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

Size: px
Start display at page:

Download "Strategy on Drug Transporter Investigation Why, How, Which & When. Jasminder Sahi"

Transcription

1 Strategy on Drug Transporter Investigation Why, How, Which & When Jasminder Sahi

2 Intestine Drug Absorption PEPT1 OATPs MCTs AE2 Epithelial Cell MCTs MRP3 Liver Excretion via Liver Kidney MRPs OATPs N PT1 PEPTs OCTN MATE OATs OCTs Blood MRP1,3,6 OATPs NTCP OATs NPT1 Vascular site MRP2 BSEP Hepatocyte Biliary tract site Excretion via Kidney MRP1,4,5 Blood-Brain Barrier OATs OCTNs Capillary vessel endothelial cell Brain Cancer Cells MRP2

3 Tissue distribution studies (rat QWBA A) Drugs are differentially distributed Vd = 3 L/kg Good general distribution Vd = 6 L/kg Good general distribution Very poor CNS penetration Pgp Substrate Vd = 1.2 L/kg Low general distribution Very high liver concentrations OATP1B1 Substrate

4 CNS efflux/uptake Pgp, OAT3, MRP1, Drug Cardiac efflux/uptake Pgp,, MRP2-5, OCTN1, OATP2B1 CNS Influx CNS Efflux Lung efflux/up Pgp, OCTN, oth Hepatic Efflux Hepatic Uptake Biliary Secretion Renal Secretion Renal up OAT1, OA OCT2, O Renal secretio Pgp, MR OAT4, OC MATE1/ Pgp, MDR3, MRP2, BSEP Intestinal Absorption Intestinal uptake OATP1A2, OATP2B1, PEPT-1, MRP3 Intestinal Secretion Renal reabsorption Intestinal efflux Pgp, MRP2, Renal re-upta OATP2B PEPT-2 URAT1

5 -Transporter Involvement in Disposition of a Drug Effects of SLCO1B1, ABCG2 & ABCB genotypes on systemic exposure of various statins. N.B. There are additional roles pl by drug metabolism enzymes for each statin. (2010) CPT 87:130

6 % (21/88) submitted with Transport er data % (53/95) submitted with Transport er data % (20/24) submitted with Transporter data 30%Labels with Transporter info 4/24 large molecu 100% of small molecule NDAs transporter data 2013

7 -Drug Interactions Because Transporter mediated DDI can cause problems Polypharmacy is common

8 3 DDI/NDA No Transporter studies 12 DDI/NDA P-gp Transporter Studies based on PK changes DDI studies/nda 7 Transporters In vitro DDI Follow-up clinical PK studies PBPK NMEs approve between

9 Object Precipitant % Change in AUC cyclosporine cyclosporine cyclosporine gemfibrozil cyclosporine cyclosporine rifampin lopinavir & ritonavir cyclosporine rifampin erythromycin rifampin cyclosporine rifampin & Transporter Drug Interaction Database-Univ of Washington OATPs NOT the only transporters involved Drug metabolizing enzymes involved as well Transporter DDI can extend Transporters and Enzymes OATP1B1, MRP2, OAT3, OATP1B1, OATP1B3, P-gp, CYP3A4 OATP1B1, P-gp,, CYP3A4, UGT1A1/3 OATP1B1, CYP3A4, CYP2C8 OATP1B1, CYP3A4 OATP1B1, OATP1B3,, CYP2C9, UGT1A1, UGT OATP1B1, UGT OATP1B1, OATP1B3, CYP3A4, CYP2C9 OATP1B1, P-gp, CYP2C8, CYP3A4, UGT1A1/3 OATP1B1, OAT1, CYP3A4 OATP1B1, CYP3A4 OATP1B1/3, P-gp, CYP3A4 OATP1B1, CYP3A4, CYP3A5, CYP2C9, CYP2C8, CY OATP1B1/3, P-gp, CYP3A4 to endogenous substrates

10 CI-1034 Endothelin A receptor antagonist No significant preclinical hepatotoxicity in rat or dog Linear PK in clinic Pharmacologically very active for pulmonary hypertension O O Et CO 2 H O S F F N O F

11 -1034 on Plasma Bile Acids in Phase I Clinical Trials Day 42: ALT 1.2 ULN AST 1.7 ULN Bil 1.8 mg/dl Placebo ALT 1.2 AST 1.4 Bil 3.3 No day Day 42: ALT 7ULN AST 5ULN Bil h 12 hr Day 1 Day 4 0 h 1 h 12 h Day 14

12 Taurocholate Uptake by CI-1034 in Primary % Taurochol late Uptake Cyclosporin A CI-1034 Glyburide Salicylic acid

13 Taurocholate Canalicular Efflux in Primary Hepatocytes 120 % Taurocho olate Efflux % Inhibition Cyclosporin A CI-1034 Glyburide (mm) Rose, Pfizer

14 -1034 on OATP Transporters OATP2B1 OATP1B1 OATP1B /BSP Uptake K i : 3.3 mm 2..0 mm 1.8 mm 1/BSP Uptake CI-1034 (µm) CI-1034 (µm) CI-1034 (µm) /BSP Uptake 0.1( ), 0.2( ) and 0.8( )µm DeMorais

15 -1034 Transporter Mediated O O Et CO 2 H 20% O N S F O F F O O Et CO 2 H O O Et BSEP S N CO 2 H O F O F F 80% O N S F O F F Inhibition of BSEP can contribute to cholestasis Inhibition of NTCP & OATP1B1 can contribute to increased bile salts in circulation

16 Intestine Drug Absorption PEPT1 OATPs MCTs AE2 Epithelial Cell MCTs MRP3 Liver Excretion via Liver Kidney MRPs OATPs N PT1 PEPTs OCTN MATE OATs OCTs Blood MRP1,3,6 OATPs NTCP OATs NPT1 Vascular site MRP2 BSEP Hepatocyte Biliary tract site Excretion via Kidney MRP1,4,5 Blood-Brain Barrier OATs OCTNs Capillary vessel endothelial cell Brain Cancer Cells MRP2

17 A -MDCKII Cells Pgp is expressed on apical (A) surface A B Assay B B-to-A/A-to-B = Efflux Ratio lines (Caco-2, MDCK, LLCPK1) expressed on apical membrane ABC Transporters: Inside out Vesicles (su assay-atp) In Vivo Models Knock Out Animal Model Chemical Inhibitors Primary Cells (hepatocytes etc)

18 Efflux Uptake ATPase assay ABC Transporter Cell SLC Transporter Inside-out Vesicle ABC Transporter ATP ADP+PO 4 2- Membrane

19 Single Transfection Double Transfection

20 for Transporter Studies Bile canaliculus

21 ols for Uptake Transporters tably / transiently transfected cell lines (HEK-293, MDCK, LLCPK) Do not have to be polarized Vesicles Primary Cells (hepatocytes etc) Single/ Double transfectant Wild-type vs transfected or +/- inhibitor(s) more transporter-specific data In Vivo Models Knock Out Animal M Chemical Inhibitors

22 uptake in vitro Tools Transfected cell lines Cryopreserved Hepatocytes with Pitavasta Hepatocytes Parallel studies at 37 C and 4 C Specific inhibitors Single Cocktail

23 Uptake Mechanism Is it Active or Passive? Evaluate in human hepatocytes Plated or suspension Active Likely to see impact (~3.3 fold change) when active > 70% > 50% Passive No additional work > 50-70% Overexpressed cell lines Evaluate OATP1B1&1B3

24 Induction Study Design for P-gp 0.25 mg oral dose Digoxin Single 0.25 mg oral dose Day 10 Day 2 to Day 10: Avasimibe 50 mg dose (8 subjects) 750 mg dose (8 subjects) - 16 healthy volunteers, cross-over design - Second dose of dogoxin administered at steady state of Avasimibe - PK for digoxin for 16 hours after each dose (Day 1 and Day 10)

25 HICH?? is more clearly defined Intestine Drug Absorption PEPT1 OATPs MCTs AE2 Epithelial Cell MCTs MRP3 Excretion via Liver Liver MRPs OATPs Vascular site OATs MRP1,3,6 OATPs N PT1 Kidney MRP2 NTCP PEPTs OCTN MATE OCTs Blood Biliary tract site Hepatocyte MRP1,4,5 Blood-Brain Barrier BSEP NPT1 Excretion via Kidney OATs MRP2 Brain OATs OCTNs Capillary vessel endothelial cell Cancer Cells

26 outes of Clearance

27 Uptake Efflux A and EMA Guidance on Transporters Inhibition studies Transporter Substrate studies EMA FDA EMA* FDA P-gp () BSEP MRPs OATP1B1 yes yes prefer no yes yes yes yes yes yes OATP1B3 yes yes 25% of elimination hepatic OCT1 no OAT1 yes yes OAT3 yes yes 25% of total clearance is hepa or biliary no 25% of total clearance is acti renal 25% of total clearance is acti renal OCT2 yes yes MATE1 MATE2

28 idance on Renal Transporters TEs gaining importance MA renal (...) secretion separately is estimated to account for more than 25% of drug elimination, empts should be made to identify the transporters involved in active secretion A. investigational drugs should be evaluated in vitro to determine whether they are a substrate of T1/3 and OCT2 when their renal active secretion is important (active secretion >25% of total arance) C.incorporate MATEs into existing OCT2 decision trees MDA r investigational drugs of which renal secretion is major (total clearance of the renal elimination is re than 25% of whole body clearance), the possibility that the drug may be a substrate of OAT1, T3, OCT2, MATE1 and MATE2-K should be studied. studied

29 off values that Trigger Clinical linical DDI Studies DA EMA Pgp/ Pgp/ Total Cmax/IC50 > 0.1 I2/IC50 > 10 Ki < 0.1x dose/250 ml ( = I2) OATPs, OATs, OCTs, MATEs OATPs Total Cmax/IC50 > 0.1 OATs and OCT2/MATEs Unbound Cmax/IC50 > 0.1 Ki < 25x [I]u, inlet,max or Ki < 50x unbound Cmax

30 HEN?? pends on so many factors Intestine Drug Absorption PEPT1 OATPs MCTs AE2 Epithelial Cell MCTs MRP3 Excretion via Liver Liver MRPs OATPs Vascular site OATs MRP1,3,6 OATPs N PT1 Kidney MRP2 NTCP PEPTs OCTN MATE OCTs Blood Biliary tract site Hepatocyte MRP1,4,5 Blood-Brain Barrier BSEP NPT1 Excretion via Kidney OATs MRP2 Brain OATs OCTNs Capillary vessel endothelial cell Cancer Cells

31 ug Transporter Assessment Strategy Discovery to First Time In Human (FTIH) CLINICAL STRATEGY herapeutically aligned co-meds target delivery roduct Profile evelopment Plan hysicochemical properties FTIH to Proof of Concept (POC) POC to New Drug Application (NDA)/Marketing TRANSLATION UNDERSTANDING Pharmacokinetics Drug labeling Non-clinical mechanistic and/or investigative studies Clinical Studies Safety PMC Non-clinical clinical studies (in ( vitro and in vivo) Clinical Studies are no agreed timings for transporter studies, they should be driven by the clinical plan, which therapeutic area, co-medications medications and the patient population

32 mmary of Role of Drug Transporters in ADME rug transporters play a significant role in ADME as effective barriers to drug exposure the rate determining step in uptake and/or excretion of a compound or metabolite mediators of drug interactions via inhibition or induction In drug discovery (development) it is important to identify key drug transporters (and their genetic variants) elucidate their role in disposition of a compound establish robust transport assays ultiple transporters from theabc & SLC families likely influence the disposition of a drug eviews Drug Discovery 9, , (2010)

33 o Keep in Mind ift in study conduct paradigm ITC White Papers and 2013 DDI guidance documents Group assays based on tissue based approach Area still evolving. Focus on your patient population Transporter data can be generated in Phase III to help draft drug label. tend interactions around clinical safety Biomarkers (e.g. bile salts), clinical chemistry to address these in the moment (e.g. BSEP, OCT..) chanistic Modeling integral for understanding and extrapolation ransporter and enzyme in vitro data. Expected by all agencies along with details of the extrapolation nsporter Assay Validation Questions uestions by agencies around the details of in vitro assays and controls

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

Comparison Between the US FDA, Japan PMDA and EMA In Vitro DDI Guidance: Are we Close to Harmonization? Comparison Between the US FDA, Japan PMDA and EMA In Vitro DDI Guidance: Are we Close to Harmonization? Brian Ogilvie, Ph.D. VP Scientific Consulting XenoTech, LLC bogilvie@xenotechllc.com 14 Jun, 2018

More information

Transporters DDI-2018

Transporters DDI-2018 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

More information

Exploiting BDDCS and the Role of Transporters

Exploiting BDDCS and the Role of Transporters Exploiting BDDCS and the Role of Transporters (Therapeutic benefit of scientific knowledge of biological transporters, understanding the clinical relevant effects of active transport on oral drug absorption)

More information

Welcome to the webinar... We will begin shortly

Welcome to the webinar... We will begin shortly Welcome to the webinar... We will begin shortly Evaluation of Ketoconazole and Its Alternative Clinical CYP3A4/5 Inhibitors as Inhibitors of Drug Transporters: The In Vitro Effects of Ketoconazole, Ritonavir,

More information

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

Complexities of Hepatic Drug Transport: How Do We Sort It All Out? Complexities of Hepatic Drug Transport: How Do We Sort It All Out? Keith A. Hoffmaster Pfizer Research Technology Center Cambridge, MA NEDMDG 2005 Summer Symposium 06.08.2005 The Challenge Intestinal uptake

More information

Evaluation of Drug-Drug Interactions FDA Perspective

Evaluation of Drug-Drug Interactions FDA Perspective Evaluation of Drug-Drug Interactions FDA Perspective Kellie Schoolar Reynolds, Pharm.D. Deputy Director Division of Clinical Pharmacology IV Office of Clinical Pharmacology Office of Translational Sciences

More information

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

FDA s Clinical Drug Interaction Studies Guidance (2017 Draft Guidance) FDA s Clinical Drug Interaction Studies Guidance (2017 Draft Guidance) Kellie S. Reynolds, Pharm.D. Deputy Director, Division of Clinical Pharmacology IV Office of Clinical Pharmacology (OCP) Office of

More information

Cryo Characterization Report (CCR)

Cryo Characterization Report (CCR) Human Cryopreserved Hepatocytes Lot number: HUM4061B Date: October 19, 2014 Cryo Characterization Report (CCR) Lot Overview Qualification Catalog Number Quantity Cryopreserved human hepatocytes, Qualyst

More information

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

Stable transfected HEK293-OATP cells for transporter analysis A model system for the assay of drug uptake. Stable transfected HEK293-OATP cells for transporter analysis A model system for the assay of drug uptake. PRIMACYT Cell Culture Technology GmbH, Hagenower Str. 73, D-19061 Schwerin, Germany E-mail: info@primacyt.com,

More information

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

Itraconazole and Clarithromycin as Ketoconazole Alternatives for Clinical CYP3A Inhibition Studies to Quantify Victim DDI Potential Itraconazole and Clarithromycin as Ketoconazole Alternatives for Clinical CYP3A Inhibition Studies to Quantify Victim DDI Potential Alice Ban Ke, Ph.D. Consultant & Scientific Advisor Simcyp Limited Alice.Ke@certara.com

More information

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

Current and Emerging Transporter Regulatory Themes in Drug Development: Relevance to Understanding PK/PD, DDIs, and Toxicity Current and Emerging Transporter Regulatory Themes in Drug Development: Relevance to Understanding PK/PD, DDIs, and Toxicity Maciej Zamek-Gliszczynski, Ph.D. 1940 s Probenecid & anion secretion 1950 s

More information

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

Biopharmaceutics Drug Disposition Classification System (BDDCS) and Its Application in Drug Discovery and Development Biopharmaceutics Drug Disposition Classification System (BDDCS) and Its Application in Drug Discovery and Development Leslie Z. Benet, Ph.D. Professor of Bioengineering and Therapeutic Sciences University

More information

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

Regulation of the cell surface expression and transport capacity of BSEP by small chemical molecules Regulation of the cell surface expression and transport capacity of by small chemical molecules Hisamitsu Hayashi and Yuichi Sugiyama Dept. of Molecular Pharmacokinetics, Graduate School of Pharmaceutical

More information

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

Evaluation of Proposed In Vivo Probe Substrates and Inhibitors for Phenotyping Transporter Activity in Humans Supplement Article Evaluation of Proposed In Vivo Probe Substrates and Inhibitors for Phenotyping Transporter Activity in Humans The Journal of Clinical Pharmacology (2016), 56(S7) S82 S98 C 2016, The

More information

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

Inhibition of Human Hepatic Bile Acid Transporters as Contributing Factors to Drug-Induced Liver Injury Inhibition of Human Hepatic Bile Acid Transporters as Contributing Factors to Drug-Induced Liver Injury Kenneth R. Brouwer, Ph.D., RPh Chief Scientific Officer DDI Meeting June 2017 Seattle, Washington

More information

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

Biopharmaceutics Drug Disposition Classification System (BDDCS) --- Its Impact and Application Biopharmaceutics Drug Disposition Classification System (BDDCS) --- Its Impact and Application Leslie Z. Benet, Ph.D. Professor of Bioengineering and Therapeutic Sciences Schools of Pharmacy and Medicine

More information

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

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 IN VIVO AND IN VITRO ASSESSMENT OF ASUNAPREVIR (ASV; BMS-650032) AS AN INHIBITOR AND SUBSTRATE OF ORGANIC ANION TRANSPORT POLYPEPTIDE (OATP) TRANSPORTERS IN HEALTHY VOLUNTEERS T Eley, Y-H Han, S-P Huang,

More information

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

Erik Mogalian, Polina German, Chris Yang, Lisa Moorehead, Diana Brainard, John McNally, Jennifer Cuvin, Anita Mathias Evaluation of Transporter and Cytochrome P450-Mediated Drug-Drug Interactions Between Pan-Genotypic HCV NS5A Inhibitor GS-5816 and Phenotypic Probe Drugs Erik Mogalian, Polina German, Chris Yang, Lisa

More information

Drug Interactions, from bench to bedside

Drug Interactions, from bench to bedside Drug Interactions, from bench to bedside Candidate to Market, The Paterson Institute for Cancer Research, Manchester, UK Michael Griffin PhD Overview of presentation To understand the importance of drug-drug

More information

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

What Can Be Learned from Recent New Drug Applications? A Systematic Review of Drug Title What Can Be Learned from Recent New Drug Applications? A Systematic Review of Drug Interaction Data for Drugs Approved by the U.S. FDA in 2015 Jingjing Yu, Zhu Zhou, Katie H. Owens, Tasha K. Ritchie,

More information

MODULE PHARMACOKINETICS WRITTEN SUMMARY

MODULE PHARMACOKINETICS WRITTEN SUMMARY MODULE 2.6.4. PHARMACOKINETICS WRITTEN SUMMARY m2.6.4. Pharmacokinetics Written Summary 2013N179518_00 TABLE OF CONTENTS PAGE 1. BRIEF SUMMARY...4 2. METHODS OF ANALYSIS...5 3. ABSORPTION...6 4. DISTRIBUTION...7

More information

Critical review of the literature on drug interactions

Critical review of the literature on drug interactions Critical review of the 2015-2016 literature on drug interactions Katie Owens, BPharm PhD Research Scientist II Drug Interaction Database (DIDB) Program Dept. of Pharmaceutics University of Washington 19

More information

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

Clinical Pharmacology of DAA s for HCV: What s New and What s in the Pipeline Clinical Pharmacology of DAA s for HCV: What s New and What s in the Pipeline Anita Mathias, PhD Clinical Pharmacology, Gilead Sciences 14 th Int. Workshop on Clinical Pharmacology of HIV Therapy April

More information

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

Use of in vitro cell assays and noninvasive imaging techniques to reduce animal experiments in drug development Use of in vitro cell assays and noninvasive imaging techniques to reduce animal experiments in drug development J. Jia, M. Keiser, S. Oswald, W. Siegmund Department of Clinical Pharmacology, Ernst-Moritz-Arndt

More information

The Future of In Vitro Systems for the Assessment of Induction and Suppression of Enzymes and Transporters

The Future of In Vitro Systems for the Assessment of Induction and Suppression of Enzymes and Transporters The Future of In Vitro Systems for the Assessment of Induction and Suppression of Enzymes and Transporters AAPS, San Diego November 6 th, 2014 Andrew Parkinson, XPD Consulting Lisa Almond, Simcyp-Certara

More information

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

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

More information

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

DRUG METABOLISM AND PHARMACOKINETICS (DMPK) Lena Gustavsson, H. Lundbeck A/S, November 2015 DRUG METABOLISM AND PHARMACOKINETICS (DMPK), H. Lundbeck A/S, LEGU@lundbeck.com November 2015 DMPK in Drug Discovery and Development Agenda Introduction Optimizing pharmacokinetic properties Absorption

More information

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

Suitability of Digoxin as a P Glycoprotein Probe: Implications of Other Transporters on Sensitivity and Specificity Review Suitability of Digoxin as a P Glycoprotein Probe: Implications of Other Transporters on Sensitivity and Specificity The Journal of Clinical Pharmacology XX(XX) 1 11 2013, The American College of

More information

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

Building innovative drug discovery alliances. Hepatic uptake and drug disposition o in vitro and in silico approaches Building innovative drug discovery alliances Hepatic uptake and drug disposition o in vitro and in silico approaches Dr Beth Williamson Evotec AG, 2017 Outline Importance of predicting clearance In vitro

More information

Caveat: Validation and Limitations of Phenotyping Methods for Drug Metabolizing Enzymes and Transporters

Caveat: Validation and Limitations of Phenotyping Methods for Drug Metabolizing Enzymes and Transporters Caveat: Validation and Limitations of Phenotyping Methods for Drug Metabolizing Enzymes and Transporters Uwe Fuhr, University Hospital Cologne 1 How to Safeguard that Metrics Reflect E/T Activity? in healthy

More information

PBPK modeling of renal impairment what is missing?

PBPK modeling of renal impairment what is missing? PBPK modeling of renal impairment what is missing? Aleksandra Galetin Centre for Applied Pharmacokinetic Research, University of Manchester, UK Outline of the presentation Physiological changes in renal

More information

RISK FACTORS AND DRUG TO STATIN-INDUCED MYOPATHY

RISK FACTORS AND DRUG TO STATIN-INDUCED MYOPATHY RISK FACTORS AND DRUG INTERACTION PREDISPOSING TO STATIN-INDUCED MYOPATHY Assist. Prof. Dr. Verawan Uchaipichat Clinical Pharmacy Department Khon Kaen University Advanced Pharmacotherapy 2012 Updated d

More information

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

Current Approaches and Applications of Phenotyping Methods for Drug Metabolizing Enzymes and Transporters Current Approaches and Applications of Phenotyping Methods for Drug Metabolizing Enzymes and Transporters Uwe Fuhr, University Hospital Cologne 1 Definition Phenotyping is quantifying the in vivo activity

More information

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

In vitro and in silico Predictions of Hepatic Transporter-Mediated Drug Clearance and Drug-Drug Interactions in vivo Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 193 In vitro and in silico Predictions of Hepatic Transporter-Mediated Drug Clearance and Drug-Drug Interactions in

More information

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

WHY... 8/21/2013 LEARNING OUTCOMES PHARMACOKINETICS I. A Absorption. D Distribution DEFINITION ADME AND THERAPEUIC ACTION PHARMACOKINETICS I Absorption & Distribution LEARNING OUTCOMES By the end of the lecture students will be able to.. Dr Ruwan Parakramawansha MBBS, MD, MRCP(UK),MRCPE, DMT(UK) (2013/08/21) Define pharmacokinetics,

More information

Interaction of baicalin with transporters

Interaction of baicalin with transporters Interaction of baicalin with transporters PhD thesis Kalaposné Kovács Bernadett Semmelweis University Doctoral School of Pharmaceutical Sciences Supervisor: External Consultant: Official reviewers: Dr.

More information

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

Culture Hepatocytes in Human Plasma to Count the free Concentration of Drug in Evaluation of Drug-drug Interaction. Chuang Lu Culture Hepatocytes in Human Plasma to Count the free Concentration of Drug in Evaluation of Drug-drug nteraction Chuang Lu Millennium, The Takeda Oncology Company Cambridge, MA, USA DD 205, Seattle, 6/29/205

More information

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

Pharmacokinetic drug drug interactions of tyrosine kinase inhibitors: A focus on cytochrome P450, transporters, and acid suppression therapy Received: 1 March 2016 Revised: 4 July 2016 Accepted: 4 July 2016 DOI: 10.1002/hon.2335 REVIEW Pharmacokinetic drug drug interactions of tyrosine kinase s: A focus on cytochrome P450, transporters, and

More information

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

Pursuing the holy grail of predicting and verifying tissue drug concentrations: A proteomics and PET imaging approach Pursuing the holy grail of predicting and verifying tissue drug concentrations: A proteomics and PET imaging approach Jashvant (Jash) Unadkat Milo Gibaldi Endowed Professor Dept. of Pharmaceutics School

More information

Physiologically-Based Simulation of Daclatasvir Pharmacokinetics With Antiretroviral Inducers and Inhibitors of Cytochrome P450 and Drug Transporters

Physiologically-Based Simulation of Daclatasvir Pharmacokinetics With Antiretroviral Inducers and Inhibitors of Cytochrome P450 and Drug Transporters Physiologically-Based Simulation of Daclatasvir Pharmacokinetics With Antiretroviral Inducers and Inhibitors of Cytochrome P450 and Drug Transporters Qi Wang, Wenying Li, Ming Zheng, Timothy Eley, Frank

More information

Supplemental material to this article can be found at:

Supplemental material to this article can be found at: Supplemental material to this article can be found at: http://dmd.aspetjournals.org/content/suppl/2016/11/07/dmd.116.073411.dc1 1521-009X/45/1/86 108$25.00 http://dx.doi.org/10.1124/dmd.116.073411 DRUG

More information

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

In vitro substrate-dependent inhibition of OATP1B1 and its impact on DDI prediction SSX 3 rd Annual Conference (Oct 11, 2018) In vitro substrate-dependent inhibition of OATP1B1 and its impact on DDI prediction Yoshitane Nozaki, PhD DMPK Tsukuba Organic Anion Transporting Polypeptide (OATP)

More information

Determinants of Drug Disposition

Determinants of Drug Disposition Drug Transporters: In Vitro and Knockout Model Systems, Pharmacogenomics, and Clinical Relevance Richard B. Kim MD, FRCP(C) Professor & Chair, Division of Clinical Pharmacology Director, Centre for Clinical

More information

Symposium: Target or Avoid?

Symposium: Target or Avoid? RSC Drug Transporters Symposium: Target or Avoid? Thursday 13 th November 2014 The exploitation ti and under-exploitation exploitation of transporters in drug discovery Steve Alexander, Pharmacology, School

More information

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

Bristol-Myers Squibb HCV DAAs: Review of Interactions Involving Transporters. Timothy Eley. 21 May 2014 Bristol-Myers Squibb HCV DAAs: Review of Interactions Involving Transporters Timothy Eley 15th HIV/HEPPK Workshop 21 May 2014 Disclosures T Eley is a full time employee and stockholder of Bristol-Myers

More information

Till David och Calle

Till David och Calle Till David och Calle List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals assigned below. I II III Bergman, E., Forsell, P., Tevell, A.,

More information

Clinical Pharmacokinetics of Tyrosine Kinase Inhibitors

Clinical Pharmacokinetics of Tyrosine Kinase Inhibitors Clinical Pharmacokinetics of Tyrosine Kinase Inhibitors 2 Nielka P. van Erp, Hans Gelderblom, Henk-Jan Guchelaar Cancer Treatment Reviews 2009 (in press) Introduction Summary In the recent years, eight

More information

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

Evaluation and Quantitative Prediction of Renal Transporter-Mediated Drug-Drug Interactions. Bo Feng, Ph.D. DDI 2017 June 19-21, 2017 Evaluation and Quantitative Prediction of Renal Transporter-Mediated Drug-Drug Interactions Bo Feng, Ph.D. DDI 2017 June 19-21, 2017 Outline Background of renal transporters. Clinically observed transporter-mediated

More information

Detail features... 1

Detail features... 1 PBPK Modelling and its Applications to Predict Transporter-Mediated Drug-Drug Interactions Masoud Jamei Senior Scientific Advisor, Head of M&S M.Jamei@Simcyp.com NEDMDG 14 th June 211, New England, USA

More information

EVALUATION OF DRUG-DRUG INTERACTION POTENTIAL BETWEEN SACUBITRIL/VALSARTAN (LCZ696) AND STATINS USING A PHYSIOLOGICALLY- BASED PHARMACOKINETIC MODEL

EVALUATION OF DRUG-DRUG INTERACTION POTENTIAL BETWEEN SACUBITRIL/VALSARTAN (LCZ696) AND STATINS USING A PHYSIOLOGICALLY- BASED PHARMACOKINETIC MODEL Drug metabolism and Pharmacokinetics/PK Sciences EVALUATIN F DRUG-DRUG INTERACTIN PTENTIAL BETWEEN SACUBITRIL/VALSARTAN (LCZ696) AND STATINS USING A PHYSILGICALLY- BASED PHARMACKINETIC MDEL Imad Hanna,

More information

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

ATP-Binding-Cassette Transporters in Biliary Efflux and Drug-Induced Liver Injury Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 172 ATP-Binding-Cassette Transporters in Biliary Efflux and Drug-Induced Liver Injury JENNY M. PEDERSEN ACTA UNIVERSITATIS

More information

Core Data Set CYP2D6 Metabolism

Core Data Set CYP2D6 Metabolism Core Data Set CYP2D6 Metabolism Oxidised metabolites seen in pre-clinical species Inhibitor Target CYP Isoform CLint (µl/min/mg protein) % Inhibition Control 12.5 - Furafylline 1A2 12.9 0 Sulfaphenoxazole

More information

CO-ADMINISTRATION WITH GRAZOPREVIR AND ELBASVIR HAS NO EFFECT ON PRAVASTATIN EXPOSURE BUT INCREASES ROSUVASTATIN EXPOSURE IN HEALTHY SUBJECTS

CO-ADMINISTRATION WITH GRAZOPREVIR AND ELBASVIR HAS NO EFFECT ON PRAVASTATIN EXPOSURE BUT INCREASES ROSUVASTATIN EXPOSURE IN HEALTHY SUBJECTS CO-ADMINISTRATION WITH GRAZOPREVIR AND ELBASVIR HAS NO EFFECT ON PRAVASTATIN EXPOSURE BUT INCREASES ROSUVASTATIN EXPOSURE IN HEALTHY SUBJECTS Luzelena Caro 1, William L. Marshall 1, Hwa-Ping Feng 1, Zifang

More information

Supporting information

Supporting information Supporting information Intracellular drug bioavailability: a new predictor of system dependent drug disposition Mateus, André 1* ; Treyer, Andrea 1* ; Wegler, Christine 1,2 ; Karlgren, Maria 1 ; Matsson,

More information

Clinical Pharmacology of DAA s for HCV: What s New & What s In Pipeline

Clinical Pharmacology of DAA s for HCV: What s New & What s In Pipeline Clinical Pharmacology of DAA s for HCV: What s New & What s In Pipeline Kirk Bertelsen, PhD Clinical Pharmacology Janssen Pharmaceuticals, Research & Development 4/24/2013 1 Incivo Simeprevir 2 Janssen

More information

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

Drug Transport in the Brain: Models of BBB and Brain Parenchyma Drug Transport in the Brain: Models of BBB and Brain Parenchyma Reina Bendayan, Pharm.D. Professor and Career Scientist, MHO Department of Pharmaceutical Sciences Leslie Dan Faculty of Pharmacy University

More information

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

Prediction of the Effects of Renal Impairment on the Clearance for Organic Cation Drugs that. undergo Renal Secretion: A Simulation-Based Study DMD Fast Forward. Published on February 28, 2018 as DOI: 10.1124/dmd.117.079558 This article has not been copyedited and formatted. The final version may differ from this version. Prediction of the Effects

More information

Effect of Daclatasvir/Asunaprevir/Beclabuvir in Fixed-dose Combination on the Pharmacokinetics of CYP450/Transporter Substrates In Healthy Subjects

Effect of Daclatasvir/Asunaprevir/Beclabuvir in Fixed-dose Combination on the Pharmacokinetics of CYP450/Transporter Substrates In Healthy Subjects Effect of Daclatasvir/Asunaprevir/Beclabuvir in Fixed-dose Combination on the Pharmacokinetics of CYP450/Transporter Substrates In Healthy Subjects Xiaolu Tao 1, Karen Sims 1, Yi-Ting Chang 1, Jignasa

More information

Pharmacologic Considerations of HCV Treatment. Autumn Zuckerman, PharmD, BCPS, AAHIVP

Pharmacologic Considerations of HCV Treatment. Autumn Zuckerman, PharmD, BCPS, AAHIVP Pharmacologic Considerations of HCV Treatment Autumn Zuckerman, PharmD, BCPS, AAHIVP Objectives Review pharmacokinetic properties of currently utilized Hepatitis C medications Review drug interactions

More information

Cytochrome P450 Drug Interaction Table Flockhart Table

Cytochrome P450 Drug Interaction Table Flockhart Table Cytochrome P450 Drug Interaction Table Flockhart Table The table contains lists of drugs in columns under the designation of specific cytochrome P450 isoforms. CYTOCHROME P450 DRUG INTERACTION TABLE A

More information

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

Efficient Liver Targeting and Uptake by Novel Tenofovir Prodrug, CMX157, For the Treatment of Hepatitis B Efficient Liver Targeting and Uptake by Novel Tenofovir Prodrug, CMX157, For the Treatment of Hepatitis B R Rush 1, J Greytok 2, T Matkovits 2, R Driz 2, JZ Sullivan-Bólyai 2, and D Standring 3 1 Allon

More information

Hepatic Efflux Transporters: Relevance to Drug-Drug Interactions and Drug Toxicity

Hepatic Efflux Transporters: Relevance to Drug-Drug Interactions and Drug Toxicity Hepatic Efflux Transporters: Relevance to Drug-Drug Interactions and Drug Toxicity Kim L. R. Brouwer, PharmD, PhD W.R. Kenan, Jr., Distinguished Professor Associate Dean for Research and Graduate Education

More information

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

Falk Symposium 156: Genetics in Liver Disease. Pharmacogenetics. Gerd Kullak-Ublick Falk Symposium 156: Genetics in Liver Disease Pharmacogenetics Gerd Kullak-Ublick Division of Clinical Pharmacology and Toxicology Department of Internal Medicine University Hospital Zurich Freiburg, 8.

More information

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

Challenges. Benefits. Control of viral load in plasma. Drug-drug interactions. Adverse effects/drug toxicities. Delay in HIV drug resistance Benefits Challenges Control of viral load in plasma Drug-drug interactions Delay in HIV drug resistance Longer life expectancy Adverse effects/drug toxicities Drug resistant HIV strains Raltegravir Structural/pharmacokinetic/pharmacodynamic

More information

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

Investigating Transporter-Mediated Drug-Drug Interactions Using a Physiologically Based Pharmacokinetic Model of Rosuvastatin Citation: CPT Pharmacometrics Syst. Pharmacol. (2017) 6, 228 238; VC 2017 ASCPT All rights reserved doi:10.1002/psp4.12168 ORIGINAL ARTICLE Investigating Transporter-Mediated Drug-Drug Interactions Using

More information

Supplemental material to this article can be found at:

Supplemental material to this article can be found at: Supplemental material to this article can be found at: http://dmd.aspetjournals.org/content/suppl/207/05/08/dmd.6.07458.dc 52-009X/45/7/755 764$25.00 https://doi.org/0.24/dmd.6.07458 DRUG METABOLISM AND

More information

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

DRUG-DRUG INTERACTIONS OF GLECAPREVIR AND PIBRENTASVIR WITH PRAVASTATIN, ROSUVASTATIN, OR DABIGATRAN ETEXILATE DRUG-DRUG INTERACTIONS OF GLECAPREVIR AND PIBRENTASVIR WITH PRAVASTATIN, ROSUVASTATIN, OR DABIGATRAN ETEXILATE Matthew P. Kosloski, Weihan Zhao, Hong Li, Stanley Subhead Wang, Calibri Joaquin 14pt, Valdes,

More information

Agents that inhibit the BSEP and mitochondrial function what do we know? Prepared by Michael D. Aleo, Ph.D. Groton, Investigative Toxicology

Agents that inhibit the BSEP and mitochondrial function what do we know? Prepared by Michael D. Aleo, Ph.D. Groton, Investigative Toxicology Agents that inhibit the BSEP and mitochondrial function what do we know? Prepared by Michael D. Aleo, Ph.D. Groton, Investigative Toxicology Declarations Nonclinical studies All procedures performed on

More information

BSEP inhibition and Drug Induced Liver Injury

BSEP inhibition and Drug Induced Liver Injury BSEP inhibition and Drug Induced Liver Injury Gerry Kenna Pharmaceutical Director, Safer Medicines Trust www.safermedicines.org Drug Safety Consultant Overview Drug Induced Liver Injury (DILI) BSEP inhibition

More information

Pharmacogenetics and Pharmacokinetics

Pharmacogenetics and Pharmacokinetics Chapter 2 Pharmacogenetics and Pharmacokinetics Mauro Saivezzo/ShutterStock, Inc. L earning O bjectives Upon completion of this chapter, the student will be able to: 1. Recognize the influence of genetic

More information

Pharmacologic Considerations when using DAAs in Cirrhosis

Pharmacologic Considerations when using DAAs in Cirrhosis Pharmacologic Considerations when using DAAs in Cirrhosis Jennifer J. Kiser, PharmD Assistant Professor University of Colorado Denver 1 st International Workshop on the Optimal Use of DAAs in Liver Transplant

More information

The Opportunity: c-ibs and pain relief with confidence YKP10811

The Opportunity: c-ibs and pain relief with confidence YKP10811 The Opportunity: c-ibs and pain relief with confidence YKP10811 1 TABLE OF CONTENTS Profile Summary Clinical Data Mode of Action Pharmacologic Profile Safety and Toxicity Profile ADME Overview vs. Competitors

More information

Pharmacokinetic Determinants of Statin-Induced Myopathy

Pharmacokinetic Determinants of Statin-Induced Myopathy Pharmacokinetic Determinants of Statin-Induced Myopathy Rommel G. Tirona, B.Sc.Phm., Ph.D. Departments of Physiology & Pharmacology and Medicine The University of Western Ontario, London, Ontario, Canada

More information

The importance of pharmacogenetics in the treatment of epilepsy

The importance of pharmacogenetics in the treatment of epilepsy The importance of pharmacogenetics in the treatment of epilepsy Öner Süzer and Esat Eşkazan İstanbul University, Cerrahpaşa Faculty of Medicine, Department of Pharmacology and Clinical Pharmacology Introduction

More information

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

Importance of Multi-P450 Inhibition in Drug Drug Interactions: Evaluation of Incidence, Inhibition Magnitude, and Prediction from in Vitro Data pubs.acs.org/crt Importance of Multi-P450 Inhibition in Drug Drug Interactions: Evaluation of Incidence, Inhibition Magnitude, and Prediction from in Vitro Data Nina Isoherranen,* Justin D. Lutz, Sophie

More information

RSC, February Interplay between enzymes and. clearance and intracellular concentration of drugs. Centre for Applied Pharmacokinetic Research

RSC, February Interplay between enzymes and. clearance and intracellular concentration of drugs. Centre for Applied Pharmacokinetic Research RSC, February 2014 Interplay between enzymes and transporters in defining hepatic drug clearance and intracellular concentration of drugs J Brian Houston Centre for Applied Pharmacokinetic Research (CAPkR)

More information

Supplemental Materials

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

More information

Case #1. Pharmacology and Drug Interactions of Newer Direct-Acting Antivirals

Case #1. Pharmacology and Drug Interactions of Newer Direct-Acting Antivirals Pharmacology and Drug Interactions of Newer Direct-Acting Antivirals Charles W. Flexner, MD Professor of Medicine, Pharmacology, and International Health The Johns Hopkins University School of Medicine

More information

Pharmacokinetic Modeling & Simulation in Discovery and non-clinical Development

Pharmacokinetic Modeling & Simulation in Discovery and non-clinical Development Pharmacokinetic Modeling & Simulation in Discovery and non-clinical Development Where do we stand? Disclaimer I am not a bioinformatician, mathematician or biomedical engineer. I am a simple minded pharmacist,

More information

Basic Concepts in Pharmacokinetics. Leon Aarons Manchester Pharmacy School University of Manchester

Basic Concepts in Pharmacokinetics. Leon Aarons Manchester Pharmacy School University of Manchester Basic Concepts in Pharmacokinetics Leon Aarons Manchester Pharmacy School University of Manchester Objectives 1. Define pharmacokinetics 2. Describe absorption 3. Describe distribution 4. Describe elimination

More information

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

Examining the Basis of Drug-Drug Interaction (DDI) Labeling Recommendations for Antiviral Approvals from 1998 to 2015 Examining the Basis of Drug-Drug Interaction (DDI) Labeling Recommendations for Antiviral Approvals from 1998 to 2015 Tyler Shugg, PharmD PhD Candidate Department of Pharmacy Practice Purdue University

More information

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

Proteomic Quantification of Kidney Transporters: Methodological Challenges, Interindividual Variability and Application in IVIVE Proteomic Quantification of Kidney Transporters: Methodological Challenges, Interindividual Variability and Application in IVIVE Bhagwat Prasad, Ph.D. University of Washington, Seattle, WA (bhagwat@uw.edu)

More information

DILI: Clinical Pharmacology Considerations for Risk Assessment

DILI: Clinical Pharmacology Considerations for Risk Assessment DILI: Clinical Pharmacology Considerations for Risk Assessment Raj Madabushi, PhD Office of Clinical Pharmacology Drug-Induced Liver Injury (DILI) Conference XVII June 06, 2017 Disclaimer: The views expressed

More information

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

Effect of Multiple-Dose Ketoconazole and the Effect of Multiple-Dose Rifampin on Pharmacokinetics (PK) of the HCV NS3 Protease Inhibitor Asunaprevir Effect of Multiple-Dose Ketoconazole and the Effect of Multiple-Dose Rifampin on Pharmacokinetics (PK) of the HCV NS3 Protease Inhibitor Asunaprevir Eley T, 1 He B, 1 Huang S-P, 2 Stonier M, 1 Bedford

More information

HTPK: Conducting PK modeling and

HTPK: Conducting PK modeling and HTPK: Conducting PK modeling and simulations at high speed November 5, 2018 Robert Fraczkiewicz, David Miller, Marvin Waldman, Robert D. Clark Slide 1 Session Description and Objectives HTPK lightens the

More information

Farmaci. Forskerne er opdelt efter fagområde. I farmaci skelnes der mellem teknologisk farmaci og lægemiddel-stof-transport. Teknologisk farmaci

Farmaci. Forskerne er opdelt efter fagområde. I farmaci skelnes der mellem teknologisk farmaci og lægemiddel-stof-transport. Teknologisk farmaci Farmaci Forskerne er opdelt efter fagområde. I farmaci skelnes der mellem teknologisk farmaci og lægemiddel-stof-transport. Teknologisk farmaci Annette Bauer-Brandl... 2 Martin Brandl... 3 Judith Kuntsche...

More information

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

DMPK. APRIL 27 TH 2017 Jan Neelissen Scientific Adviser Science & Technology DMPK APRIL 27 TH 2017 Jan Neelissen Scientific Adviser Science & Technology What I learned is a good DMPK profile have acceptable water solubility for development be completely absorbed, preferably via

More information

Pharmacokinetics for Physicians. Assoc Prof. Noel E. Cranswick Clinical Pharmacologist Royal Children s Hospital Melbourne

Pharmacokinetics for Physicians. Assoc Prof. Noel E. Cranswick Clinical Pharmacologist Royal Children s Hospital Melbourne Pharmacokinetics for Physicians Assoc Prof. Noel E. Cranswick Clinical Pharmacologist Royal Children s Hospital Melbourne The Important Therapeutic Questions What drug? What dose? How long? Drug Dosage

More information

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

Role of metabolism in Drug-Induced Liver Injury (DILI) Drug Metab Rev. 2007;39(1): Role of metabolism in Drug-Induced Liver Injury (DILI) Drug Metab Rev. 2007;39(1):159-234 Drug Metab Rev. 2007;39(1):159-234 Drug Metab Rev. 2007;39(1):159-234 A schematic representation of the most relevant

More information

Leslie Z. Benet, PhD. Professor of Bioengineering and Therapeutic Sciences Schools of Pharmacy and Medicine University of California San Francisco

Leslie Z. Benet, PhD. Professor of Bioengineering and Therapeutic Sciences Schools of Pharmacy and Medicine University of California San Francisco Biopharmaceutics Drug Disposition Classification System (BDDCS) and Drug Interactions Leslie Z. Benet, PhD Professor of Bioengineering and Therapeutic Sciences Schools of Pharmacy and Medicine University

More information

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

12/9/2015. Drug Interactions. Sarah Robertson, Pharm.D. Director, Department of Clinical Pharmacology Vertex Pharmaceuticals Inc. Drug Interactions Sarah Robertson, Pharm.D. Director, Department of Clinical Pharmacology Vertex Pharmaceuticals Inc. Boston, MA, USA December 10, 2015 1 1 Overview Epidemiology and Categories of Drug

More information

Drug Interactions: Definition

Drug Interactions: Definition Drug Interactions Scott R. Penzak, Pharm.D. Director, Clinical Pharmacokinetics Research Laboratory Clinical Center Pharmacy Department National Institutes of Health December 9, 2010 Drug Interactions:

More information

Effects of Uptake and Efflux Transporter Inhibition on Erythromycin Breath Test Results

Effects of Uptake and Efflux Transporter Inhibition on Erythromycin Breath Test Results nature publishing group Effects of Uptake and Efflux Transporter Inhibition on Erythromycin Breath Test Results LA Frassetto 1, S Poon 2, C Tsourounis 2, C Valera 2 and LZ Benet 3 The erythromycin breath

More information

Endogenous Biomarkers for OATP1B: Preclinical to Clinical Translations. Yurong Lai, PhD Drug Metabolism Gilead Sciences

Endogenous Biomarkers for OATP1B: Preclinical to Clinical Translations. Yurong Lai, PhD Drug Metabolism Gilead Sciences Endogenous Biomarkers for OATP1B: Preclinical to Clinical Translations Yurong Lai, PhD Drug Metabolism Gilead Sciences Outlines Current strategies to assess clinical DDIs for OATP inhibitor Endogenous

More information

Pathophysiology of Bile Secretion

Pathophysiology of Bile Secretion Pathophysiology of Bile Secretion Martin C. Carey, D.Sc., M.D. Division of Gastroenterology, Brigham and Women s Hospital and Department of Medicine, Harvard Medical School Boston, MA, U.S.A. Functions

More information

PRODUCT MONOGRAPH VOLIBRIS. ambrisentan. 5 mg and 10 mg Tablets. Endothelin Receptor Antagonist

PRODUCT MONOGRAPH VOLIBRIS. ambrisentan. 5 mg and 10 mg Tablets. Endothelin Receptor Antagonist PRODUCT MONOGRAPH Pr VOLIBRIS ambrisentan 5 mg and 10 mg Tablets Endothelin Receptor Antagonist GlaxoSmithKline Inc. 7333 Mississauga Road Mississauga, Ontario L5N 6L4 Date of Revision: June 23, 2016 Submission

More information

Montpellier and Nimes University Hospital. 2nd International Workshop on Clinical Pharmacology of Anticancer Drugs Madrid, September the 13th and 14th

Montpellier and Nimes University Hospital. 2nd International Workshop on Clinical Pharmacology of Anticancer Drugs Madrid, September the 13th and 14th Association of NR1I2, CYP3A5 and ABCB1 genetic polymorphisms with variability of temsirolimus pharmacokinetics and toxicity in patients with metastatic bladder cancer Litaty MBATCHI, Matthieu GASSIOT,

More information

The extended clearance model and its use for the interpretation of hepatobiliary elimination data

The extended clearance model and its use for the interpretation of hepatobiliary elimination data ADMET & DMPK 3(1) (2015) 1-14; doi: 10.5599/admet.3.1.144 Open Access : ISSN : 1848-7718 Review http://www.pub.iapchem.org/ojs/index.php/admet/index The extended clearance model and its use for the interpretation

More information

Objectives Making CYP450, Drug Interactions, & Pharmacogenetics Easy

Objectives Making CYP450, Drug Interactions, & Pharmacogenetics Easy Objectives Making, Drug Interactions, & Pharmacogenetics Easy Anthony J. Busti, MD, PharmD, FNLA, FAHA Describe the differences between phase I and phase II metabolic pathways. Identify the most common

More information

Assessment of inhibitory effect of many therapeutically important drugs on bile acid transport by NTCP, BSEP and other transporters

Assessment of inhibitory effect of many therapeutically important drugs on bile acid transport by NTCP, BSEP and other transporters ct 6, 26 Falk Symposium 155; XIX International Bile Acid Meeting Assessment of inhibitory effect of many therapeutically important drugs on bile acid transport by NTCP, BSEP and other transporters Kazuya

More information