Development & Characterization of Pooled and Plated Hepatocytes to Support the Evolving DMPK Landscape
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1 Development & Characterization of Pooled and Plated Hepatocytes to Support the Evolving DMPK Landscape April Downey Senior Production and Inventory Scientist In Vitro
2 Presentation Overview Introduction of HepatoSure, XenoTech s 100 donor hepatocyte pool Review of new characterization data for HepatoSure Overview of XenoTech s plateablehuman hepatocyte products Introduction of new characterization data of our plateablehuman hepatocyte lots, RIS (Relative Induction Score) Closing remarks 2
3 What is HepatoSure? Mix gender pool of cryopreserved human hepatocytes, 100 donors Largest hepatocyte donor pool available Assured minimum yield (AMY) of 5 million cells, viability of >75% Full enzymatic characterization, now including intrinsic clearance, AO activity and transporter uptake activities Large donor size provides activities closer to the average American population Minimal enzymatic variation from one lot to the next 3
4 350 Comparison of 4 Pools of HepatoSure Average of 4 Pools 300 Rate of Reaction (pmol/million cells/min) A2 2A6 2B6 2C8 2C9 2C19 2D6 2E1 3A4/5 (Test) CYP 3A4/5 (Mid) 4
5 Rate of Reaction (pmol/million cells/min) Comparison of 4 Pools of HepatoSure Lot Lot Lot Lot A2 2A6 2B6 2C8 2C9 2C19 2D6 2E1 3A4/5 (Test) CYP 3A4/5 (Mid) 5
6 Characterization What We ve Added Aldehyde Oxidase activity, using 2 marker substrates AO metabolism can play an extensive role in the clearance of many drugs Intrinsic clearance values, using 5 marker substrates Uptake activity looking at 4 specific transporters 6
7 7
8 Applications of HepatoSure Met ID Metabolic stability Drug inhibition Uptake assays Metabolism by aldehyde oxidase 8
9 Plateable Cryopreserved Human Hepatocytes XenoTech offers a variety of plateablehuman hepatocyte lots. Each lot is characterized for P450/UGT/SULT activities, as well as induction of CYP1A2, 2B6 and 3A4 Photomicrographs are provided for each lot Each lot has recommended cell seeding concentrations High quality, XenoTech s hepatocyte lots are used by our Enzyme Induction department for contract studies. 9
10 XenoTech s Cryopreserved Human Plateable Hepatocytes 10
11 Plateable Cryopreserved Human Hepatocytes Attaching versus non-attaching lots Day 2 Non-Attaching Day 2 Attaching Initial evaluation of enzyme induction: Treatment for three days with DMSO (vehicle), OME, PB and RIF 11
12 Plateable Cryopreserved Human Hepatocytes Assessing the change in morphology and confluency with time Day 2 Day 7 Day 2 = Typically 1 st day of treatment with inducers Day 7 = Typical day of enzyme activity assays and mrna harvest 12
13 Plateable Cryopreserved Human Hepatocytes Two recommended approaches Enzyme induction in human hepatocytes Option 1 Multi-well plates Cryopreserved hepatocytes Cells cultured in multi-well plates CYP mrna measured by RT-PCR CYP activity measured in situ (Individual substrate or cocktail) Data interpretation: Analysis of RIS characterization or other correlation method Option 2 Microsomes Fresh hepatocytes Cells cultured in 60-mm dishes CYP mrna measured by RT-PCR Microsomes prepared CYP activity measured in microsomes Data interpretation: Can we still utilize correlation methods? 13
14 Design of in vitro enzyme induction studies Two recommended approaches Advantages and disadvantages Option 1: CYP induction in multi-well plates Advantages Disadvantages Convenient culture anytime Large number of TA concentrations (8) Evaluation multiple compounds Can extend mrna analysis to additional enzymes if required Can evaluate clinical induction potential with pre-characterized hepatocytes Additional enzyme activities will necessitate new cultures of human hepatocytes Correlation methods require extensive pre-characterization TA not fully removed from hepatocytes potential for inhibition of activities 14 14
15 RIS (Relative Induction Score) A mechanistic tool that can be used to evaluate the potential of a clinically significant DDI due to induction of particular CYP enzymes By relating the EC 50 and E max of a compound with efficacious free plasma concentrations This score is then correlated to the magnitude of clinical DDI for midazolam or ethinylestradiol (as reported from previously published studies) RIS is a tool, there is still much work being done in this area 15
16 Relative induction score (RIS) A correlation-based approach for induction IVIVE What endpoints are necessary for the RIS? 1. In vitro E max and EC 50 data (mrna) 2. Unbound C max,ss (systemic) 3. Calculated RIS (eqn. above) with 7 probe drugs (must be done for each hepatocyte lot) 4. Observed clinical AUCR with multiple victim drugs (challenging for non- 3A4 enzymes) Content adapted from Rippet al., (2006) DMDand Fahmi et al, (2008) DMD 16
17 Relative induction score (RIS) A correlation-based approach for induction IVIVE Prediction of induction-mediated CYP3A4 DDIs from RIS data in three cultures of human hepatocytes RIS > 0.1 typically indicates clinically significant CYP3A4 induction RIS < 0.01 typically indicates lack of clinical CYP3A4 induction Content adapted from Fahmi and Ripp, (2010) Expert Opinion in Drug Metab and Tox 17
18 RIS (Relative Induction Score) XenoTech s RIS Evaluation Project To meet the continually evolving needs or our clients, both products and services XenoTech will continue to evaluate our commercially available plateable human hepatocytes for RIS Currently work is being done to evaluate RIS in other CYP enzymes Data is in the early stages and will be released after thorough review and analysis 18
19 RIS (Relative Induction Score) Compound Observed Midazolam AUC % Decrease Free of co-administered EC 50 midazolam cultured human hepatocytes Effect of co-administered E C max (µm) (µm) max RIS midazolam cultured (HC5-25) on CYP3A4 RIS (Sigmoid, DMSO=0 data; Hill graph) human hepatocytes on CYP3A4 Carbamazepine Rifampin Nifedipine Phenytoin Rosiglitazone Midazolam AUC (% Decrease) Pioglitazone Pleconaril PLC PIO 20 RSG 0 NIF PHE CMB RIF Relative Induction Score 19
20 Plateable Cryopreserved Human Hepatocytes Applications of Plateable Human Hepatocytes Induction assays Long-term stability assays Uptake assays 20
21 Closing Remarks All of XenoTech s hepatocytes come with an easy to understand thawing protocol XenoTech offers all medias needed to complete both suspension and plated incubations Strong technical support to assist with troubleshooting and assay design 21
22 Thank You! Please feel free to contact XenoTech s Product Sales Team for further questions. Elizabeth Jackson ejackson@xenotechllc.com Lexi Hayman ahayman@xenotechllc.com Teresa Martin tmartin@xenotechllc.com
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