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, 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 (Vd(ss)), 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 (t1/2) was consistent across species and independent of bodyweight. The prediction of CLs, Vd(ss), CLint, and t1/2 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.
Sukbuntherng
J
J
SUGEN, Inc, South San Francisco, California 94080, USA. juthamas-sukbuntherng@sugen.com
Cropp
G
G
Hannah
A
A
Wagner
G S
GS
Shawver
L K
LK
Antonian
L
L
D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics*; D000818:Animals; D004285:Dogs; D005260:Female; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D011758:Pyrroles / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor; D013045:Species Specificity
D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D017978:Receptors, Growth Factor; C116890:Semaxinib; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor