PHARMACOKINETICS OF HIGH DOSE ABETIMUS SODIUM IN NORMAL SUBJECTS WITH SPECIFIC ASSESSMENT OF EFFECT ON COAGULATION

M. D. Linnik*1, A. M. O'Rourke1, M. A. Crowther2
1Research and Development, La Jolla Pharmaceutical Company, San Diego, United States, 2Department of Hematology, McMaster University & St Joseph's Hospital, Hamilton, Canada

Background: Abetimus sodium (Riquent®) is an oligonucleotide-based investigational drug designed to treat patients with lupus nephritis by specifically reducing anti-dsDNA antibody levels.

Objectives: The clinical study was designed to characterize the safety and pharmacokinetics of high doses of abetimus after intravenous administration to normal subjects. The in vitro mechanistic studies were designed to evaluate the effect of abetimus on coagulation factors.

Methods: Three cohorts of 8 patients were randomized at a ratio of 3:1 to receive single i.v. dose 600 mg, 1200 mg or 2400 mg abetimus or placebo. PK parameters were analyzed by non-compartmental analysis. Activated partial thromboplastin (aPTT) and prothrombin (PT) times were measured in the same subject plasma samples. In vitro studies were also carried out to evaluate the effect of abetimus on specific coagulation pathways, including aPTT with or without heparin, lupus anticoagulant aPTT (LA-aPTT), dilute Russell Viper Venom test (DRVVT), PT, and functional assays of Factors VIII, IX, XI and XII activities.

Results: Abetimus was well tolerated, with adverse events in 3 of 18 patients in the abetimus group and in 2 of 6 patients in the placebo group. The mean half-life of abetimus was 1.54 hours, 1.12 and 0.82 hours for the 600, 1200 and 2400 mg dose groups, respectively. Mean clearance was similar for the 1200 mg and 2400 mg abetimus groups and slightly greater in the 600 mg group. A dose-normalized proportionality test showed exposure by AUC was greater than dose proportional, and maximum exposure assessed by Cmax was dose proportional. Administration of abetimus was associated with a dose-dependent increase in aPTT; there was no effect on PT. The maximum mean change in aPTT from baseline was 5.3, 12.9 and 21.4 seconds for the 600, 1200 and 2400 mg dose groups, respectively. A detailed in vitro assessment of the effect on coagulation confirmed the in vivo effect, with significant prolongation of clotting time at 250 μg/ml abetimus in the standard aPTT, and at 50 μg/ml in the LA-aPTT. A modest effect of abetimus only at high concentration was seen in vitro on DRVVT, Factor VIII, IX, XI and XII assays.

Conclusion: High doses of abetimus administered i.v. had no impact on any clinical laboratory parameters except a transient, dose-proportional increase in aPTT. In vitro coagulation studies suggested that the effect of abetimus on aPTT values was due to a non-specific interaction with coagulation factors, rather than a direct inhibitory effect or depletion of individual coagulation factors.

Poster Session
Annual European Congress of Rheumatology "EULAR 2008"
Paris, France
June 12, 2008