Pharmacokinetics and interspecies scaling of a novel VEGF receptor inhibitor, SU5416

The pharmacokinetics and allometric relationships of SU5416, a novel small anti‐angiogenesis agent, were studied. The pharmacokinetics of SU5416 were examined in mice, rats, dogs, and cancer patients. The in‐vitro intrinsic clearance (CLint) was estimated from the in‐vitro metabolism study in mouse,...

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Published in:Journal of pharmacy and pharmacology 2001-12, Vol.53 (12), p.1629-1636
Main Authors: Sukbuntherng, Juthamas, Cropp, Gillian, Hannah, Alison, Wagner, Gregory S., Shawver, Laura K., Antonian, Lida
Format: Article
Language:English
Subjects:
Angiogenesis Inhibitors - pharmacokinetics
Animals
Dogs
Female
Humans
Indoles - pharmacokinetics
Male
Metabolic Clearance Rate
Mice
Pyrroles - pharmacokinetics
Rats
Rats, Sprague-Dawley
Receptor Protein-Tyrosine Kinases - antagonists & inhibitors
Receptors, Growth Factor - antagonists & inhibitors
Receptors, Vascular Endothelial Growth Factor
Species Specificity
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Summary:The pharmacokinetics and allometric relationships of SU5416, a novel small anti‐angiogenesis agent, were studied. The pharmacokinetics of SU5416 were examined in mice, rats, dogs, and cancer patients. The in‐vitro intrinsic clearance (CLint) was estimated from the in‐vitro metabolism study in mouse, rat, dog, monkey and human liver microsomes. The parameters of interest were correlated across species as a function of bodyweight using an allometric approach. The steady‐state volume of distribution (Vdss), plasma clearance (CLs), and CLint of SU5416 were well correlated across species. The exponent of the allometric relationship (b) of the corresponding parameters was 0.92, 0.80 and 0.66, respectively. The elimination half‐life (t½) was consistent across species and independent of bodyweight. The prediction of CLs, Vdss, CLint, and t½ in humans using the data from mouse, rat, and dog, and monkey (for CLint) was reasonably good (within 4‐fold of the observed values). However, an improved prediction (within 2‐fold of the observed values) of the corresponding parameters in humans was obtained when extrapolation from only the rodent data was performed, suggesting that the rodent data are sufficient for the scale‐up of SU5416 pharmacokinetic parameters in humans. Using allometry, it was possible to achieve reasonable predictions of the pharmacokinetic parameters of SU5416 in cancer patients with various solid tumours.
ISSN:0022-3573
2042-7158
DOI:10.1211/0022357011778232