An In Vitro Alternative For Predicting Systemic Toxicity. By: James McKim, Ph.D., DABT Chief Science Officer

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1 An In Vitro Alternative For Predicting Systemic Toxicity By: James McKim, Ph.D., DABT Chief Science Officer

2 What is Systemic Toxicity and What do We Want From Alternative Methods? Toxicity that occurs after a chemical is absorbed into general circulation Acute systemic toxicity Single dose, and short exposure time Intrinsic toxicity of a chemical, LD50, organ effects Subacute systemic toxicity Repeated-dose study, typically 14 day Information on toxicity following repeated exposure Helps establish doses for subchronic studies Subchronic systemic toxicity Repeated-dose, typically 28 and 90 days Organ specific effects Establish NOAEL and LOAEL Regulatory implications FDA and EPA Chronic systemic toxicity

3 The Goal is to Predict Human Systemic Toxicity Most value = Subchronic Realistically What data are required for risk assessment NOAEL, LOAEL RfD, Benchmark dose Ideally

4 Building an In Vitro Model to Predict Repeat Dose Systemic Toxicity is Too Complex to Achieve Within the Next 10 Years! Most models focus on predicting organ specific toxicity BARRIER to SUCCESS Alternative approach is to identify a plasma concentration that results in general systemic toxicity Proprietary to CeeTox, Inc.

5 Relating Plasma Concentration to Toxicity Start with pharmaceuticals Intended for internal exposure at higher doses Environmental chemicals typically not intended to be ingested, exposure to lower doses, but for longer times Develop a means to estimate the plasma concentration where general toxicity would occur Develop a relationship between concentration response curves in vitro and Cmax in vivo at the dose where toxicity was observed in rat 14-day repeated oral dose studies Clinical chemistry Histopathology

6 The Relationship Between In Vivo Plasma Concentration (Bioavailability) and Toxicity Provides the Basic Model JL Stevens (2006) Chem Res Toxicol 19, Toxicity increases with potency = target Cell models that lack target show toxicity = chemistry Proprietary to CeeTox, Inc.

7 Developing the Hypothesis and Testing it When the in vivo Cmax for toxicity is identified at steady state for the lowest dose that results in toxicity, and compared to in vitro concentration response curves for toxicity, a relationship can be identified that enables the prediction of the in vivo plasma concentration where general toxicity would be expected to occur.

8 Building the Predictive Model Based on Empirical Data Sets Acquired in vivo data for pharmacokinetic parameters Developed concentration response data in vitro Based on multiple endpoint analysis developed a relationship between in vivo and in vitro data sets Tested the model with small number of drugs Validated model in large blinded study

9 Focus on Cell Biology and Physical Chemical Properties Improves the Model Biochemical Function Membrane Integrity Mitochondrial Function Cell Proliferation Redox-State Oxidative Stress Apoptosis Pharmacology CNS receptors Cardiovascular receptors and ion channels Physical-Chemical Properties Solubility Partition coefficients Pka Protein binding Metabolic stability Metabolic activation Transporter interaction Pharmacokinetic Parameters Clearance Bioavailability Volume of distribution

10 Selecting a Cell Model That Consistently Provides Accurate Data Rat hepatoma (H4IIe) Cell line Retains oxidative metabolism Low constitutive metabolism Accepts a wide range of serum concentrations

11 Analysis of In Vitro Concentration-Response to In Vivo Plasma Levels Multiple endpoints improve interpretation Membrane integrity Cell number or mass Mitochondrial function Analysis and comparison to in vivo plasma C max Development of weighting factors for each endpoint Result was an estimate of the plasma concentration where toxicity would be expected to occur (C tox )

12 Multiple Endpoints Are Essential For Correct Interpretation of In Vitro Data CMPD H4IIE 24HR Cell# MemTox MTT ATP GSH % Control FIG. A: Exposure Concentration (µm)

13 Determining Weighting Factors Membrane integrity Highest weight = cell death Concentration response and potency Time adjustment Mitochondrial function Moderate weighting Concentration response and potency Time adjustment

14 Evaluating Assumptions Against Rat In Vivo Data 100 R2 = Keto (rat) Predicted Concentration (um)

15 In Vitro Toxicity Data Correlates With Adverse Effects in Animals and Humans CHLOROQUINE H4IIE 24HR C tox = 5µM Cell# MemTox MTT ATP Rat actual C tox = 8 µm, Human actual C tox = 1-3 µm KETOCONAZOLE H4IIE 24HR C tox = 55 µm Cell# MemTox MTT ATP Exposure Concentration (µm) C tox = 1 METHOTREXATE H4IIE 24HR , FIG. A: Exposure Concentration Cell# MemTox MTT ATP Rat actual C tox = 0.7 µm, Human actual C tox = 0.88 µm % Control Rat Actual Ctox = 60 µm, Human actual Ctox = 30 µm Exposure Concentration (µm)

16 Metabolic Activation Identifies False Negative Results Tacrine = liver Flutamide = liver Acetaminophen = liver GSH Depletion relative to no drug control after 3.5 hr incubation with induced microsomes % GSH relative No Drug Flutamide NEM Acetaminophen Tacrine Test Article Full Reaction -NADPH reaction

17 Determining Relevance to Human Systemic Toxicity Ctox (µm) Azathioprine 1 1e-8 1e-7 1e-6 1e-5 1e-4 1e-3 max therapeutic [plasma] (log M) Ctox = 5 µm MTPC = 8 µm In vitro margin of safety <= 1 Proprietary to CeeTox, Inc.

18 Azathioprine: Inhibits Purine Synthesis and Produces Toxicity Under Clinical Conditions AZATHIOPRINE H4IIE 24HR AZATHIOPRINE H4IIE 24HR % Control Cell# MemTox MTT ATP GSH % Control Isoprostane (pg/ml) GSH ISO FIG. A: Exposure Concentration (µm) FIG. B: Exposure Concentration (µm) 0 AZATHIOPRINE H4IIE 24HR Caspase 3 Extremely Toxic C tox = < 5 µm Fluorescence Units FIG. C: Exposure Concentration (µm) Proprietary to CeeTox, Inc.

19 There is Good Concordance Between Predicted Toxicity Validated to Rat Data and Human Clinical Data Ctox (µm) Thioridazine Azathioprine 1 1e-8 1e-7 1e-6 1e-5 1e-4 1e-3 max therapeutic [plasma] (log M)

20 THIORIDAZINE H4IIE 24HR Cell# MemTox MTT ATP Exposure Concentration (µm) Ctox = 11 µm MTPC = 6 µm In vitro margin of safety = 1.83

21 Drug Potency Can Influence Plasma Concentration and Toxicity Valproic acid Ctox (µm) Paroxetine Chloroquine Thioridazine Azathioprine 1 1e-8 1e-7 1e-6 1e-5 1e-4 1e-3 max therapeutic [plasma] (log M)

22 Antidepressant Paxil (SSRI) Considered Safe Under Appropriate Use: Rare Incidences of Hepatotoxicity Paroxetine H4IIE 24HR FIG. A: Exposure Concentration Cell# MemTox MTT ATP Ctox = 15 µm MTPC = 0.3 µm In Vitro Margin of Safety = 50

23 Predicting Bioavailability of a New Drug and Maximum Therapeutic Plasma Concentration In Vitro CL int (human microsomes) Scaled in vitro CL int Calculate bioavailability (%f) f = 1 E E = f u x CL int / Q H Kuhnz and Gieschen (1998) Drug Metab Disp 26, 1120.

24 What is Systemic Toxicity and What do We Want From Alternative Methods? Toxicity that occurs after a chemical is absorbed into general circulation Acute systemic toxicity Single dose, and short exposure time Intrinsic toxicity of a chemical, LD50, organ effects Subacute systemic toxicity Repeated-dose study, typically 14 day Information on toxicity following repeated exposure Helps establish doses for subchronic studies Subchronic systemic toxicity Repeated-dose, typically 28 and 90 days Organ specific effects Establish NOAEL and LOAEL Regulatory implications FDA and EPA Chronic systemic toxicity

25 Predicting a Rat Acute Oral LD50 Dose Collaborative research effort with LOREAL Paris Integrative or systems biology + Computational Toxicology Multiple endpoints related to cell health Receptor binding data (pharmacology) Physical Chemical parameters Approach has been evaluated with more than 200 chemicals Posters at the World Congress in Rome 2009, SOT 2010 Results show that an integrated in vitro approach can provide good estimates of an LD50

26 Addition of Pharmacology and Physical Chemistry Properties Improves Model Performance Performance of the standard model at the LD50 threshold of 500 mg/kg Performance of the integrated model at the LD50 threshold of 500 mg/kg REDUCTION OF THE FALSE NEGATIVE RATE (yellow area)

27 Conclusions There is a robust model capable of identifying acute and subchronic systemic toxicity (Today) Chemicals can be evaluated for systemic toxicity potential High level of concordance with in vivo toxicity An acute LD50 can be determined

28 Future Improvements to the Model Develop a drug database with animal preclinical data and in vitro toxicity data Determine a calculation for NOAEL and LOAEL Broaden the chemical space to include nonpharmaceutical agents and test the model

29 CeeTox Overview of Services a wide range of in vitro toxicology and safety assessment services Systemic Toxicity Services CTOX Panel Acute Toxicity Screen In vitro LD50 (acute tox) Dermal Toxicity Percutaneous Absorption Corrosion Irritation Sensitization Photo Toxicity Ocular Toxicity Endocrine Disruption Estrogen receptor (ER) binding Estrogen transcriptional activation Androgen receptor (AR) binding Steroidogenesis Aromatase Organ Specific Toxicity Models Heart (CardioTox ) Kidney Liver CYP Induction/Inhibition Drug / Drug Interaction Target / Pathway Assays Acute Inflammatory Response Apoptosis Cell Proliferation Cell Viability Glutathione Homeostasis Hepatobiliary Toxicity Kidney Collecting Duct Toxicity Kidney Distal Tubular Toxicity Kidney Proximal Tubule Toxicity Lipidosis Membrane Integrity Metabolism Mitochondrial Function

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