his predictions. It is customary in our laboratory, for example, to explore any species-specific pharmacokinetic properties of a compound of interest. A comparison in rodents versus primates provides some of the additional parameters necessary for projecting success or failure in humans.In this study, species-specific pharmacokinetics of two recently reported, structurally similar ( Fig. la and b) lipopeptide antifungal antibiotics, L-671,329 and cilofungin (LY-121019, L-646,991), are presented. These agents have fungicidal, narrow-spectrum activity against Candida and Aspergillus spp. (1,5,6), and L-671,329 has also been shown to have activity against Pneumocystis cannii (9, 10). They both have the potential for improved efficacy and tolerance over existing therapy. MATERUILS AND METHODSMice. Female DBA/2 mice weighing 20 + 2 g were used in these studies. The mice were housed and fed in accordance with National Institutes of Health guidelines (2).Rhesus monkeys. Two male rhesus monkeys (Macaca mulatta) weighing 4.8 kg were used in these studies. They were also housed and fed in accordance with National Institutes of Health guidelines (2).Drugs. L-671,329 and cilofungin were prepared in our laboratory by published methods (4, 11). They were diluted in 5% dimethyl sulfoxide to 1.0 mg/ml or phosphate-buffered saline-26% polyethylene glycol (molecular weight, 300) to 10 mg/ml. Samples were kept on ice at 0°C and administered the same day.HPLC conditions. Conditions for high-pressure liquid chromatography (HPLC) areas were linear from 200 to 0.5 ,ug/ml (limit of detection based on a ...

Antifungal effects of the nonlinear pharmacokinetics of cilofungin, a 1,3-beta-glucan synthetase inhibitor, during continuous and intermittent intravenous infusions in treatment of experimental disseminated candidiasis

“…Other promising echinocandin compounds have been described before (2,8). Some members of the echinocandin class of cell wall-active agents, other than cilofungin, appear to have similar properties of relatively short plasma half-lives at alpha and beta phases as in L-671,329 (26 could potentially achieve the high peak plasma concentrations and sustained plasma levels that appear to be required for optimal fungicidal activity of these compounds. Whether other 1,3-p-glucan synthetase inhibitors follow nonlinear saturable plasma kinetics associated with increased pharmacodynamic activity remains to be determined.…”

Preliminary animal pharmacokinetics of the parenteral antifungal agent MK-0991 (L-743,872)

“…Further development efforts leading to MK-0991 involved pharmacokinetic optimization in nonhuman primates. It was learned early on that the pharmacokinetics of the echinocandins were highly species specific (15,25). In general, the usual rules for body weight correlation with pharmacokinetic parameters were reversed, i.e., clearance (CL) was slower in rodents than in larger species.…”