Relationship between ASO Pharmacokinetics and Clinical Outcome

ASO was used either concomitantly with other marketed agents of different mechanisms, or as monotherapy. 

Three approaches have been used to estimate pharmacodynamics using plasma concentrations as surrogate for target tissue exposure  

A PK/PD relationship in humans has recently been reported for a novel hypolipidemic agent, ISIS 301012, a 2 -MOE partially modified antisense inhibitor of human apoB-100 [59, 64]. ApoB-100 is a structural component of LDL-cholesterol, and plays a key role in its metabolism and transport Prefiminary data from this study indicate that antisense inhibition of apoB-100 results in both dose- and concentration-dependent sustained reductions in serum levels of apoB-100, LDL-cho-lesterol and total cholesterol, but does not affect levels of HDL-cholesterol. 

This chapter has described the pharmacokinetics of PT 2 -MOE partially modified ASO following parenteral administration, and has shown that ASOs in this chemical class distribute extensively to many tissue types, with prolonged half-lives. Moreover, exposure-response relationships have been established in both animal models and humans. However, there are a few tissues to which parenter-ally administered oligonucleotides do not distribute, or are distributed minimally these include brain, muscle, eyes, and skin. Consequently, ASOs targeted to these tissues will require local delivery, as outlined in Chapter 10. 

The PK/PD properties of ASOs provide a framework for rapid drug development. Challenges to the promise of antisense therapeutics are not unlike those for any other new chemical entity, and they include proper application of the pharmacokinetic properties in order to select both target and delivery methods. The profound difference from the situation of small molecule discovery is the relative predictability of the pharmacokinetics, independent of target selection. 

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