1994 Gerhard Levy mab target-mediated drug disposition TM- DD TMDD TMDD TMDD TMDD PK / PK / PD PK

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1 481 CN /R ISSN http / /www. cjcpt. com 2018 May R969 A doi /j. issn Gerhard Levy mab target-mediated drug disposition TM- DD TMDD TMDD TMDD PK PD TMDD 1 PD TMDD 1994 Levy target-mediated drug disposition TMDD TMDD PK PD PD PK 2 TMDD TMDD - exposureresponse ER PK /PD pharmacokinetics PK pharmacodynamics PD 1 ER TMDD TMDD PD - PK ER TMDD ER 3 monoclonal antibodies Tel jishm@ cde. org. cn Tel gaocy@ cde. org. cn PD PK / PK / PD PK PK TMDD TMDD TMDD TMDD

2 482 Chin J Clin Pharmacol Ther 2018 May 23 5 dcr dt on C R - k off CR - k e CR CR 1 TMDD Formula TMDD 1994 Levy TMDD inf TMDD C C TMDD CR 0 R C R indirect response IDR CR R 0 in k on k off k out k e C k e CR Fig. 2 C p R p k in k out 5 TMDD TMDD Buffalo Mager Jusko Fig. 3 7 Tab. 1 TMDD 4 TMDD Fig. 1 4 Formula 1-4 Fig. 1 Two-compartment TMDD model with binding only in the central compartment dc dt = inf - k e C + k cp C - k on C R + k off CR + k pc Ap Formula 1 da p dt cp C - k pc A p Formula 2 dr dt in - k out R - k on C R + k off CR Formula 3 Fig. 2 Two-compartment TMDD model with binding in both central and peripheral compartment two-to-one-binding Leonid Gibiansky TMDD 8 Fig. 4 C R RCR C C R C R CR RC CR RC R RCR

3 2018 May 23 5 Fig. 3 One-compartment TMDD model with two drugs competing for the same receptor 483 quasi-equilibrium QE rapid binding RB 13 Gibiansky quasi-steady-state QSS 14 Michaelis- Menten MM QE /RB QE /RB k on C R off CR QE /RB Leonid Gibiansky k e CR k off QE 16 = C R CR C tot C = C + CR R tot = R + CR QE /RB Fig. 4 One-compartment TMDD model with one drug Formula 5-8 having two binding sites QE QE TMDD TMDD QE TMDD Tab. 1 The extensions of TMDD models da Published p Description Reference dt cp C - k pc A p Formula 5 year Multiple Targets 2010 Gibiansky et al. 8 Two drugs competing 2012 Yan et al. 7 for same target Receptor mediated 2009 Krippendorff et al. 9 endocytosis Cell-level kinetic 2012 Krippendorff et al. 10 and PK model FcRn recycling 2010 Xiao et al. 11 Immune response 2013 Perez-Ruixo et al. 12 K D K D off dc tot dt R tot k e CR C K d + C dr tot dt R tot C K d + C 1. 2 TMDD 1 C = C TMDD 2 tot - R tot - K d + PK 槡 C tot - R tot - K d 2-4K d Ctot Formula 8 TMDD QSS QSS PK /PD k on C R off CR + k e CR k on k off CR K SS QE /RB TMDD QSS K SS = K D + k e CR k k e CR on Mager Krzyzanski k off QE /RB k on = inf - k e C + k cp C - + k pc Ap Formula 6 in - k out R tot - k e CR - k out Formula 7

4 484 Chin J Clin Pharmacol Ther 2018 May 23 5 QSS QSS dc 0 C CR dt = inf - k V e C + k cp C - V max C c K m + C + k pc A p Formula 10 R R 0 dr tot QSS QSS dt in - k out R tot - k e CR - k out R tot C Formula 11 K d + C QE MM Formula 6 V max MM R tot CR V max K m V max = R tot k int K m = K ss int + k off k on RB QSS MM QSS MM Tab. 2 CR Formula 6 R tot = R + CR MM Wagner da p dt cp C - k pc A p Formula 9 Tab. 2 The assumptions for different approximate models MM TMDD Fig. 5 Description Assumption Reference Rapid Binding Equilibrium between the binding and dissociation of the complex has been achieved Quasi-steady-state Binding rate is balanced by the sum of 14 the dissociation and internalization rates Michaelis-Menten Binding rate is balanced by the sum of 15 the dissociation and internalization rates 2005 Mager - 2 TMDD RB -RB RB TMDD RB TMDD - - RB 19 Fig Abraham PK A TMDD k on R 0 TMDD

5 2018 May TMDD RB K D Gibiansky 21 PK TMDD 1 TM- Fig. 6 Schematic representation of how the parameters DD may be derived from four phases of mab 21 RB QSS MM 3 TMDD 2 RB QSS MM TMDD 2012 Peletier IL-1b Hepcidin ALK1 c-mpl EROR IFNAR VEGF CD4 Fig. 6 TMDD TMDD A Dua P 2 compartment model non-compart- R 0 k on B ment analysis NCA TMDD PK k e c 1 TMDD k in k out C - PK 2 KD k off D / PK k e CR K ss 22 Fig. 5 General TMDD model and the corresponding simplified model Assumption was indicated by arrows. Blue arrows QSS assumption Green arrows RB assumption Red arrows Constant total target assumption Black arrow Assumptions from Wagner equations TMDD PK TMDD TMDD TMDD TMDD TMDD 23 TMDD PF-

6 486 Chin J Clin Pharmacol Ther 2018 May 23 5 TMDD MABEL Mager Jusko 2001 TMDD PF Wang Y Booth B Rahman A et al. Toward greater in- PK /PD sights on pharmacokinetics and exposur-response relationships for therapeutic biologics in oncology drug development J. Clin Pharmacol Ther MABEL Dkk-1 4 Mager DE Jusko WJ. General pharmacokinetic model for Dkk-1 10% drugs exhibiting target-mediated drug disposition J. J MABEL mg /kg Pharmacokinet Pharmacodyn mg /kg mg /kg DKK-1 50% PF Luu KT TMDD Dkk-1 PF- PK PK TMDD TMDD TMDD 25 Dkk-1 TMDD TMDD PF TMDD 1 No Observed Adverse Effect Level NO- 4 AEL 2 Minimal Anticipated Biological TMDD Effeect Level MABEL 3 TMDD TMDD MABEL FDA2005 NOAEL human equivalent dose HED 100 TMDD maximum recommended starting dose MRSD MRSD TMDD mg /kg mg /kg MABEL receptor occupation RO MA- 1 Levy G. Pharmacologic target mediated drug disposition J. Clin Pharmacol Ther BEL 10% RO 2 Dua P Hawkins E Van PDG. A tutorial on target-mediated drug disposition TMDD models J. CPT MABEL mg /kg Pharmacometrics Syst Pharmacol Cao Y Jusko WJ. Survey of monoclonal antibody disposition in man utilizing a minimal physiologicallybased pharmacokinetic model J. J Pharmacokinet Pharmacodyn Kagan L Turner MR Balu-Iyer SV et al. Subcutaneous absorption of monoclonal antibodies role of NOAEL dose site of injection and injection volume on rituximab pharmacokinetics in rats J. Pharm Res MABEL 7 Yan X Chen Y Krzyzanski W. Methods of solving TMDD MABEL rapid binding target-mediated drug disposition model for two drugs competing for the same receptor J. J

7 2018 May 23 5 Pharmacokinet Pharmacodyn Gibiansky L Gibiansky E. Target-mediated drug disposition model for drugs that bind to more than one target J. J Pharmacokinet Pharmacodyn Krippendorff BF Kuester K Kloft C et al. Nonlinear pharmacokinetics of therapeutic proteins resulting from receptor mediated endocytosis J. J Pharmacokinet Pharmacodyn Krippendorff BF Oyarzún DA Huisinga W. Predicting the F ab -mediated effect of monoclonal antibodies in vivo by combining cell-level kinetic and pharmacokinetic modelling J. J Pharmacokinet Pharmacodyn Xiao JJ Krzyzanski W Wang YM et al. Pharmacokinetics of anti-hepcidin monoclonal antibody Ab 12B9m and hepcidin in cynomolgus monkeys J. AAPS J Ruixo JJP Ma P Chow AT. The Utility of Modeling and Simulation Approaches to Evaluate Immunogenicity Effect on the Therapeutic Protein Pharmacokinetics J. AAPS J Mager DE Krzyzanski W. Quasi-equilibrium pharmacokinetic model for drugs exhibiting target-mediated drug disposition J. Pharm Res Peletier LA Gabrielsson J. Dynamics of target-mediated drug disposition characteristic profiles and parameter identification J. J Pharmacokinet Pharmacodyn Yan X Mager DE Krzyzanski W. Selection between Michaelis-Menten and target-mediated drug disposition pharmacokinetic models J. J Pharmacokinet Pharmacodyn Gibiansky L Gibiansky E Kakkar T et al. Approximations of the target-mediated drug disposition model and identifiability of model parameters J. J Pharma- 487 cokinet Pharmacodyn Ma P. Theoretical considerations of target-mediated drug disposition models simplifications and approximations J. Pharm Res Wagner JG. A new generalized nonlinear pharmacokinetic model and its implications M. / /Biopharmaceutics and relevant pharmacokinetics drug Intelligence publications. Hamilton Hamilton Press Mager DE Krzyzanski W. Quasi-equilibrium pharmacokinetic model for drugs exhibiting target-mediated drug disposition J. Pharm Res Abraham AK Krzyzanski W Mager DE. Partial derivative-based sensitivity analysis of models describing target-mediated drug disposition J. Aaps Journal E181-E Gibiansky L Gibiansky E Kakkar T et al. Approximations of the target-mediated drug disposition model and identifiability of model parameters J. J Pharmacokinet Pharmacodyn Peletier LA Gabrielsson J. Dynamics of target-mediated drug disposition characteristic profiles and parameter identification J. J Pharmacokinet Pharmacodyn J Betts AM Clark TH Yang J et al. The application of target information and preclinical pharmacokinetic / pharmacodynamic modeling in predicting clinical doses of a Dickkopf-1 antibody for osteoporosis J. J Pharmacol Exp Ther Luu KT Bergqvist S Chen E et al. A model-based approach to predicting the human pharmacokinetics of a monoclonal antibody exhibiting target-mediated drug disposition J. J Pharmacol Exp Ther Research advances on target-mediated drug disposition TMDD models JI Shuangmin 1 ZHU Xiao 2 GAO Liucun 1 YANG Huan 1 GAO Chenyan 1 1 Center for Drug Evaluation China Food and Drug Administration Beijing China 2 School of Pharmacy University of Otago Dunedin 9016 New Zealand ABSTRACT Since the formal concept of targetmediated drug disposition TMDD was proposed by Dr. Gerhard Levy in 1994 great progress has been a- chieved in this area. Thanks to the development of experimental techniques more and more data are a- vailable for the mathematical modeling of TMDD. As the rise of biologics the application of TMDD models becomes more and more prevalent in drug development. This review introduces the development of TM- DD models and discusses the application of different variants. KEYWORDS target-mediated drug disposition modeling and simulation biologics