ORIGINAL ARTICLE Prediction of human pharmacokinetics and tissue distribution of apicidin, a potent histone deacetylase inhibitor, by physiologically based pharmacokinetic modeling Beom Soo Shin • Ju ¨ rgen B. Bulitta • Joseph P. Balthasar • Minki Kim • Yohan Choi • Sun Dong Yoo Received: 6 June 2010 / Accepted: 26 October 2010 / Published online: 11 November 2010 Ó Springer-Verlag 2010 Abstract Purpose 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 pre- dicting human blood and tissue concentrations of apicidin under different exposure conditions. Keywords Apicidin  Pharmacokinetics  Tissue distribution  Physiologically based models  Human prediction Introduction Histone deacetylases and histone acetyl transferases are two types of enzymes involved in the modulation of chro- matin structure and regulation of the cell cycle, including differentiation, proliferation, and apoptosis [1, 2]. Lately, the therapeutic potential for anti-proliferative activity has been reported for several histone deacetylase inhibitors, including suberoylanilide hydroxamic acid (SAHA) [3], depsipeptide [4], and apicidin [5]. Apicidin [cyclo(N–O- methyl-L-tryptophanyl-L-isoleucinyl-D-pipecolinyl-L-2- amino-8-oxodecanoyl)], a cyclic tetrapeptide isolated from the cultures of Fusarium pallidoroseum, is a potent histone deacetylase inhibitor that non-selectively induces histone hyperacetylation in parasites and mammals [6]. Apicidin has been shown to exhibit anti-proliferative activity against various cancer cell lines [7–10] and potential anticancer activity [11, 12]. The pharmacokinetics (PK) of apicidin in experimental animals have been previously reported by our B. S. Shin College of Pharmacy, Catholic University of Daegu, Gyeongsan-si, Gyeongbuk, Korea J. B. Bulitta Ordway Research Institute, Albany, NY, USA J. P. Balthasar Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, USA M. Kim  Y. Choi  S. D. Yoo (&) School of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon, Gyeonggi-do 440-746, Korea e-mail: sdyoo@skku.ac.kr 123 Cancer Chemother Pharmacol (2011) 68:465–475 DOI 10.1007/s00280-010-1502-y