Drug Metab. Pharmacokinet. 26 (6): 612­620 (2011). Copyright © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX) Regular Article Bridging from Preclinical to Clinical Studies for Tyrosine Kinase Inhibitors Based on Pharmacokinetics/Pharmacodynamics and Toxicokinetics/Toxicodynamics Azusa HOSHINO-YOSHINO1,2,MotohiroKATO2,KohnosukeNAKANO2, Masaki ISHIGAI2,ToshiyukiKUDO1 and Kiyomi ITO1,* 1Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo, Japan 2Pre-clinical Research Department, Chugai Pharmaceutical Co. Ltd., Kanagawa, Japan Full text of this paper is available at http://www.jstage.jst.go.jp/browse/dmpk Summary: The purpose of this study was to provide a pharmacokinetics/pharmacodynamics and toxi- cokinetics/toxicodynamics bridging of kinase inhibitors by identifying the relationship between their clinical and preclinical (rat, dog, and monkey) data on exposure and efficacy/toxicity. For the eight kinase inhibitors approved in Japan (imatinib, gefitinib, erlotinib, sorafenib, sunitinib, nilotinib, dasatinib, and lapatinib), the human unbound area under the concentration-time curve at steady state (AUCss,u) at the clinical dose correlated well with animal AUCss,u at the no-observed-adverse-effect level (NOAEL) or maximum tolerated dose (MTD). The best correlation was observed for rat AUCss,u at the MTD (p < 0.001). Emax model analysis was performed using the efficacy of each drug in xenograft mice, and the efficacy at the human AUC of the clinical dose was evaluated. The predicted efficacy at the human AUC of the clinical dose varied from far below Emax to around Emax even in the tumor for which use of the drugs had been accepted. These results suggest that rat AUCss,u attheMTD,butnottheefficacy in xenograft mice, may be a useful parameter to estimate the human clinical dose of kinase inhibitors, which seems to be currently determined by toxicity rather than efficacy. Keywords: kinase inhibitors; PK/PD; TK/TD; prediction; human clinical dose; bridging determine the human first dose of anticancer drugs from Introduction ¥ animal studies.2 However, it does not distinguish between In recent years, the focus of anticancer drug development conventional cytotoxic agents and molecular-targeted drugs. has moved from cytotoxic agents to molecular-targeted For conventional drugs, the maximum tolerated dose ¤MTD¥ drugs that are designed to target specific molecules which is generally administered as the clinical dose to get the are mutated or overexpressed in tumor cells.1¥ Molecular- maximum efficacy, based on the idea that efficacy is targeted drugs were thought to have broader therapeutic proportional to exposure.3¥ As for predicting human MTD windows than conventional cytotoxic agents and to exhibit in conventional drugs, Fuse et al. reported an excellent less toxicity because of their high selectivity to tumor. correlation between the log area under the concentration- ¤ ¥ ¤ ¥ There are two types of molecular-targeted drugs: tyrosine time curve AUC at the dose lethal for 10% of mice LD10 kinase inhibitors as small molecular drugs and monoclonal and log AUC at MTD for humans for AUC-dependent antibodies as large molecular drugs. Currently, eight oral drugs, but not for time-dependent drugs.4¥ However, the tyrosine kinase inhibitors ¤imatinib, gefitinib, erlotinib, relationship between human and animal AUC for molecular- sorafenib, sunitinib, nilotinib, dasatinib, and lapatinib¥ have targeted drugs has never been reported. The purpose of this been approved in Japan. study was to provide a PK/PD and TK/TD bridging of A guideline published by the International Conference on kinase inhibitors by identifying the relationship between the Harmonization of Technical Requirements for Registration clinical and preclinical data for their AUC and efficacy/ of Pharmaceuticals for Human Use ¤ICH¥ describes how to toxicity. Received; May 18, 2011, Accepted; August 24, 2011 J-STAGE Advance Published Date: September 6, 2011, doi:10.2133/dmpk.DMPK-11-RG-043 *To whom correspondence should be addressed: Kiyomi ITO, Ph.D., Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo, Tokyo 202-8585, Japan. Tel/Fax. +81-42-468-9199, E-mail: [email protected] 612 Preclinical to Clinical PK/PD Bridging for Kinase Inhibitors 613 Table 1. Tyrosine kinase inhibitors approved in Japan Approval in Japan Drugs ¤ ¥ MTD Clinical dose Dosage form year/month. Trade name Generic name 2001.11 Glivec Imatinib h1000 mg, b.i.d. 400 mg, q.d. Tablet 2002.7 Iressa Gefitinib 700 mg, q.d. 250 mg, q.d. Tablet 2007.10 Tarceva Erlotinib 150 mg, q.d. 150 mg, q.d. Tablet 2008.1 Nexavar Sorafenib 600 mg, b.i.d. 400 mg, b.i.d. Tablet 2008.4 Sutent Sunitinib 50 mg, q.d. 50 mg, q.d. Capsule 400 mg, b.i.d. ¤for chronic-phase and accelerated-phase of chronic myelogenous leukemia¥, 2009.1 Tasigna Nilotinib 600 mg, b.i.d. Capsule 300 mg, b.i.d. ¤for newly diagnosed chronic-phase myelogenous leukemia¥ 100 mg, q.d. ¤for chronic phase¥, 2009.1 Sprycel Dasatinib h120 mg b.i.d. Tablet 70 mg, b.i.d. ¤for accelerated phase and blast phase¥ 2009.4 Tykerb Lapatinib 1800 mg, q.d. 1250 mg, q.d. Tablet These data were obtained from interview forms for each drug.5®12¥ MTD, maximum tolerated dose; q.d., once-daily regimen; b.i.d., twice-daily regimen. Relationship between human AUCss,u at the Methods in vitro clinical dose and IC50 values for target Data collection: For the eight tyrosine kinase kinase inhibition: In vitro IC50 values for target kinase inhibitors approved in Japan ¤Table 1¥, pharmacokinetics, inhibition were obtained from the inhibition studies efficacy, and toxicity data were obtained from application described in the interview form5,12¥ and the litera- documents, interview forms, and the literature. ture.22®26¥ The smallest values were adopted among those fi Relationship between human AUCss,u at the using a variety of puri ed kinases. Then the correlation clinical dose and animal AUCss,u at the NOAEL or between the in vitro IC50 values and human AUCss,u at the ¤ ¥ MTD: AUCss AUC per dose at steady state values at the clinical dose obtained above was evaluated. no-observed-adverse-effect level ¤NOAEL¥ or MTD in Relationship between efficacy in animals and 2-week toxicity studies using rats, dogs, and monkeys were humans: Tumor growth inhibition ¤TGI, %¥ was obtained from the pharmacokinetic analysis described in the calculated using the following equation: ® ¥ application documents.13 20 AUC data from 1-month toxicity ð Þ ð Þ¼ À Tumor growth Treated animals studies were adopted if 2-week toxicity studies had not been TGI % 1 ð Þ conducted. Male data were adopted when available. All Tumor growth Control animals ¤ ¥ animal AUCss data were from studies with a once-daily q.d. Â 100 ð2Þ regimen. For humans, AUCss at the clinical dose was obtained from the application documents13®20¥ describing repeated For all drugs except nilotinib, tumor growth was fi administration studies. Human AUCss data were from studies evaluated at the nal evaluating point of tumor volume with a q.d. regimen except for sorafenib, nilotinib, and obtained from efficacy studies with tumor-bearing mice. As dasatinib, which were given according to a twice-daily for nilotinib, tumor growth was evaluated by measuring the ¤ ¥ fi b.i.d. regimen. For ge tinib and lapatinib, AUCss values luciferase activity in an acute model, in which mice were were calculated by extrapolation from pharmacokinetic injected with murine 32D cells harboring the firefly studies at other doses under linear assumption. Values for luciferase gene and transfected to be dependent upon p210 the unbound fraction ¤fu¥ in plasma or serum were obtained Bcr-Abl. These efficacy data were obtained from the from the application documents13®15,17®20¥ and the literature21¥ efficacy studies described in the application documents13®20¥ 5®12¥ and were multiplied by AUCss to calculate the AUCss,u. The and interview form. Pharmacodynamic analysis using ¤ correlation was evaluated using average fold-error afe, an Emax model was performed to assess the AUC-effect Eq. 1¥ and correlation coefficient ¤r¥: ¤TGI¥ relationship and the E and EðAUC were P max u,50 1 Animal AUCss,u at the NOAEL or MTD calculated based on the following equation using a computer N log afe ¼ 10 Human AUCss,u at the clinical dose ð1Þ program for the non-linear least squares regression method ¤MULTI;27¥¥ Copyright © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX) 614 Azusa HOSHINO-YOSHINO, et al. Table 2. The data of human AUCss at the clinical dose and animal AUCss at the no-observed-adverse-effect level (NOAEL) and the maximum tolerated dose (MTD) ¤ & ¥ ¤ & ¥ Human AUCss Animal AUCss at the NOAEL ng h/mL Animal AUCss at the MTD ng h/mL Drugs at the clinical dose ¤ng&h/mL¥ Rat Dog Monkey Rat Dog Monkey Imatinib 33200 ¯b ¯b 4150 2 Weeks 4930 2 Weeks 445000 2 Weeks ¯b ¯b 17800 2 Weeks Gefitinib 7251.5 4611 1 Month 9700 1 Month ¯b ¯b 22753 1 Month 9700 1 Month ¯b ¯b Erlotinib 42679 4159 1 Month 2682 1 Month ¯b ¯b ¯b ¯b 14334 1 Month ¯b ¯b Sorafenib 36690a ¯b ¯b ¯b ¯b ¯b ¯b 67000 1 Month 52000 1 Month ¯b ¯b Sunitinib 1406 1317 2 Weeks ¯b ¯b 1276 2 Weeks 10190 2 Weeks ¯b ¯b 13174 2 Weeks Nilotinib 19000a 46100c 1 Month 4680 2 Weeks 12040 1 Month 224000 2 Weeks 20370 2 Weeks 12040 1 Month Dasatinib 398.8a 35 2 Weeks ¯b ¯b 181 1 Month 899 2 Weeks ¯b ¯b 634 2 Weeks Lapatinib 33836.5 ¯b ¯b ¯b ¯b ¯b ¯b ¯b ¯b ¯b ¯b ¯b ¯b The AUC per dose at steady state were obtained from application documents for each drug.13®20¥ Human data were from studies with a q.d.