Plasma Pharmacokinetics Across Species

The initial rapid distribution to tissues dominates plasma clearance ( 90%), which is characterized by a near-complete distribution with a several-fold log decline of plasma ISIS 104838 concentrations over a 24-h period. The rapid and complete distribution phase is similar to that of the first-generation PS oligodeox-ynucleotides. However, plasma concentrations of 2 -MOE partially modified ASOs 

Protein binding may explain many other pharmacokinetic properties of this class of compounds. The high degree of protein binding in the circulation prevents any significant urinary excretion. Therefore, there is minimal glomerular filtration of the protein-bound oligonucleotide, and the excretion of intact compound in urine is a minor pathway in its clearance from the plasma [26]. 

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Based on rat neuropharmacokinetic concepts, it has been proposed [37,42,45] that Cb/U may be projected directly from Cp for large animal species (i.e., dog, monkey, and human) in which Cb are rarely measured. For such species, in which serial blood sampling is common for determining plasma pharmacokinetics, compound Cb,u may be extrapolated using its Cp, species-specific /u,p, and rat-derived Cb,u CP/U assuming a fixed ratio across species ... 

A recent variation on the prediction of human VD using allometric scaling involves the use of what has been termed "fractal volume of distribution (vf) [7], This refers to the VD value corrected to within the bounds of actual volumes within the body - in the case of human the upper and lower bounds would be 70 1 and plasma volume, respectively. Thus, even if a compound were to have a VDSS of 1000 1, its Vf would be 69.8 1. The authors of this approach have shown that Vf scales allometrically across species better than VD [8], with the explanation that body volume and body mass are exactly scaleable across species. Animal values for Vf are calculated from VD obtained from pharmacokinetic studies using the relationship ... 

Finally, no discussion of human pharmacokinetic predictions is complete without a consideration of allometric scaling [67-69]. In general, allometry is the examination of relationships between size and function and it has been applied to the prediction of human pharmacokinetic parameters from animal pharmacokinetic parameters for decades [70]. Allometry has been shown to work reasonably well for predicting human VD from animal VD data, probably because volumes of plasma and various tissue across species are allometrically scaleable to body weight, a notion reinforced... 

Preclinical pharmacokinetic parameters for ABT-594 are summarized in Table 11. ABT-594 shows good oral bioavailability across species, with oral half-lives ranging between 1.4 and 4.2 h, and rapidly enters the brain, exhibiting a brain to plasma ratio of about 2 within 1.5 h (K. Marsh, et al., unpublished data). In vitro metabolism studies using liver homogenates from several species indicated very little metabolism of ABT-594, whereas positive controls were extensively metabolized. In radiotracer studies in vivo, ABT-594 was mainly excreted unchanged in the urine (J. Ferrero, B. Surber, et al., unpublished data). 

The PGDE scheme is based on the key assumptions that the drug concentration in the plasma can be used as a predictor for dose-limiting toxicity (DLT) and that the quantitative relationship between toxicity and drug exposure (AUC) is similar across species [56]. Practical limitations of this scheme include the difficulty in obtaining real-time pharmacokinetic data at each dose level, extrapolation of preclinical pharmacokinetic data especially when the dosing... 

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