Antisense oligonucleotides pharmacokinetics

Crooke, R.M., In vitro toxicology and pharmacokinetics of antisense oligonucleotides, Anti-Cancer Drug Design, 1991, 6, 609-646. 

Wang, H., Cai, Q., Zeng, X., Yu, D., Agrawal, S. and Zhang, R. (1999a) Anti-tumor activity and pharmacokinetics of a mixed-backbone antisense oligonucleotide targeted to RIa subunit of protein kinase A after oral administration. Proc. Natl. Acad. Sci. USA, 96, 13989-13994. 

Similar to pDNA, the pharmacokinetics of oligonucleotides can be controlled by using delivery systems. Mahato et al. (1997) studied the pharmacokinetic characteristics of antisense oligonucleotides complexed with Gal-PLL or mannosylated PLL (Man-PLL), whose mannose residues can be recognized by mannose... 

Agrawal, S., Temsamani, J., Galbraith, W. and Tang, J. (1995) Pharmacokinetics of antisense oligonucleotides. Clin. Pharmacokinet., 28, 7-16. 

Yu RZ, Geary RS, Leeds JM, Watanabe T, Fitchett JR, Matson JE, Mehta R, Hardee GR, Templin MV, Huang K, Newman MS, Quinn Y, Uster P, Zhu G, Working PK, Homer M, Nelson J, Levin AA (1999) Pharmacokinetics and tissue disposition in monkeys of an antisense oligonucleotide inhibitor of Ha-ras encapsulated in stealth liposomes. Pharm Res 16(8) 1309—1315... 

Parenteral administration has been the preferred route because it allows complete systemic availability. Non-parenteral administration of antisense oligonucleotides is only made possible with the aid of novel formulations intended to overcome barriers to absorption (see Chapter 10). Similar to first-generation anti-sense oligonucleotides (ASOs), the pharmacokinetics of2 -MOE partially modified ASOs are characterized by ... 

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. 

D.K. Monteith, and A.A. Levin. 1997. Antisense oligonucleotide inhibitors for the treatment of cancer 1. Pharmacokinetic properties of phosphorothioate oligodeoxynucleotides. Anti-Cancer Drug Design 12 383-393. 

J. Matson, H. Sasmor, L. Cummins, and A.A. Levin. 2003. Pharmacokinetics of a tumor necrosis factor-alpha phosphorothioate 2 -0-(2-methoxyethyl) modified antisense oligonucleotide comparison across species. Drug Metah. Dispos. 31 1419-1428. 

Levin, A.A. 1999. A review of issues in the pharmacokinetics and toxicology of phosphorothioate antisense oligonucleotides. Biochim. Biophys. Acta 1489 69-84. 

Following a short introduction, the book is structured into three sections The Basics section discusses individually the pharmacokinetics of peptides, monoclonal antibodies, antisense oligonucleotides and gene delivery vectors. The subsequent Challenges and Opportunities section includes more detailed considerations on selected topics, including technical challenges such as bioanalytical... 

It has been shown that the Raf-1 protein serine/threonine kinase is a druggable signaling molecule in cancer therapy (5). and Kasid and co-workers have developed cationic liposomes for in vivo delivery of raf antisense oligonucleotides and raf siRNA into human tumor xenografts established in immunodeficient mice. The authors provide very useful protocols for the preparation of a modified cationic liposome/antisense oligonucleotide formulation as well as toxicology, pharmacokinetics, biodistribution, and anti-tumor efficacy studies in mice (5). 

Key Words Raf-1 Antisense oligonucleotide siRNA Cationic liposomes Dimyristoyl 1,2-diacy 1-3-tri methyl ammonium-propane (DMTAP) Systemic delivery Toxicology Pharmacokinetics and biodistribution Ionizing radiation Prostate cancer. 

Levin AA, Yu RZ, Geary RS. Basic Principles of the Pharmacokinetics Of antisense Oligonucleotide drugs. In Crooke ST, ed. Antisense Drug Technology. New York Dekker, 2007. 

Kinetics of Effects. Many rate constants may affect the activities of antisense oligonucleotides, such as the rate of synthesis and degradation of the target RNA and its protein the rates of uptake into cells the rates of distribution, extrusion, and metabolism of an oligonucleotide in cells and similar pharmacokinetic considerations in animals. Fortunately, in the past several years, many more careful dose-response and kinetic studies have been reported and in general they demonstrated a relatively slow onset of action and a duration of response consistent with the elim-. ination rates of the drugs tested (see below). 

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