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This Article Full Text Full Text (PDF) All Versions of this Article: 0091270008319465v1 48/8/909    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Google Scholar Articles by Linnik, M. D. Articles by Crowther, M. A. PubMed PubMed Citation Articles by Linnik, M. D. Articles by Crowther, M. A.

Pharmacokinetics of High-Dose Abetimus Sodium in Normal Subjects With Specific Assessment of Effect on Coagulation

From La Jolla Pharmaceutical Company, San Diego, California (Dr Linnik, Dr O'Rourke) and McMaster University & St Joseph's Hospital, Hamilton, Ontario, Canada (Dr Crowther).

Abetimus sodium is an oligonucleotide-based investigational drug designed to treat patients with lupus nephritis by specifically reducing anti-double-stranded DNA antibody levels. The safety and pharmacokinetics of abetimus were evaluated in 24 healthy volunteers at intravenous doses of 600 mg, 1200 mg, and 2400 mg. The mean half-life ranged from 0.8 to 1.5 hours. Maximum exposure assessed by maximum observed plasma concentration was dose proportional. Total exposure assessed by area under the plasma concentration–time curve was dose proportional between 1200-mg and 2400-mg doses and greater than proportionate between the 600-mg and 1200-mg doses. Abetimus was well tolerated in all dose groups, with adverse events observed in 33.3% (2/6) of placebo subjects and 16.7% (3/18) subjects receiving abetimus. No clinically significant effects were observed on laboratory values, vital signs, or electrocardiogram, with the exception of a transient, dose-dependent, prolongation in activated partial thromboplastin time. In vitro coagulation studies suggested that the effect on activated partial thromboplastin time was attributable to a nonspecific interaction rather than specific factor depletion. Exposure to abetimus at intravenous doses of 600 mg, 1200 mg, and 2400 mg was well tolerated. Total exposure assessed by area under the plasma concentration–time curve was greater than dose proportional across the dose range of 600 mg to 2400 mg.

Key Words: Pharmacokinetics • coagulation • abetimus

Address for reprints: Matthew D. Linnik, PhD, La Jolla Pharmaceutical Company, 6455 Nancy Ridge Drive, San Diego, CA 92121; e-mail: Linnik{at}ljpc.com.