DRUG CANDIDATE ASSESSMENT PACKAGE
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1 DRUG CANDIDATE ASSESSMENT PACKAGE Eurofins Cerep Panlabs has developed this package in response to many questions from our clients about the type of data that is useful in moving their drug candidates along a drug development pathway. The assays contained and data generated by these cost-effective packages help our clients characterize and better understand these candidates. In addition, they also provide the type of information that potential partners or investors request as part of the due diligence that is performed prior to making partnering or investment decisions. August 2014
2 ffcore PACKAGE BIOAVAILABILITY P12 Bioavailability G228 Aqueous solubility (PBS, SGF, SIF) (1) 2194 Protein binding (plasma, human) (2) 3318 A-B permeability (Caco-2, ph 6.5/7.4) 3320 B-A permeability (Caco-2, ph 6.5/7.4) 0607 Intrinsic clearance (liver microsomes, human) (2) (1) PBS = Phosphate Buffered Saline; SGF = Simulated Gastric Fluid; SIF = Simulated Intestinal Fluid (2) Additional Species Available hwhat h information will these assays provide? This package is designed to provide an early assessment of how a drug candidate may behave under conditions it may encounter after oral administration and, ultimately, its availability in the circulatory system. Specifically, these assays test: --Solubility under conditions it would encounter transitioning from the stomach to the intestine --The ability to pass through the cells lining the intestine --The amount of the drug candidate that is free or protein bound once in the circulatory system ffcore PACKAGE DRUG INTERACTIONS zcyp INHIBITION G232 CYP INHIBITION 2064 CYP1A inhibition (HLM (3), phenacetin substrate) 2065 CYP2B6 inhibition (HLM, bupropion substrate) 2244 CYP2C8 inhibition (HLM, paclitaxel substrate) 2066 CYP2C9 inhibition (HLM, diclofenac substrate) 1772 CYP2C19 inhibition (HLM, omeprazole substrate) 1838 CYP2D6 inhibition (HLM, dextromethorphan substrate) 1770 CYP3A inhibition (HLM, midazolam substrate) 1769 CYP3A inhibition (HLM, testosterone substrate) (3) HLM = Human Liver Microsomes zdrug TRANSPORTERS 1324 P-gp inhibition (MDR1-MDCKII, calcein AM substrate) (4) 3633 BCRP inhibition (BCRP-CHO, Hoechst substrate) (4) 3878 MRP1 inhibition (MRP1-HEK, calcein AM substrate) 3879 MRP2 inhibition (MRP2-HEK, CDCF substrate) 3880 MRP3 inhibition (MRP3-HEK, CDCF substrate) 3658 OAT1 inhibition (OAT1-CHO, CF substrate) (4) 3659 OAT3 inhibition (OAT3-CHO, CF substrate) (4) 3660 OATP1B1 inhibition (OATP1B1-CHO, FMTX substrate) (4) 3661 OATP1B3 inhibition (OATP1B3-CHO, FMTX substrate) (4) 3746 OCT1 inhibition (OCT1-CHO, ASP+ substrate) (5) 3726 OCT2 inhibition (OCT2-CHO, ASP+ substrate) (4) 3656 ASBT inhibition (ASBT-CHO, 3H-taurocholic acid substrate) 3657 NTCP inhibition (NTCP-CHO, 3H-taurocholic acid substrate) (4) recommended by FDA and EMA (5) recommended by EMA hwhat h information will these assays provide? This package is designed to provide an assessment of how a potential drug may affect the major drug metabolizing enzymes or drug transporters. Specifically, these assays test: --Possible inhibitory effect on the cytochrome P450 (CYP) enzymes. Inhibition of these enzymes can lead to a buildup of a co-administered drug --Possible inhibition of drug transporters, which can interfere with the trafficking of the drug itself and/or coadministered drug, leading to undesired disposition or cellular accumulation --Possible induction of the CYP enzymes, which can lead to decreased plasma concentration of the drug itself and/or a co-administered drug zcyp INDUCTION 3860 CYP1A2 induction (human hepatocytes, mrna level, 3 donors) 3861 CYP2B6 induction (human hepatocytes, mrna level, 3 donors) 3864 CYP3A4 induction (human hepatocytes, mrna level, 3 donors)
3 ffcore PACKAGE IN VITRO TOXICITY This package is designed to assess the potential cytotoxicity, cardiac toxicity and genotoxicity of a test compound by a variety of in vitro toxicity assays. zcytotoxicity The cytotoxicity assay directly assesses toxic effects of a test compound on a cell line. Five parameters are analyzed (cell number, membrane permeability, intracellular calcium, mitochondrial membrane potential and nuclear size) using a liver derived cell line (HepG2) and High Content Analysis. G202 Cytotoxicity (HepG2, 5 endpoints, HCA) zcardiac TOXICITY The cardiac toxicity is assessed by measuring the inhibitory effect of a test compound on human cardiac potassium (herg) and sodium (Nav1.5) channels over-expressed in a cell line using automated or conventional patch clamp herg (automated patch-clamp) 2393 Nav1.5 (automated patch-clamp) hwhat h information will these assays provide? --This assay may provide mechanistic information on toxicity. The end-points show a better correlation with clinical toxicity events than more classic cytotoxicity end-points such as alamarblue reduction. Toxicity may be more clearly reflected in a particular cell function endpoint, giving insight into mechanism of toxicity. --The automated patch clamp assay measures interaction with the Potassium channel, herg. Such interactions could result in a cardiac tachyarrhythmia potentially leading to death. --Interaction with the Nav1.5 channel can be detected in the Automated Patch Clamp assay. This can reveal adverse effects on the cardiac action-potentials and change in the QT intervals, providing additional information to assess cardiac safety. zgenotoxicity The genotoxicity assays are designed according to ICH S2(R2) guidelines. A test battery including Ames and in vitro micronucleus assays (with and without metabolic activation by S9) is performed. The Ames fluctuation test assesses the mutagenic potential of compounds. The in vitro micronucleus assay complements the Ames fluctuation test in the evaluation of genotoxicity effects such as chromosomal damage. Cytotoxicity is assessed in parallel in both Ames and in vitro micronucleus assay to identify possible false negative results due to cytotoxicity. P14 Genotoxicity G175 Ames fluctuation test (TA98, TA100, TA1535, and TA1537; with and without S9) 1560 In vitro micronucleus (CHO-K1, without S9) 1684 In vitro micronucleus (CHO-K1, with S9) hwhat h information will these assays provide? Testing for genetic toxicity is an integral part of evaluating a potential drug s overall characteristics. No single test can effectively evaluate all types of genetic toxicity so these in vitro assays are used as a screening tool to evaluate whether a drug candidate can: --Cause direct DNA mutation (the Ames assay) --Cause chromosomal damage through introduction of double stranded DNA breaks or interaction with the mitotic cell division apparatus (micronucleus assay) --Potential bacterial cytotoxicity of the drug is assessed in parallel along with the Ames assay to identify possible false negative results due to cytotoxicity --Potential cytotoxicity of the drug is assessed simultaneously in the same wells in the micronucleus assay to identify possible false negative results due to cytotoxicity
4 ffcore PACKAGE SAFETY SCREEN 44 P270 SafetyScreen 44 Family RECEPTORS Adenosine 0004 A 2A (agonist radioligand) Adrenergic 2338 a 1A (antagonist radioligand) 0013 a 2A (antagonist radioligand) 0020 b 2 (agonist radioligand) 0018 b 1 (agonist radioligand) Cannabinoid 0036 CB 1 (agonist radioligand) 0037 CB 2 (agonist radioligand) Cholecystokinin 0039 CCK 1 (CCK A ) (agonist radioligand) Dopamine 0044 D 1 (antagonist radioligand) 1322 D 2S (agonist radioligand) Endothelin 0054 ET A (agonist radioligand) Histamine 0870 H 1 (antagonist radioligand) 1208 H 2 (antagonist radioligand) Muscarinic 0091 M 1 (antagonist radioligand) 0093 M 2 (antagonist radioligand) 0095 M 3 (antagonist radioligand) Opioid and opioid-like 0114 delta 2 (DOP) (agonist radioligand) 1971 kappa (KOP) (agonist radioligand) 0118 mu (MOP) (agonist radioligand) Serotonin HT 1A (agonist radioligand) HT 1B (antagonist radioligand) HT 2A (agonist radioligand) HT 2B (agonist radioligand) Vasopressin 0159 V 1a (agonist radioligand) Steroid nuclear receptors 0933 AR (agonist radioligand) 469 GR (agonist radioligand) Other receptors 3029 N neuronal a4b2 (agonist radioligand) ION CHANNELS Voltage-gated channels 0161 Ca 2+ - L (dihydropyridine site) 1868 herg (membrane preparation) 0166 K V 0169 Na + - site 2 Membrane ligand-gated channels 0028 BZD (central) 0066 NMDA HT 3 TRANSPORTERS Dopamine 0052 dopamine transporter Norepinephrine 0355 norepinephrine transporter Serotonin HT transporter KINASES Protein-tyrosine kinases 2906 Lck kinase OTHER ENZYMES Phosphodiesterases 2432 PDE 3A Monoamine & neurotransmitter synthesis & metabolism 2434 PDE 4D acetylcholinesterase 0443 MAO-A (antagonist radioligand) Arachidonic acid metabolism 0726 COX COX 2 hwhat h information will these assays provide? The SafetyScreen 44 is performed at Eurofins Cerep. All the 44 selected targets, recommended by 4 major pharmaceutical companies (6), are gathered in a cost-effective panel that associates robustness (each assay is HTS-compatible) and strategy. Thus, the SafetyScreen 44 is a rational first step in the drug discovery process. This profiling panel provides both early identification of significant off-target interactions on sets of NCEs likely to fail in next stage and the optimization of safety margins. (6) Reducing safety-related drug attrition: the use of in vitro pharmacological profiling. By Joanne Bowes, Andrew J. Brown, Jacques Hamon, Wolfgang Jarolimek, Arun Sridhar, Gareth Waldron & Steven Whitebread. Nature Reviews Drug Discovery 11: (December 2012).
5 ffollow-up f FOLLOW-UP TO BIOAVAILABILITY If efflux (B-A permeability more than 2-fold of A-B permeability) is observed, the following suite of assays can be performed to verify whether the drug candidate is a P-gp substrate. Assays are performed in the absence and presence of a known inhibitor (verapamil) of the P-gp transporter. G206 P-gp substrate assessment (Caco-2) 3319 A-B permeability (Caco-2, ph 7.4/7.4) 3321 B-A permeability (Caco-2, ph 7.4/7.4) 3325 A-B permeability (Caco-2, ph 7.4/7.4 + verapamil) 3326 B-A permeability (Caco-2, ph 7.4/7.4 + verapamil) If metabolism is observed in the intrinsic clearance assay then the following suite of assays can be performed to identify which specific CYP isoform is responsible for the observed metabolism. G232 CYP-Phenotyping 1645 Intrinsic clearance (CYP1A2) 2387 Intrinsic clearance (CYP2B6) 2384 Intrinsic clearance (CYP2C8) 1646 Intrinsic clearance (CYP2C9) 1647 Intrinsic clearance (CYP2C19) 1648 Intrinsic clearance (CYP2D6) 1649 Intrinsic clearance (CYP3A4) FOLLOW-UP TO DRUG INTERACTIONS This set of assays can determine whether a drug candidate can irreversibly or quasi-irreversibly inhibit a CYP isoform through damaging or persistently binding to the enzyme. This panel of enzymes is selected based on recommendations in the FDA guidance released in February of G235 G197 G199 G198 G200 G201 Time-Dependent CYP Inhibition (HLM, package of 10 assays) Time-dependent CYP1A inhibition (HLM, phenacetin substrate ± NADPH) Time-dependent CYP2C9 inhibition (HLM, diclofenac substrate ± NADPH) Time-dependent CYP2C19 inhibition (HLM, omeprazole substrate ± NADPH) Time-dependent CYP2D6 inhibition (HLM, dextromethorphan substrate ± NADPH) Time-dependent CYP3A inhibition (HLM, midazolam substrate ± NADPH)
6 ffadditional SERVICES IN VIVO RODENT PK AND BBB, EXPOSURE, SAFETY AND EFFICACY STUDIES Eurofins Panlabs has been performing in vivo studies for over 40 years, from pharmacokinetic and tolerability (MTD and non-glp toxicology) studies through primary pharmacodynamic screening, disease-specific efficacy and dose-dependent proof-of-concept and translational in vivo models. The experienced expert staff can formulate and dose test articles by virtually any route, as well as short or long-term continuous infusion. Eurofins Panlabs can monitor blood and organ exposure for PK/PD studies, and can conduct biomarker analyses. Studies with biologics, vaccines, RNAi, liposomal formulations, nanoparticles, cellular agents or small molecule NCEs are regularly conducted. Facility and capabilities information are listed below. Please contact your Business Development representative to design a study according to your needs. zvivarium AAALAC-accredited and ISO 9001 compliant, Japanese JRS, International Guiding Principles for Biomedical Research (CIOMS), Agricultural Council (Taiwan) and NIH OLAW compliant (Foreign Assurance # A ) zspecies Mouse, rat, suncus murinus, guinea pig, hamster ztherapeutic AREAS Bacterial and Fungal MICs in antibiotic sensitive and/or resistant strains + in vivo infection models, Metabolic/Endocrine Diseases, CNS, Inflammation, Allergy, Oncology, Safety, Gastrointestinal, Cardiovascular, and Renal Diseases zcapabilities --Formulation --Administration (IV, Topical, SC, ID, PO, IT, IN, IP, IM, intra-tumoral, bolus, fractionated, short or long term continuous Infusion) --Combination Therapies --Ancillary services: Clinical Chemistry, Hematology, Drug Concentration, Blood Gases, Surgery, Bioassay, Necropsy, Gross Pathology --Wild-type or genetically modified animals --30 Dedicated FTEs --3 staff veterinarians --Average experience ~15 years METABOLITE IDENTIFICATION In addition to an extensive panel of in vitro metabolism screening assays, Eurofins Panlabs is able to perform studies to thoroughly characterize the products of drug compounds that are extensively metabolized. --Employing state-of the art mass spectrometry instrumentation for sensitive and accurate detection of metabolic products and software tools to efficiently process the complex datasets produced from these analyses. --A comparison of the metabolite profile in multiple species can be used to guide the selection of animal models to use for toxicology studies. --Localizing the site of metabolic transformation of labile compounds makes possible the design and synthesis of additional analogs with improved metabolic stability. Eurofins Cerep SA Le bois l Evêque Celle l Evescault FRANCE T l +33 (0) F l +33 (0) Eurofins Panlabs Inc NE 95th Street Redmond, WA USA T l +1 (425) F l +1 (425) Eurofins Panlabs Taiwan, Ltd. No. 158 Li Teh Road, Peitou Taipei, TAIWAN T l F l CerepPanlabs@eurofins.com
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