SAFETY AND PHARMACOKINETIC ASSESSMENT OF ABETIMUS SODIUM IN HEALTHY VOLUNTEERS

Matthew D Linnik, PhD, Tenshang Joh, PhD, and Andrew Wiseman, PhD, La Jolla Pharmaceutical Company, San Diego, CA, USA

Abstract

Purpose. This study was conducted to evaluate the safety, tolerability and pharmacokinetic parameters of abetimus sodium (LJP 394; abetimus) doses up to 2400 mg in healthy male and female volunteers.

Methods. We conducted a single center randomized, double-blind, placebo-controlled, single-dose, dose escalation study. Within each dose group, 8 subjects were treated, six with abetimus, two with placebo. Single doses of 600mg, 1200mg or 2400mg were administered by intravenous injection. Plasma concentrations were measured by high performance liquid chromatography and analyzed by noncompartmental analysis (WinNonlin 4.1).

Results.There was a dose-dependent increase in plasma concentration of abetimus, the maximal concentration (Cmax) occurred 5-10 minutes after infusion. For doses of 600mg, 1200mg and 2400mg, the mean AUC was 171, 498, and 1037 µg*h/ml, Cmax was 192, 459 and 763 µg/mL, t1/2 was 1.54, 1.12, and 0.82 hrs, Vd was 8.50, 4.55, 2.99 L. Most subjects had no detectable drug 8 hours post dose. Abetimus was associated with a dose-dependent increase in activated partial thromboplastin time (aPTT), but not prothrombin time (PT). Mean aPTT increases returned to baseline within 4 to 6 hours. The maximum mean change in aPTT for placebo, 600mg, 1200mg and 2400mg was 1.9, 5.3, 12.9 and 21.4 seconds and peaked within 30 minutes post infusion. Abetimus was well tolerated. Other than changes in aPTT, there were no clinically significant changes in any other safety parameter, including vital signs, electrocardiogram, hematology, serum chemistry, or urinalysis.

Conclusion. Abetimus was well tolerated at single doses up to 2400 mg. APTT increased with increasing dose. At the 2400mg dose, the increase was approximately 1.5 times the upper limit of normal range in the immediate post infusion period and returned to normal within 6 hours. In vitro studies demonstrate that this prolongation was not due to a depletion of coagulation factors or a heparin-like effect, but was likely due to a non-specific inhibitory effect. Abetimus is being evaluated in an international Phase 3 clinical study at doses of 100mg, 300mg or 900mg per week in lupus patients with history of renal disease.

Presented at the
The 8th International Congress on SLE
Shanghai, China
May 23-27, 2007