Pharmacokinetic and pharmacodynamic evaluation of liposomal cyclosporine

The pharmacokinetics and renal toxicity of two liposomal intravenous preparations of cyclosporine (CSA) (A, dimyristoylphosphatidylcholine (DMPC): stearylamine molar ratio 7:1; and B, DMPC: dimyristoylphosphatidylglycerol molar ratio 4:1) were assessed in the murine model and compared to the commercially available intravenous formulation of CSA (IV) and drug-free controls. No significant differences in steady-state area beneath the whole blood concentration-time curves were found between formulations and IV following 10 mg/kg per day CSA for 10 days. However, the apparent volume of distribution was significantly greater in A compared to B or IV formulations (13.82 ± 2.9 vs. 7.23 ± 3.98 and 7.67 ± 3.01 l/kg, p < 0.05), most likely due to the significantly prolonged biologic half-life of this formulation. Although the glomerular filtration rate was not significantly different between A and saline controls (1056 ± 536 and 1130 ± 550 μl/min per g KW, respectively), dosing with B or IV resulted in significant impairment (522 ± 429 and 572 ± 353 μl/min per g kidney weight (KW), respectively; p < 0.05). Triglyceride levels remained unchanged in all groups. However, cholesterol concentrations were significantly increased compared to baseline in rats administered formulation A (98 ± 31 vs. 70 ± 19 mg/dl; p < 0.05). In summary, dosing of liposomal formulation A resulted in equivalent concentrations of CSA as the IV formulation without the dose-limiting nephrotoxicity. These data offer a nontoxic delivery system for intravenous CSA.