In vitro-in vivo extrapolation from organ on a chip systems. Iain Gardner

Transcription

1 In vitr-in viv extraplatin frm rgan n a chip systems Iain Gardner ELRIG cnference 23 rd May 2018

2 OUTLINE IVIVE-PBPK mdels Regulatry acceptance Limitatins f current IVIVE-PBPK mdels Hw can OOC/MPS help Current status f IVIVE in MPS Cnclusins Cpyright 2018 Certara, L.P. All rights reserved. 2

3 Ppulatins n frm a chip Cpyright 2018 Certara, L.P. All rights reserved.

4 PBPK and MPS Edingtn et al (Nature SCIENTIFIC REPORTS; 2018, 8:4530 DOI: /s Cmplementary systems Similar mdelling appraches can help understand the ADME prcesses within the MPS Cpyright 2018 Certara, L.P. All rights reserved.

5 IVIVE what parameters can be predicted Absrptin CL Permeability, slubility, precipitatin In vitr metablism rate Transprt In vitr transprter kinetics Tissue distributin Physicchemical data, prtein binding, BP rati Drug interactins Fractin cleared by different pathways Transprter kinetics Ki, Ki app, k inact, Ind max, INDC 50, k deg, peratinal cncentratin, Cpyright 2018 Certara, L.P. All rights reserved. 5

6 Determinatin f CL int in vitr [S] (μm) [S] (μm) FIRST ORDER PROCESS [S] 1 CL int [S] 2 ln [S] V (ml) 1 t2 t1(min) P (mg) [S] Time (min) Time (min) t 1 t 2 Simplest methd is via substrate depletin Cpyright 2018 Certara, L.P. All rights reserved.

7 Quantitative Scaling Factrs in Human IVIVE In vitr system In vitr CLu int? Scaling Factr 1 CLu int per g Liver? Scaling CLu Factr 2 int per Liver HHEP µl.min cells X HPGL HLS9 HLM HLC µl.min -1 mg prtein X S9PPGL MPPGL CPPGL X Liver Weight rcyp µl.min -1 pml CYP X ISEF X pml CYP/mg prtein X MPPGL Cpyright 2018 Certara, L.P. All rights reserved.

8 Predicting DDI Change in Clu int f an enzyme in presence f an inhibitr Level f DDI depends n Ptency and cncentratin f the inhibitr Hw imprtant the inhibited pathway is t the verall Clearance f the substrate Cnduct simulatin in presence and absence f inhibitr Cmpare AUC t define the AUC rati Cpyright 2018 Certara, L.P. All rights reserved.

9 Prspective DDI predictin - inhibitin 15 substrate mdels submitted by 9 spnsrs; mainly CYP3A4 metablised Wagner et al., Clinical Pharmackinet, 2015 Cpyright 2018 Certara, L.P. All rights reserved. 9

10 PBPK Impact n New Drug Apprvals Almst 1012 fast 100 nclgy track, label claims breakthrugh, infrmed by PBPK, pririty 2 anti-viral r including DDI, absrptin, accelerated 4 rphan ethnic 1 gastr bridging, apprval frmulatin 1 - CNS 3 pulmnary Cpyright 2018 Certara, L.P. All rights reserved.

11 Industry perspective n predictin f DDIs Scenari Applicatin Level f cnfidence Limitatins & challenges DDIs Reversible CYP inhibitin alne r inductin alne Time-dependent CYP inhibitin Cmbined reversible, inductin and inhibitin Mdulatin f nn-cyp pathways Mderate t high Lw t mderate Lw Lw t mderate Accurate determinatin in vitr f fractin metablised by P450, especially when nn-p450 enzyme invlved. IV clearance and mass balanced data fr victim nt readily available at early stages f drug develpment. Uncertainty in CYP phentyping and measured in vitr inhibitr cnstant. General ver-predictin f in viv DDI frm in vitr data Difficult t evaluate mechanism when multiple prcesses are invlved because f limited clinical data. Lack f prspective evaluatin Apical active transprt Mderate Nt all in vitr assays prvide apprpriate inhibitin cnstants Baslateral active transprt Lw As abve. Predicting intracellular cncentratins frm uptake and efflux transprt activity is challenging. Jnes et al., CPT 2015 Cpyright 2018 Certara, L.P. All rights reserved. 11

12 Gaps in current IVIVE appraches that MPS culd fill? Lw Clearance Labile enzyme systems AO, FMO Prvide missing physilgical data that is hard t get in viv k deg Multiple clearance pathways Especially multiple tissues Metablite kinetics and metablite/parent interplay Cmplex metablic DDI Inductin (takes time) MBI (takes time) Transprter IVIVE Tissue distributin Diclfenac Kpu = 120 in liver MPS, Kpu in viv = 60 Physilgical changes in tissues and impact n CL Integrated Metablism and Txicity testing Cpyright 2018 Certara, L.P. All rights reserved. 12

13 Sme Limitatins f substrate depletin appraches Standard micrsmal incubatins run ut f pwer t metablise cmpunds need a certain amunt f turnver t be able t measure it accurately <7 ml/min/mg prtein Generally mre metablic pwer in recmbinant systems Althugh they t will have a limit Other appraches being investigated Tissue reactrs, c-culture systems, rgan n a chip/mps etc Cpyright 2018 Certara, L.P. All rights reserved.

14 Determinatin f Clint in OOC/MPS and qualitative scaling Reasnable crrelatin between in vitr Clint in OOC/MPS system and in viv CLu (Dash et al, 2009, Exp. Opinin n Drug Met & Tx, 5, 1159) Cpyright 2018 Certara, L.P. All rights reserved. 14

15 Current status f QIVIVE frm MPS systems? Data cllated frm literature and re-analysed with cnsistent scaling factrs AAFE = 8.2 n=16 Cpyright 2018 Certara, L.P. All rights reserved. 15

16 Imprvements t IVIVE predictin methdlgy Rat Human Uptake f unbund cmpund is faster in the presence f serum albumin Prpsed mechanism invlves facilitated disassciatin f bund ligand fllwing interactin between binding prteins and hepatcyte surface Extraplatin t humans accunting fr facilitated diffusin increases scaled Clint by ~ 11-fld; 1.6 fld lwer than in viv Clint Cpyright 2018 Certara, L.P. All rights reserved. (Miyauchi, DMD 46,259, 2018) 16

17 Imprving IVIVE f Clint (Static systems) Albumin effect Shaking Varius factrs can imprve predictin f CL Presence f an UWL in static systems may cntribute t bserved underpredictin f Clint Shuld be an advantage f MPS systems with flw if UWL can be cntrlled (Cha, 2009 Drug Met Lett, 3, 296; Wd, 2018,DMD, 46, 278) Cpyright 2018 Certara, L.P. All rights reserved. 17

18 Metablite frmatin and metablite kinetics PBPK MPS system shws sequential frmatin f 1º and 2º metablites Cpyright 2018 Certara, L.P. All rights reserved. (Vivares et al, Xenbitica, 45, 29, 2015) 18

19 Cmplex metablic DDI Perpetratr is bth an inducer and mechanism-based inhibitr f DDI MBI (AUC rati = 3.7) Inducer (AUC rati = 0.2) Bth (AUC rati = 0.9) Accurate predictin depends n Cmpund parameters K I, Kinact, Ind max, Ind C 50 System parameters - k deg Hard t measure Kdeg in viv Need bimarkers/specific substrates, inhibitrs/inducers Been dne fr CYP 3A4 and a few ther enzymes In vitr determinatins hampered by nt having systems with stable expressin ver a number f days/weeks Rle fr liver MPS in determining these parameters? Cpyright 2018 Certara, L.P. All rights reserved. 19

20 Physilgical changes in tissues and impact n CL Changes in CYP activity in disease: NAFLD (Kstrzewski, W J Gastrenterl, 2017, 23, 204) Infrmatin can be incrprated in t IVIVE:PBPK mdels tgether with ther relevant physilgy changes/ demgraphic infrmatin in the NAFLD ppulatin - age, gender, bdy cmpsitin changes Predict changes in drug distributin and clearance, DDI susceptibility in this ppulatin Cpyright 2018 Certara, L.P. All rights reserved. 20

21 Cnclusins IVIVE-PBPK appraches have been used successfully fr a number f different applicatins Used in regulatry arena t replace clinical studies in sme cases There are still a number f areas where imprvement in predictability frm in vitr systems is desirable Transprter mediated prcesses Cmplex DDI MPS systems have the ptential t address these areas as well as t prvide sme f the key missing physilgical parameters fr PBPK mdels Cpyright 2018 Certara, L.P. All rights reserved. 21

22 IVIVE f txicity 5-FU txicity in MPS with liver, tumur and bne marrw cells Cells mre sensitive t 5-FU induced cell death in dynamic vs static culture - differential txicity bserved in different cells in dynamic but nt static mdels Biggest effect n 5-FU cncentratin at which cell death was half maximal (KC 50 ) Cpyright 2018 Certara, L.P. All rights reserved. (Sung et al., Lab n a chip, 2010) 22

23 Binding t apparatus? Lg P Lg D ph 7.4 fu mic Diclfenac acidic Ibuprfen acidic Lidcaine basic (8.01) Prednislne Prpranll basic (9.67) Phenacetin Tested with the 6 cmpunds abve but nne are particularly lipphilic at physilgical ph? Cpyright 2018 Certara, L.P. All rights reserved. 23

24 Tissue distributin Distributin int liver tissue MPS measured fr diclfenac - Kp = 16; fu med = 0.13; Kpu = Predicted liver Kpu in PBPK mdel = 60 Predicting distributin f drugs int different tissues? Hard t verify clinically but ptential t use multi rgan MPS fr verificatin and als fr refinement f PBPK mdel parameters (Tsamanduras, AAPS J, 2017) Cpyright 2018 Certara, L.P. All rights reserved. 24

25 Metablite frmatin and subsequent metablism? MPS PBPK C0 = 78 mm Hw well is sulfatin maintained in this in vitr experiment? CL f APAP seems t be well maintained in sme MPS systems (Prt, 2014) (Tsamanduras, JPET, 2017) Cpyright 2018 Certara, L.P. All rights reserved. 25