STABILITY AND PHARMACOKINETICS OF LJP 920, AN OCTAMERIC GAL (a1-3) GAL CONJUGATE FOR INHIBITION OF XENOTRANSPLANTATION REJECTION.

Lee Jia, Lin Yu, Matthew D. Linnik, Richard M. Jack.

La Jolla Pharmaceutical Company, 6455 Nancy Ridge Dr., San Diego, CA 92121

Purpose. To investigate the pharmacokinetic profiles of LJP 920, a galactosyl a 1-3 galactose [Gal (a1-3) Gal] coupled to a non-immunogenic platform at valencies of 8 Gal (a1-3) Gal molecules/platform for inhibition of hyperacute rejection after xenotransplantation. To determine the stability of LJP 920 in serum and liver microsomes.

Methods. LJP 920 was injected (i.v.) to mice at 20 and 100 mg/kg, and the blood was withdrawn at 0.5, 5, 10, 30, 60 and 120 min after dosing. The concentrations of LJP 920 in serum and erythrocyte were measured by chromatographic HPLC after liquid extraction. In addition, LJP 920 was incubated at 37°C with serum and liver microsomes, and the in vitro stability of LJP 920 was determined by quantifying the chromatographic peak area at varying time.

Results. Incubation of LJP 920 with serum and liver microsomes for 48 h showed no indication of enzymatic degradation. After administration, LJP 920 disappeared from the mouse systemic circulation with a biexponential decay. The distribution half-life was 3 min and the elimination half-life was more than 30 min. The serum to erythrocyte concentration ratio of LJP 920 was 33 and 36-fold excess and 0.5 and 5 min following i.v. administration (100 mg/kg). Both Cmax and AUC values increased in a dose-proportional manner.

Conclusions. LJP 920 is not a subject to enzymatic metabolism in serum and liver microsomes. The drug is quickly cleared from mouse systemic circulation probably by tissue distribution and renal excretion.

Presented at the American Association of Pharmaceutical Scientists (AAPS) Annual Meeting, Nov. 14-18, 1999, New Orleans, LA.