PHARMACOKINETICS OF 2 ALTERNATIVE DOSAGE FORMS FOR CYCLOSPORINE - LIPOSOMES AND INTRALIPID

Cyclosporine (CsA), commercially available as iv or oral Sandimmune, is a potent immunosuppressant which can induce dose‐related nephrotoxocity. In addition, the iv product contains a solubilizing agent, Cremophore EL, which in itself is reported to be nephrotoxic and can induce, in sensitized patients, anaphylactic reactions. Solubilization of CsA with liposomes or lipid emulsions could provide a suitable alternative dosage form for iv administration. With this in mind, male New Zealand white rabbits were given iv CsA (10 mg/kg) in three different dosage forms: (1) CsA:liposomes; (2) CsA:Intralipid (soybean oil and phospholipids); and (3) the commercially available Sandimmune (cyclosporine). The CsA concentration in whole blood samples was analyzed by HPLC. The terminal disposition half‐life of CsA (t1/2 β) ranged from 400 to 475 min and was not statistically different among the three groups. However, the distribution characteristics of CsA changed dramatically depending on the dosage form. The volume of distribution of CsA at steady state (Vdss) in Sandimmune was 2.7 ± 0.2 L/kg and was significantly lower than that of either Intralipid (10.6 ± 2.7 L/kg) or liposomes (7.4 ± 2.3 L/kg). A significantly lower total body clearance (TBC) of CsA also was seen for Sandimmune (12.7 ± 0.3 mL/min/kg) as compared with that of either Intralipid (24.4 ± 8.2 mL/min/kg) or liposomes (18.9 ± 3.9 mL/min/kg). Since CsA is extensively bound to lipoproteins, it is surprising that both test vehicles showed a different distribution pattern. It is speculated that in addition to the benefit of removing Cremophore EL from the product, the different distribution of CsA:liposomes or CsA:Intralipid may prove useful in altering the nephrotoxocity and immunosuppression of CsA during iv therapy. Copyright © 1990 Wiley‐Liss, Inc., A Wiley Company