High affinity target binding: a cause of non-linear Pharmacokinetics of drugs (Target mediated drug disposition: TMDD)

Transcription

1 High affinity target binding: a cause of non-linear Pharmacokinetics of drugs (Target mediated drug disposition: TMDD) Devang Shah Senior Principal Investigator Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization, Biocon-Bristol Myers Squibb Research Centre, Syngene International Ltd, Bangalore, India Society for Study of Xenobiotics, 3 rd Conference, Bengaluru, India, th October

2 High affinity drugs nm pm 2

3 Especially biologics Small molecule Protein Therapeutics ~1-2 digit nm ~1-2 digit pm 3

4 Top drug by sales in pm 5000 pm: Rituximab Adalimumab 100 pm: Trastuzumab 50 pm: Bevacizumab 450 pm: Infliximab 1200 pm: Etanercept 4

5 Can it have a down side? 5

6 Clinical Example: REGN1193 (68 pm), hu anti-glucagon receptor mab Dose CL T 1/2 12x lower dose; 65x higher CL Kostic et al. Diabetes Obes Metab Feb;20(2):

7 Dr. Levy thought about it in 80s and 90s and Target mediated drug disposition high affinity and significant binding to target Pharmacokinetic 7

8 Landmark article: 8

9 Non-specific linear and target mediated saturable Clearance mechanism 9

10 Typical TMDD profile Peletier, Gabrielsson. J Pharmacokinet Pharmacodyn (2012) 39:

11 Should we be concerned? Target is impacting the PK of drug. Drug Target Target Drug Direct impact: Human PK and dose projection 11

12 g *10-13/mL TNFa (pg/ml) 1. Target level differences Patient Normal human Target levels Target Levels 2 Normal SLE IL6 Markers IL10 0 Control RA RA with CP Population Ripley et al. Ann Rheum Dis Jun;64(6): Thilagar et al. J Indian Soc Periodontol Mar-Apr; 22(2):

13 Drug Conc (nm) Target Inhibtion (%) Impact of target parameters: Baseline levels Baseline levels: nm nm 200 nm nm 200 nm Time (days) Time (days) 90% inhibition: Dose 100 mg to 500 mg 13

14 Preclinical Example: 4-7x higher CL in tumor bearing vs naïve mice Urva et al: J Pharm Sci Mar;99(3):

15 Clinical example: Dose optimization for Rituximab Tailor made medicines Tout et al. Blood May 11;129(19):

16 Time (h) Time (min) 2. Target turn-over can be different across species: IgE half-life DKK1 half-life Mouse Human 0 Rat Monkey Human Betts et al. J Pharmacol Exp Ther Apr;333(1):

17 Impact of target parameters: Target turn-over Drug Conc (nm) Target Inihbition (%) h 20h h h Time (days) Time (days) Higher the target turn-over, more rapidly will be free target synthesized 90% target inhibition 7 mg to 80 mg 17

18 Important to scale target parameters: Parameter 18

19 Single species Allometry using monkey: Fixed exponent of CL 0.85 and Vss 1 Deng et al. mabs 3:1, 61-66; January/February

20 Case studies: 20

21 I. Do drugs with comparable PK always exhibit comparable efficacy? 21

22 Comparable PK between IMA026 and IMA638 Tiwari et al, MABS, 2016, VOL. 8, NO. 5,

23 Surprise!!!!!!!!!!!!!!!! Shorter duration of target inhibition by IMA026 23

24 Total target accumulation: IMA026 IMA638 24

25 What s happening? IMA-026 IMA-638 K D (nm) k e (1/day) k int (1/day) k syn k on Drug Target Complex k off k e k deg k int Total target accumulation: Lower degree of inhibition 25

26 2. Does improvement in affinity always result in improved efficacy? 26

27 Probability of target attainment HAE1 ~10-20x higher affinity and potency as compared to Omalizumab Yet high doses required for meaningful increase in clinical end-point Putnam et al. AAPS J Jun; 10(2):

28 Law of diminishing return 28

29 Day ~33 35: Rapid decrease in target inhibition High CL for a high affinity drug Chimalakonda et al. AAPS J Jul; 15(3):

30 Fraction eliminated via TMDD increases for high affinity drug at lower doses Fel Low/Poor affinity: Low Fel (<0.1) at all the doses. High affinity: High Fel at lower doses (10 50 mg) 30 Anjaneya 2013

31 Is it relevant to small molecule Modality? Nature Reviews Drug Discovery 17, 299 (2018) 31

32 Less frequently observed/identified Drug Non-specific binding Target Target comprises only a tiny fraction of binding constituent. Drug always overwhelms the target Waterschoot et al. Nature Reviews Drug Discovery volume17, page 299 (2018) 32

33 Encountered especially Microdosing Nonspecific binding Drug Target Availability of increasingly sensitive analytical techniques 33

34 For HSP90 inhibitors, Vss increased with affinity Target in tissue and is major binding constituent Yamazaki et al. Drug Metab Dispos Jun;41(6):

35 Linagliptin: CL and Vss increasing with the increase of dose in wild type rats Target in plasma: Typically impacts CL and Vss 35

36 Take home message High affinity target binding: Non-linear PK Understand target kinetics: Non clinical vs clinical Healthy vs diseased Clinical translatability: Human PK and RO Improvement of affinity not always improve target inhibition. Modeling can play an important role. Protein therapeutics 36

37 Acknowledgments: SSX committee My collaborators at BMS Punit Marathe Anjaneya Chimalakonda Great publications out there Data!!!!!!!!!!! More you see, more you learn 37