Transporters DDI-2018

Similar documents
Strategy on Drug Transporter Investigation Why, How, Which & When. Jasminder Sahi

Stable transfected HEK293-OATP cells for transporter analysis A model system for the assay of drug uptake.

Comparison Between the US FDA, Japan PMDA and EMA In Vitro DDI Guidance: Are we Close to Harmonization?

Welcome to the webinar... We will begin shortly

Use of in vitro cell assays and noninvasive imaging techniques to reduce animal experiments in drug development

Symposium: Target or Avoid?

Complexities of Hepatic Drug Transport: How Do We Sort It All Out?

Evaluation of Drug-Drug Interactions FDA Perspective

Evaluation of Proposed In Vivo Probe Substrates and Inhibitors for Phenotyping Transporter Activity in Humans

MODULE PHARMACOKINETICS WRITTEN SUMMARY

What Can Be Learned from Recent New Drug Applications? A Systematic Review of Drug

Cryo Characterization Report (CCR)

Current and Emerging Transporter Regulatory Themes in Drug Development: Relevance to Understanding PK/PD, DDIs, and Toxicity

FDA s Clinical Drug Interaction Studies Guidance (2017 Draft Guidance)

Current Approaches and Applications of Phenotyping Methods for Drug Metabolizing Enzymes and Transporters

Evaluation and Quantitative Prediction of Renal Transporter-Mediated Drug-Drug Interactions. Bo Feng, Ph.D. DDI 2017 June 19-21, 2017

Exploiting BDDCS and the Role of Transporters

Biopharmaceutics Drug Disposition Classification System (BDDCS) --- Its Impact and Application

ASSESSMENT OF THE ROLE OF SOLUTE CARRIER DRUG TRANSPORTERS IN THE SYSTEMIC DISPOSITION OF FLUOROQUINOLONES: AN IN VITRO - IN VIVO COMPARISON

Interaction of baicalin with transporters

Determinants of Drug Disposition

Building innovative drug discovery alliances. Hepatic uptake and drug disposition o in vitro and in silico approaches

Biochemical and Molecular Toxicology. The Role of Transporters (Phase III) in Xenobiotic Disposition

Role of metabolism in Drug-Induced Liver Injury (DILI) Drug Metab Rev. 2007;39(1):

Regulation of renal drug transport under physiological and pathological conditions

Causes and Consequences of Variability in Drug Transporter Activity in Pediatric Drug Therapy

Predict GENES. Select right drug. Select right dose. Develop new drugs. Non-Response Response Adverse Reaction

Drug-Dietary Supplement Interactions What Have We Learned?

Biopharmaceutics Drug Disposition Classification System (BDDCS) and Its Application in Drug Discovery and Development

Proteomic Quantification of Kidney Transporters: Methodological Challenges, Interindividual Variability and Application in IVIVE

In vitro and in silico Predictions of Hepatic Transporter-Mediated Drug Clearance and Drug-Drug Interactions in vivo

DRUG-DRUG INTERACTIONS OF GLECAPREVIR AND PIBRENTASVIR WITH PRAVASTATIN, ROSUVASTATIN, OR DABIGATRAN ETEXILATE

Pharmacokinetic Determinants of Statin-Induced Myopathy

Publications directly related to the thesis

Prediction of the Effects of Renal Impairment on the Clearance for Organic Cation Drugs that. undergo Renal Secretion: A Simulation-Based Study

Till David och Calle

In Vitro and In Vivo Interaction Studies Between Lesinurad, a Selective Urate Reabsorption Inhibitor, and Major Liver or Kidney Transporters

Pharmacokinetic drug drug interactions of tyrosine kinase inhibitors: A focus on cytochrome P450, transporters, and acid suppression therapy

Drug Drug and Drug Transporter Interactions as Obstacles for Absorption

T Eley, Y-H Han, S-P Huang, B He, W Li, W Bedford, M Stonier, D Gardiner, K Sims, P Balimane, D Rodrigues, RJ Bertz

Detail features... 1

Drug Transport in the Brain: Models of BBB and Brain Parenchyma

Drug Interactions, from bench to bedside

Suitability of Digoxin as a P Glycoprotein Probe: Implications of Other Transporters on Sensitivity and Specificity

HEK293 cells transfected with human MATE1, MATE2-K, or vector control were established by

DRUG METABOLISM AND PHARMACOKINETICS (DMPK) Lena Gustavsson, H. Lundbeck A/S, November 2015

ATP-Binding-Cassette Transporters in Biliary Efflux and Drug-Induced Liver Injury

Classification of Inhibitors of Hepatic Organic Anion Transporting Polypeptides (OATPs): Influence of Protein Expression on Drug Drug Interactions

Supporting information

Interaction of innovative small molecule drugs used for cancer therapy with drug transporters

Efficient Liver Targeting and Uptake by Novel Tenofovir Prodrug, CMX157, For the Treatment of Hepatitis B

Evaluation of Ketoconazole and its Alternative Clinical CYP3A4/5 Inhibitors. as Inhibitors of Drug Transporters: The In Vitro Effects of Ketoconazole,

Matthew D. Hall, NCI PCP 01/03/13

Inhibition of Human Hepatic Bile Acid Transporters as Contributing Factors to Drug-Induced Liver Injury

Supplemental Materials

Pharmacogenetics and Pharmacokinetics

Pharmacologic Considerations when using DAAs in Cirrhosis

Regulation of the cell surface expression and transport capacity of BSEP by small chemical molecules

Overview of Drug in Drug

In vitro substrate-dependent inhibition of OATP1B1 and its impact on DDI prediction

Effect of Multiple-Dose Ketoconazole and the Effect of Multiple-Dose Rifampin on Pharmacokinetics (PK) of the HCV NS3 Protease Inhibitor Asunaprevir

Supporting Information

Transporters and Drug-Drug Interactions: Important Determinants of Drug Disposition and Effects s

Strategies for Developing and Validating PBPK Models for Extrapolation to Unstudied Population

"The Transporter Company" VP, Global Operations & Services

Clinical Pharmacology of DAA s for HCV: What s New and What s in the Pipeline

Itraconazole and Clarithromycin as Ketoconazole Alternatives for Clinical CYP3A Inhibition Studies to Quantify Victim DDI Potential

Investigating Transporter-Mediated Drug-Drug Interactions Using a Physiologically Based Pharmacokinetic Model of Rosuvastatin

Models of the Choroid Plexus Epithelium

Erik Mogalian, Polina German, Chris Yang, Lisa Moorehead, Diana Brainard, John McNally, Jennifer Cuvin, Anita Mathias

Falk Symposium 156: Genetics in Liver Disease. Pharmacogenetics. Gerd Kullak-Ublick

DARUNAVIR/COBICISTAT MODULE PHARMACOKINETICS WRITTEN SUMMARY

PBPK modeling of renal impairment what is missing?

Examining the Basis of Drug-Drug Interaction (DDI) Labeling Recommendations for Antiviral Approvals from 1998 to 2015

Drug Absorption and Bioavailability

Drug Absorption and Bioavailability

Critical review of the literature on drug interactions

Intracellular Drug Concentrations and Transporters: Measurement, Modeling, and Implications for the Liver

Drug Interactions Year 2 Clinical Pharmacology

Importance of Multi-P450 Inhibition in Drug Drug Interactions: Evaluation of Incidence, Inhibition Magnitude, and Prediction from in Vitro Data

REVIEW Xenobiotic Transporters: Ascribing Function from Gene Knockout and Mutation Studies

Investigation of Probe Substrates to Assess Hepatic Transport Function. Brandon Swift

Impact of Drug Transporter Studies on Drug Discovery and Development

Summary of the risk management plan (RMP) for Sirturo (bedaquiline)

Pharmacological determinants of long-term treatment success

Review of Transporter-Related Postmarketing Requirement or Postmarketing Commitment Studies

Culture Hepatocytes in Human Plasma to Count the free Concentration of Drug in Evaluation of Drug-drug Interaction. Chuang Lu

WHY... 8/21/2013 LEARNING OUTCOMES PHARMACOKINETICS I. A Absorption. D Distribution DEFINITION ADME AND THERAPEUIC ACTION

DMPK. APRIL 27 TH 2017 Jan Neelissen Scientific Adviser Science & Technology

Bristol-Myers Squibb HCV DAAs: Review of Interactions Involving Transporters. Timothy Eley. 21 May 2014

Summary of the risk management plan (RMP) for Intuniv (guanfacine)

Objectives Making CYP450, Drug Interactions, & Pharmacogenetics Easy

Challenges. Benefits. Control of viral load in plasma. Drug-drug interactions. Adverse effects/drug toxicities. Delay in HIV drug resistance

Mechanistic Modeling of Pitavastatin Disposition in Sandwich-Cultured Human Hepatocytes: A Proteomics-Informed Bottom-Up Approach s

Cytochrome P450 Suppression in Human Hepatocyte Cultures by Small and Large Molecules. George Zhang, Ph.D. April 18, 2012

Fundamentals of Membrane Transporters and their Role in In Vivo PK/PD of Drugs

Pursuing the holy grail of predicting and verifying tissue drug concentrations: A proteomics and PET imaging approach

What s All the Flux About? An Industrial Perspective on the Drug Transporter Whitepaper and Recent Regulatory Guidances. Joseph W. Polli, Ph.D.

Cytochrome P450 Drug Interaction Table Flockhart Table

12/9/2015. Drug Interactions. Sarah Robertson, Pharm.D. Director, Department of Clinical Pharmacology Vertex Pharmaceuticals Inc.

Transcription:

Transporters DDI-2018 Mark S. Warren, Ph.D. June 16, 2018 Senior Director of Assay Services

DDI-2018: 21 st Conference on DDIs FDA guidance documents: A 21 year history 1997 2006 2012 2017 Each year, large numbers of new drugdrug interactions are discovered, precluding the possibility that any prescriber could memorize them all. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) September 2006 Clinical Pharmacology Transporter-based interactions have been increasingly documented. Examples of these include the inhibition or induction of transport proteins, such as P-glycoprotein (P-gp), organic anion transporter (OAT), organic anion transporting polypeptide (OATP), organic cation transporter (OCT), multidrug resistance-associated proteins (MRP), and breast cancer resistant protein (BCRP). The role of transporters in drug interactions should be evaluated. Membrane transporters can have clinically relevant effects on the pharmacokinetics and pharmacodynamics of a drug in various organs and tissues by controlling its absorption, distribution, and elimination 2

Regulatory Guidance on Transporter DDIs Transporter DDI studies are now expected by global regulatory agencies FDA draft (2017) EMA (2012) PMDA draft (2013) Understanding the effect of a NME (drug) on induction and inhibition of both enzymes and transporters is crucial in determining appropriate labelling language, and in the safe and effective use of the NME (drug). J. Woodcock, Director of CDER/FDA & S.M.Huang, Deputy Director of OCP, CDER/FDA 3

Drug-Drug Interactions (DDIs) Among Americans 60 or over, 76% used two or more prescription drugs, 64% used 3 or more, and 37% used 5 or more. CDC, NCHS Data brief #42, Sept. 2010 4

Which Transporters Are the Regulatory Agencies Most Focused On? Transporter P-gp (MDR1) BCRP OATP1B1 OATP1B3 BSEP * OCT1 * OAT1 OAT3 OCT2 MATE1 MATE2-K Gene ABCB1 ABCG2 SLCO1B1 SLCO1B3 ABCB11 SLC22A1 SLC22A6 SLC22A8 SLC22A2 SLC47A1 SLC47A2 Expression liver, kidney, intestine liver, kidney, intestine liver liver liver liver, intestine kidney kidney kidney kidney kidney * BSEP and OCT1 studies are recommended by the EMA, but not by the FDA 5

Optivia Biotechnology: Transporter Assays Liver transporters Transporter Gene Probe substrate Reference inhibitor OATP1B1 SLCO1B1 E17bGlu rifampicin OATP1B3 SLCO1B3 CCK8 rifampicin P-gp ABCB1 quinidine elacridar BCRP ABCG2 prazosin Ko143 BSEP ABCB11 taurocholate rifampicin OCT1 SLC22A1 MPP+ quinidine MATE1 SLC47A1 metformin cimetidine Kidney transporters Transporter Gene Probe substrate Reference inhibitor OAT1 SLC22A6 PAH probenecid OAT3 SLC22A8 E3S probenecid OCT2 SLC22A2 metformin quinidine MATE1 SLC47A1 metformin cimetidine MATE2-K SLC47A2 metformin cimetidine P-gp ABCB1 quinidine elacridar BCRP ABCG2 prazosin Ko143 6

Optivia Biotechnology: Transporter Assays Liver transporters Transporter Gene Probe substrate Reference inhibitor OATP1B1 SLCO1B1 E17bGlu rifampicin OATP1B3 SLCO1B3 CCK8 rifampicin P-gp ABCB1 quinidine elacridar BCRP ABCG2 prazosin Ko143 BSEP ABCB11 taurocholate rifampicin OCT1 SLC22A1 MPP+ quinidine MATE1 SLC47A1 metformin cimetidine MRP2 ABCC2 E17bGlu benzbromarone NTCP SLC10A1 taurocholate chenodeoxycholate OATP2B1 SLCO2B1 E3S BSP MRP3 ABCC3 E17bGlu benzbromarone MRP4 ABCC4 E17bGlu benzbromarone OCT3 SLC22A3 metformin quinidine OAT2 SLC22A7 cgmp indomethacin ENT1 SLC29A1 adenosine NBMPR ENT2 SLC29A2 hypoxanthine adenosine CNT2 SLC28A2 uridine adenosine Kidney transporters Transporter Gene Probe substrate Reference inhibitor OAT1 SLC22A6 PAH probenecid OAT3 SLC22A8 E3S probenecid OCT2 SLC22A2 metformin quinidine MATE1 SLC47A1 metformin cimetidine MATE2-K SLC47A2 metformin cimetidine P-gp ABCB1 quinidine elacridar BCRP ABCG2 prazosin Ko143 MRP2 ABCC2 E17bGlu benzbromarone OCT3 SLC22A3 metformin quinidine MRP3 ABCC3 E17bGlu benzbromarone MRP4 ABCC4 E17bGlu benzbromarone MRP1 ABCC1 E17bGlu benzbromarone OAT2 SLC22A7 cgmp indomethacin OAT4 SLC22A11 E3S indomethacin OCTN1 SLC22A4 ergothioneine verapamil OCTN2 SLC22A5 carnitine verapamil OATP1A2 SLCO1A2 E3S BSP SGLT2 SLC5A2 Me-D-glucopyranoside phloridzin ASBT SLC10A2 taurocholate chenodeoxycholate URAT1 SLC22A12 uric acid benzbromarone PEPT1 SLC15A1 GlySar Losartan PEPT2 SLC15A2 GlySar Losartan ENT1 SLC29A1 adenosine NBMPR ENT2 SLC29A2 hypoxanthine adenosine CNT1 SLC28A1 uridine adenosine CNT2 SLC28A2 uridine adenosine CNT3 SLC28A3 uridine adenosine 7

Optivia Biotechnology: Now With 100+ Transporter Assays 8

% of control Transport rate (pmoles/min/cm 2 ) OCT1 mediated transport (pmoles/cm 2 ) MPP+ transport rate (pmoles/min/cm 2 ) Transport rate (pmoles/min/cm 2 ) Rigorous Assay Characterization and Validation 40 30 Assay robustness and consistency (average FOA: 32.2x, CV: 15.8%) OCT1 Mock control 140 120 100 80 OCT1 Mock control 20 60 40 10 20 0 0 Fig 1. Inter- and intra-day variability for OCT1 assay Fig 2. Transport of multiple substrates by OCT1 60 50 50 40 40 30 20 10 K m = 37.8 ± 11.0 µm 30 20 10 r 2 = 0.974 0 0 20 40 60 80 100 MPP+ [µm] Fig 3. Kinetics of OCT1 mediated MPP + uptake 0 0 2 4 6 8 10 Time (min) Fig 4. Time course of OCT1 mediated MPP + uptake 120 100 80 60 40 20 0 1 10 100 1000 Inbibitor concentration [µm] Cimetidine Qunidine Verapamil IC 50 = 569 ± 210 µm IC 50 = 88.8 ± 11.1 µm IC 50 = 18.9 ± 1.5 µm 9

MATE assays Efflux transporters, even though they are SLC transporters. Can be difficult to measure as efflux transporters, as the substrates are generally low permeability polar compounds. 10

MATE assays MATEs are organic cation/h+ antiporters. By artificially creating an outward flow of protons (acidifying the cells), MATEs can be studied as uptake transporters as opposed to efflux transporters. Pre-treat cells with 20mM NH 4 Cl prior to assay H + H + H + 11

MATE assays To simplify assays, the ph gradient is flipped either by acidifying the inside of the cells (NH 4 Cl pretreatment) or by using a high ph buffer outside of the cells. By doing this, the MATEs function as uptake transporters. H + H + H + Or H +? H + H + But is this the best way to assay? 12

Directional Asymmetry of MATE1 Mediated Transport MATE1 is much more efficient as an efflux transporter than as an uptake transporter Zhang et al., ISSX poster P437 (2014) 13

Multi-Transporter Assays Unique multiple-transporter models Allows studies of MATE transporters in their efflux mode Creatinine renal secretion model 14

Established Leader in Transporter Studies The world s largest portfolio of transporter assays 100 transporter assays and models Unique multi-transporter expressing models Ability of integrating transporter and CYP enzyme Transporter panels for specific tissues and diseases FDA/EMA/PMDA-compliant transporter mediated DDI studies FDA approved study protocol FDA&EMA approved submissions Certified PMDA data integrity compliance Extensive experience and in-depth expertise The first provider of FDA transporter DDI panel 400+ customers worldwide 1000+ client sponsored transporter studies (ranging from discovery phase to PMS) Free technical consultation on regulatory DDI and complex drug disposition studies Solid reputation and customer satisfaction A proud winner of Reliability, Regulatory and Accessibility, for customer rated excellence in Productivity, 15

Service and Product Offerings Transporter assay services Regulatory: FDA/EMA/PMDA-compliant DDI studies Mechanistic: complex ADME/Tox MOA studies Discovery: early-stage transporter inhibitor/substrate screening Customized assay/model development Transporter assay products TransFlex TM assay-ready transporter plates Certified GenoMembrane TM efflux transporter vesicles Others capabilities CYP DDI studies (through partnership) CYP Induction CYP inhibition Rxn Phenotyping Protein binding, transporter expression analysis, cytotoxicity assay, etc. 16

Transporter Research Solutions by Application Opti-DDI Definitive assessment of DDI liability for regulatory submission Opti-Discovery Opti-Safety Opti-ADME Screen against transporters as therapeutic targets Identify safety liabilities of compounds by screening against toxicity related transporters Augment the rational design of compounds or pro-drugs that target specific transporters for improved bioavailability, PK profile and tissue targeting 17

Contact Jeffrey Oakes 617-244-0055 joakes@optiviabio.com Yong Huang, Ph.D. (510) 206-3407 yhuang@optiviabio.com Or visit us at www.optiviabio.com 18

Thank you! info@optiviabio.com 1-650-324-3177 19

2024 © healthdocbox.com Privacy Policy | Terms of Service | Feedback