Summary of Pharmacokinetic and Biodistribution Properties of Aptamers

In general, metabolic and nuclease stability is not limiting with respect to the pharmacokinetic properties of therapeutic aptamers. The terminal half-life of a typical therapeutic aptamers after parenteral administration (e.g. intravenous bolus) ranges from 3 to 22 h in rodent, and 30-60 h in primate, depending on sequence composition, modifications, and conjugation. An aptamer with a fixed composition and variable 5'-PEG conjugation (0, 20, 30, and 40kDa) exhibits a variation in t1/2 (p) of approximately 5- to 20-fold. For a fixed aptamer sequence and 5'-PEG group with variable composition terminal half-life, t1/2 (p), varies approximately 14-fold, whereas for a fixed 5'-PEG conjugation (40kDa) with variable sequence and composition t1/2 (p) varies approximately six-fold. Thus composition and conjugation (e.g. PEGylation) have significant and comparable effects on the systemic half-lives of therapeutic aptamers in vivo. Though the primary effect of PEGylation is to retard aptamer clearance, the presence of the 20 kDa moiety appears to facilitate distribution of aptamer to tissues, with sites of local inflammation showing significantly higher levels of accumulation than do either unconjugated or fully 2'-O-methyl modified aptamers with the same sequence.

Typical aptamer volumes of distribution, Vss, vary from approximately two- to five-fold larger than the known plasma volume (~40mL/kg) in rodent and primate, depending on aptamer composition and PEGylation, suggesting significant distribution into tissues with a moderate degree of binding or sequestration of the aptamer to proteins and/or tissue matrix in the extravascular space. Therapeutic aptamers and their conjugates do not appear to cross the blood/brain barrier at a level greater than 0.1% of the total dose. Urinary elimination is a significant route of clearance for all aptamers. Major organs of accumulation include the liver, kidney, and other highly perfused tissues such as bone marrow. Cellular distribution of aptamers has been demonstrated by micro-autoradiogra-phy. The presence of radiolabeled aptamer can be observed in sinusoidal lining cells, and the proximal and distal tubular cells of the kidney following intravenous administration.

Thus, the pharmacokinetic parameter space for therapeutic aptamers is large, while the existing data matrix is still relatively sparse. The process of data generation, filling out this matrix with respect to composition, PEGylation, route of administration, and model species, is still under way. All of these factors have been shown to have significant effects of comparable magnitude on the pharmacoki-netic profile of aptamers in vivo. Finally, the ideal set of pharmacokinetic properties for therapeutic aptamers are not universal, but depend entirely on the specific indication and anticipated context of use.

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