Antisense pharmacokinetics

McMahon B.M., Mays D., Lipsky J., Stewart J.A., Fauq A., Richelson E. Pharmacokinetics and tissue distribution of a peptide nucleic acid after intravenous administration. Antisense Nucleic Acid Drug Dev. 2002 12 65-70... 

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

RNAi technology has obvious therapeutic potential as an antisense agent, and initial therapeutic targets of RNAi include viral infection, neurological diseases and cancer therapy. The synthesis of dsRNA displaying the desired nucleotide sequence is straightforward. However, as in the case of additional nucleic-acid-based therapeutic approaches, major technical hurdles remain to be overcome before RNAi becomes a therapeutic reality. Naked unmodified siRNAs for example display a serum half-life of less than 1 min, due to serum nuclease degradation. Approaches to improve the RNAi pharmacokinetic profile include chemical modification of the nucleotide backbone, to render it nuclease resistant, and the use of viral or non-viral vectors, to achieve safe product delivery to cells. As such, the jury remains out in terms of the development and approval of RNAi-based medicines, in the short to medium term at least. 

Other agents such as actinomycin D, C-Myc antisense, dexamethasone, and matrix metalloproteinase inhibitors, aimed at altering inflammatory and smooth muscle actions in the biological repair response to vascular injury, are being evaluated. The success of these devices depends upon multiple issues, including stent platform, carrier, drug properties, and pharmacokinetic profile (18-26). Large randomized, controlled trials, demonstrate a restenosis rate of 5% to 10% with DES (27). 

Pharmacokinetic Aspects of Antisense Oligodeoxynucleotides and Renal Distribution... 

Agrawal, S. and Zhang, R. (1998) Pharmacokinetics and bioavailabihty of oligonucleotides following oral and colorectal administrations in experimental animals. In S.Crooke (ed.) Antisense Research and Applications, Springer-Verlag, Heidelberg, pp. 525-543. 

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. 

Miyao, T., Takakura, Y., Akiyama, T., Yoneda, F., Sezaki, H. and Hashida, M. (1995) Stability and pharmacokinetic characteristics of oligonucleotides modified at terminal linkages in mice. Antisense Res. Develop., 5,115-121. 

Nakajima, S., Koshino, Y., Nomura, T., Yamashita, F., Agrawal, S., Takakura, Y. and Hashida, M. (2000) Intratumoral pharmacokinetics of oligonucleotides in a tissue-isolated tumor perfusion system. Antisense Nucleic Acid Drug Develop., 10, 105-110. 

Peng, B., Andrews, J., Nestorov, I., Brennan, B., Nicklin, P. and Rowland, M. (2001) Tissue distribution and physiologically based pharmacokinetics of antisense phosphorothioate oligonucleotide ISIS 1082 in rat. Antisense Nucleic Acid Drug Develop., 11, 15-27. 

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. 

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