Pharmacokinetics and Pharmacodynamics of Antisense Oligonucleotides

Significant resources have been applied towards the identification of chemical modifications that further improve upon the pharmacokinetic and pharmacodynamic properties of PS oligodeoxynucleotides (Table 4.2). The vast majority of 

Oligonucleotide Molecular target Disease indication Route of administration Sponsor 

Vitravene (fomivirsen, ISIS 2922) Human cytomegalovirus IE-2 gene CMV retinitis Intravitreal Isis/Ciba Vision 

Alicaforsen (ISIS 2302) ICAM-1 Ulcerative colitis Topical Enema Isis 

Affinitac (ISIS 3521, LY900003) PKC-a Cancer Intravenous Lilly/1 sis 

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R. Crooke, N.M. Dean, and A.A. Levin. 2001. Pharmacokinetics and pharmacodynamics of an antisense phosphorothioate oligonucleotide targeting Fas mRNA in mice./. Pharmacol. Exp. Ther. 296 388-395. 

Therefore, this review of pharmacokinetic/pharmacodynamics (PK/PD) correlation will include investigations between the effective concentrations at the target sites of antisense oligonucleotides with each of the pharmacological effects discussed above. Moreover, an establishment of the correlation between plasma equilibrium concentrations with concentrations at the target sites is pertinent, enabling plasma concentrations to be used as a surrogate in clinical studies to establish relationships between pharmacodynamics and pharmacokinetics. 

Yu, R.Z., Geary, R.S., and Levin, A.A. (2004) Application of novel quantitative bioanalytical methods for pharmacokinetic and pharmacokinetic/pharmacodynamic assessments of antisense oligonucleotides. Current Opinion in Drug Discovery and Development, 7, 195 203. 

Chi K N, Eisenhauer E, et al. (2005). A phase I pharmacokinetic and pharmacodynamic study of OGX-011, a 2 -methoxyethyl antisense oligonucleotide to clusterin, in patients with localized prostate cancer. J. Natl. Cancer Inst. 97 1287-1296. 

Geary RS, Yu RZ, Siwkowski A. Pharmacokinetic/pharmacodynamic properties of phosphorothioate 2 -0-(2-methoxyethyl) modified antisense oligonucleotides in animals and man. In Crooke ST, ed. Antisense Drug Technology. New York Dekker, 2007. 

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