Prediction of human pharmacokinetics and tissue distribution of apicidin, a potent histone deacetylase inhibitor, by physiologically based pharmacokinetic modeling.
OBJECTIVE
The objectives of this study were to develop physiologically based models for the pharmacokinetics (PK) and organ distribution of apicidin in rats and mice and to predict human PK in blood and organs.


METHODS
The PK of apicidin was characterized in rats and mice after i.v. bolus injection, and distribution to various tissues was determined in rats following i.v. infusions at steady state. The developed models were prospectively validated within rat and within mouse and by scaling from rat to mouse using data after multiple i.v. injections. Human PK was predicted by the physiologically based modeling using intrinsic clearance data for humans from in vitro experiments.


RESULTS
The Cl(s) predicted for human (9.8 ml/min/kg) was lower than those found in mice (116.9 ml/min/kg) and rats (61.6 ml/min/kg), and the V(ss) predicted for human (1.9 l/kg) was less than in mice (2.0 l/kg) and rats (2.5 l/kg). Consequently, the predicted t (1/2) was longer in human (2.3 h) than in mice and rats (0.4 and 0.9 h, respectively). The highest concentrations of apicidin were predicted in liver followed by adipose tissue, kidney, lung, spleen, heart, arterial blood, venous blood, small intestine, stomach, muscle, testis, and brain.


CONCLUSIONS
The developed models adequately described the PK of apicidin in rats and mice and were applied to predict human PK. These models may be useful in predicting human blood and tissue concentrations of apicidin under different exposure conditions.
College of Pharmacy, Catholic University of Daegu, Gyeongsan-si, Gyeongbuk, Korea.
Beom Soo
BS
Shin
Jürgen B
JB
Bulitta
Joseph P
JP
Balthasar
Minki
M
Kim
Yohan
Y
Choi
Sun Dong
SD
Yoo
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D005670:Fusarium / Q000737:chemistry; D006207:Half-Life; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008813:Mice, Inbred ICR; D008954:Models, Biological; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; C102351:apicidin