![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
PHOSPHOROTHIOATE 2'-O-(2-METHOXYETHYL) MODIFIED ANTISENSE OLIGONUCLEOTIDE: COMPARISON ACROSS SPECIES
Isis Pharmaceuticals, Carlsbad, California
The pharmacokinetics of a 2'-O-(2-methoxyethyl)-ribose modified phosphorothioate oligonucleotide, ISIS 104838 (human tumor necrosis factor-
antisense), have been characterized in mouse, rat, dog, monkey, and human. Plasma pharmacokinetics after i.v. administration exhibited relatively rapid distribution from plasma to tissues with a distribution half-life estimated from approximately 15 to 45 min in all species. Absorption after s.c. injection was high (80-100%), and absorption after intrajejunal administration in proprietary formulations was as high as 10% bioavailability compared with i.v. administration. Urinary excretion of the parent drug was low, with less than 1% of the administered dose excreted in urine after i.v. infusion in monkeys at clinically relevant doses (
5 mg/kg). ISIS 104838 is highly bound to plasma proteins, likely preventing renal filtration. However, shortened oligonucleotide metabolites of ISIS 104838 lose their affinity to bind plasma proteins. Thus, excretion of radiolabel (mostly as metabolites) in urine (75%) and feces (5-10%) was nearly complete by 90 days. Elimination of ISIS 104838 from tissue was slow (multiple days) for all species, depending on the tissue or organ. The highest concentrations of ISIS 104838 in tissues were seen in kidney, liver, lymph nodes, bone marrow, and spleen. In general, concentrations of ISIS 104838 were higher in monkey tissues than in rodents at body weight-equivalent doses. Plasma pharmacokinetics scale well across species as a function of body weight alone. This favorable pharmacokinetic profile for ISIS 104838 provides guidance for clinical development and appears to support infrequent and convenient dose administration.
This article has been cited by other articles:
|
|
 |
|
  N. Goebl, B. Berridge, V. J. Wroblewski, and P. L. Brown-Augsburger Development of a Sensitive and Specific in Situ Hybridization Technique for the Cellular Localization of Antisense Oligodeoxynucleotide Drugs in Tissue Sections Toxicol Pathol, June 1, 2007; 35(4): 541 - 548. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Z. Yu, T.-W. Kim, A. Hong, T. A. Watanabe, H. J. Gaus, and R. S. Geary Cross-Species Pharmacokinetic Comparison from Mouse to Man of a Second-Generation Antisense Oligonucleotide, ISIS 301012, Targeting Human Apolipoprotein B-100 Drug Metab. Dispos., March 1, 2007; 35(3): 460 - 468. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. E. Swayze, A. M. Siwkowski, E. V. Wancewicz, M. T. Migawa, T. K. Wyrzykiewicz, G. Hung, B. P. Monia, and a. C. F. Bennett Antisense oligonucleotides containing locked nucleic acid improve potency but cause significant hepatotoxicity in animals Nucleic Acids Res., January 28, 2007; 35(2): 687 - 700. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J.P. Kastelein, M. K. Wedel, B. F. Baker, J. Su, J. D. Bradley, R. Z. Yu, E. Chuang, M. J. Graham, and R. M. Crooke Potent Reduction of Apolipoprotein B and Low-Density Lipoprotein Cholesterol by Short-Term Administration of an Antisense Inhibitor of Apolipoprotein B Circulation, October 17, 2006; 114(16): 1729 - 1735. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G Tachas, S Lofthouse, C J Wraight, B F Baker, N B Sioufi, R A Jarres, A Berdeja, A M Rao, L M Kerr, E M d'Aniello, et al. A GH receptor antisense oligonucleotide inhibits hepatic GH receptor expression, IGF-I production and body weight gain in normal mice. J. Endocrinol., April 1, 2006; 189(1): 147 - 154. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
