The Future of In Vitro Systems for the Assessment of Induction and Suppression of Enzymes and Transporters
|
|
- Kathleen Neal
- 5 years ago
- Views:
Transcription
1 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 Jane Kenny, Genentech Harma Ellens, GSK 1
2 Induction and Suppression Induction Can increase clearance and cause loss of therapeutic action (e.g., OCS) Xenosensor FDA CYP Control Inducer AhR CYP1A2 Omeprazole Direct agonist CITCO Direct agonist CAR CYP2B6 Phenobarbital Indirect agonist PXR CYP3A4 Rifampin Direct agonist Suppression Can decrease clearance Activators of other nuclear receptors Cytokines (e.g., TNF, IL-6) NF- B activation xenosensor inactivation (and vice versa) Biologics may act directly on hepatocytes/kupffer cells or release cytokines from PBMC Inducers tend to be small drug molecules Suppressors tend to be biologics (therapeutic proteins) but there are exceptions 2
3 3 Induction studies before and after the FDA 2012 DDI Guidance 3 Induction assay Before 2012 After 2012 Endpoints Positive attribute Negative attribute CYP activity Fold induction Percent of positive control Endpoint = net effect of induction & irreversible inhibition CYP inhibition could mask induction CYP mrna EC 50 and E max Endpoint = induction only (inhibition examined separately) Assumes induction is always due to increased transcription (not so for CYP2C19 or 2E1) control criteria > 2 fold > 6 fold Test article (TA) concentration Up to10 x plasma C max In vitro E max TA treatment 3 days 2 or 3 days IVIVE >2 fold (or >1.5 fold) >40% (or >20%) control R 3 < 0.9
4 CYP3A4 induction (E max ) : mrna versus activity Predictive utility of in vitro rifampin induction data generated in fresh and cryopreserved human hepatocytes, Fa2N-4, and HepaRG cells. Templeton IE, Houston JB, Galetin A. Drug Metab Dispos 39: , 2011 Relatively large Relatively small 4
5 CYP3A4 induction (EC 50 ) : mrna versus activity Predictive utility of in vitro rifampin induction data generated in fresh and cryopreserved human hepatocytes, Fa2N-4, and HepaRG cells. Templeton IE, Houston JB, Galetin A. Drug Metab Dispos 39: , 2011 Comparable but Fa2N-4 EC 50 values are high 5
6 CYP3A4 mrna induction: EC 50 in different cells Comparison of immortalized Fa2N-4 cells and human hepatocytes as in vitro models for cytochrome P450 induction. Hariparsad N, Carr BA, Evers R, Chu X. Drug Metab Dispos 36: , 2008 Fa2N-4 cells EC 50 = 8 µm Human hepatocytes EC 50 = 0.8 µm 6 Levels of PXR mrna in Fa2N-4 cells human hepatocytes but CAR mrna is <1% Rifampicin is an OATP substrate Levels of OATP1B1 and OAPT1B3 mrna levels in Fa2N-4 cells <1% of hepatocytes
7 [Drug] Measuring the in vitro concentration of the inducing drug seems like a good idea but... where is the drug? Whole-system loss In many cases most of the drug moves from the medium to the cells after only a few minutes Medium loss Time (min) 7
8 Measuring the in vitro concentration of the inducing drug seems like a good idea but... where is the drug? For certain basic drugs, they undergo extensive partitioning into phospholipid membranes (not shown) or ion-partitioning into the acidic lysosomes Total cell concentration >> unbound intracellular concentration 8
9 Measuring the in vitro concentration of the inducing drug seems like a good idea but... where is the drug? 9 For certain acidic/zwitterion drugs, they undergo transporter-mediated uptake and efflux into the bile canaliculi Total cell concentration >> unbound intracellular concentration
10 Should we correct for variation in EC 50? 10 Perfect results in all 3 human hepatocyte preparations. Correction? None
11 Should we correct for variation in EC 50? 11 A high EC 50 value observed for both the positive control and test article in 1 of 3 preparations of human hepatocyte preparations. Correction? Probably YES
12 Should we correct for variation in EC 50? 12 A high EC 50 value observed for ONLY the positive control in 1 of 3 preparations of human hepatocyte preparations. Correction? Case-by-case
13 In vitro to in vivo extrapolation (IVIVE) A comparison of 5 models of CYP3A4 induction Evaluation of various static and dynamic modeling methods to predict clinical CYP3A induction using in vitro CYP3A4 mrna induction data. Einolf HJ, Chen L, Fahmi OA, Gibson CR, Obach RS, Shebley M, Silva J, Sinz MW, Unadkat JD, Zhang L, Zhao P. Clin Pharmacol Ther 95: ,
14 In vitro to in vivo extrapolation (IVIVE) A comparison of 5 models of CYP3A4 induction Correlation approach = C max EC 50 Relative induction score Basic static model (R 3 ) 14
15 In vitro to in vivo extrapolation (IVIVE) A comparison of 5 models of CYP3A4 induction Mechanistic static model (AUC Ratio) Liver Intestine where A, B and C are terms for TDI, induction, and reversible inhibition in the liver, respectively and X, Y and Z are terms for TDI, induction, and reversible inhibition in the intestine, respectively Mechanistic dynamic model (modeling & simulation) 15 AUCR + PBPK modeling. Incorporates such variables such as time-dependent changes in inducer concentration, which is complex when the drug is an auto-inducer
16 In vitro to in vivo extrapolation (IVIVE) A comparison of 5 models of CYP3A4 induction Model False negative False positive True negative True positive Within 2 fold Correlation RIS R 3 (d = 1) Mechanistic Static 2 (0) 0 (3) 6 (3) 20 (22) 19 (20) Mechanistic Dynamic 2 (0) 1 (3) 5 (3) 20 (22) 11 (14) 16 [I] = total plasma C max (bound + unbound) Values in parentheses are without the time-dependent inhibition component, which tends to be overestimated for CYP3A4
17 The FDA s R 3 Raising the negative result bar If we assume d=1 and use plasma C max as the in vivo inducer concentration, then the equation for R 3 is: 1 R 3 = 1 + E max + C max EC 50 + C max The bare minimum cutoff value of is R 3 is (marginally below 0.9). This value is obtained when: E max + C max EC 50 + C max = Accordingly, EC 50 C max = E max To fall just below the FDA s cutoff of 0.9, EC 50 (as a multiple of C max ) increases almost linearly with E max. 17
18 The FDA s R 3 Raising the negative result bar This graph shows the relationship between EC 50 (as a multiple of C max ) and E max when the value of R 3 is (marginally below the FDA s cutoff of 0.9) Note the near linear relationship General Rule You are safe if EC 50 is greater than C max x 10 E max 18
19 The FDA s R 3 Raising the negative result bar This graph shows the dividing line between a positive and negative result for CYP induction when E max = 10 (the induced activity was 11 times control) Note that the EC 50 value is 89 times C max 19
20 The FDA s R 3 Raising the negative result bar This graph shows a series positive results for CYP induction when E max = 10. R 3 values range from 0.9 (safe) to 0.167, which is achieved when EC 50 = C max. Note that when the in vitro concentration of inducer equals C max (or even 10 x C max ), the degree of induction is far less than 40% of E max in the majority of cases 20
21 The FDA s R 3 Raising the negative result bar This graph shows the dividing line between a positive and negative result for CYP induction when E max ranges from 1 to 10 (the induced activity was 2 to 11 times control) Note that for ALL these safe curves, negligible induction is observed when the in vitro concentration of inducer equals C max regardless of the value of E max 21
22 The FDA s R 3 Raising the negative result bar To be sure of a negative result (defined as an R 3 of 0.9 or greater), it is necessary to test concentrations of test article that exceed C max As E max increases (as it does when mrna levels are measured) so must the concentration of test article (as a multiple of C max ) to demonstrate no potential for clinical induction 22
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 informationCytochrome P450 Suppression in Human Hepatocyte Cultures by Small and Large Molecules. George Zhang, Ph.D. April 18, 2012
Cytochrome P450 Suppression in Human Hepatocyte Cultures by Small and Large Molecules George Zhang, Ph.D. April 18, 2012 Presentation Overview Regulatory guidance Brief review on drug-drug (Disease) interactions
More informationDevelopment & Characterization of Pooled and Plated Hepatocytes to Support the Evolving DMPK Landscape
Development & Characterization of Pooled and Plated Hepatocytes to Support the Evolving DMPK Landscape April Downey Senior Production and Inventory Scientist In Vitro adowney@xenotechllc.com www.xenotechllc.com
More informationEvaluation 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 informationItraconazole 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 informationDrug 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 informationSupplemental material to this article can be found at:
Supplemental material to this article can be found at: http://dmd.aspetjournals.org/content/suppl/2017/01/06/dmd.116.072124.dc1 1521-009X/45/2/198 207$25.00 http://dx.doi.org/10.1124/dmd.116.072124 DRUG
More informationA unified in vivomodelingapproach for quantitative prediction of the impact of gene polymorphism and drug interactions on drug exposure
A unified in vivomodelingapproach for quantitative prediction of the impact of gene polymorphism and drug interactions on drug exposure Sylvain Goutelle, Michel Tod, Laurent Bourguignon, Nathalie Bleyzac,
More informationConsiderations from the IQ Induction Working Group in Response to Drug-Drug Interaction
Considerations from the IQ Induction Working Group in Response to Drug-Drug Interaction Guidances from Regulatory Agencies: Focus on CYP3A4 mrna in vitro response thresholds, variability, and clinical
More informationCulture 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 informationPrediction of DDIs Arising from CYP3A Induction Using a Physiologically-based Dynamic Model. Lisa Almond 22 nd June 2016
Prediction of DDIs Arising from CYP3A Induction Using a Physiologically-based Dynamic Model Lisa Almond 22 nd June 2016 Growing impact of PBPK on drug labels Revatio (Sildenafil) Pulmonary Arterial Hypertension
More informationDRUG 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 informationEffect of BD Matrigel Matrix Overlay and BD Matrigel Matrix Thin Coat on CYP450 Activities in Cryo Human Hepatocytes. Rongjun Zuo.
Effect of BD Matrigel Matrix Overlay and BD Matrigel Matrix Thin Coat on CYP450 Activities in Cryo Human Hepatocytes Rongjun Zuo November 10, 2010 Topics Overview of Hepatocyte Products P450 Induction
More informationCYP3A Induction Can Predict P-gp Induction: An Example of Sofosbuvir (a P-gp Substrate) with Rifampin, Carbamazepine or Rifabutin
CYP3A Induction Can Predict P-gp Induction: An Example of ofosbuvir (a P-gp ubstrate) with Rifampin, Carbamazepine or Rifabutin Justin D. Lutz, Brian J. Kirby, Benedetta assetto, Qinghua ong, Angela orth,
More informationMODELING MECHANISM BASED INACTIVATION USING PBPK JAN WAHLSTROM DIRECTOR, PRECLINICAL
MODELING MECHANISM BASED INACTIVATION USING PBPK JAN WAHLSTROM DIRECTOR, PRECLINICAL ABSTRACT Quantitative prediction of the magnitude of drug-drug interactions (DDI) is critical to underwriting patient
More informationIn 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 informationStrategy on Drug Transporter Investigation Why, How, Which & When. Jasminder Sahi
Strategy on Drug Transporter Investigation Why, How, Which & When Jasminder Sahi Intestine Drug Absorption PEPT1 OATPs MCTs AE2 Epithelial Cell MCTs MRP3 Liver Excretion via Liver Kidney MRPs OATPs N PT1
More informationSupplemental material to this article can be found at:
Supplemental material to this article can be found at: http://dmd.aspetjournals.org/content/suppl/2018/06/29/dmd.118.081927.dc1 1521-009X/46/9/1285 1303$35.00 https://doi.org/10.1124/dmd.118.081927 DRUG
More informationFDA 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 informationA 96-well Plate Assay for CYP3A Induction Using Cryopreserved Human Hepatocytes. Naomi Kamiguchi, Eiji Aoyama, Teruaki Okuda, and Toshiya Moriwaki
DMD Fast This article Forward. has not Published been copyedited on and August formatted. 10, The 2010 final version as doi:10.1124/dmd.109.028613 may differ from this version. A 96-well Plate Assay for
More informationChris Bohl, Ph.D. Global Technical Support Manager- Products
Chris Bohl, Ph.D. Global Technical Support Manager- Products cbohl1@xenotechllc.com Sekisui XenoTech Overview GLP-compliant in vitro ADME-DMPK CRO founded in 1994 at the University of Kansas Medical Center
More informationSupplemental 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 informationRSC, 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 informationConstitutive Regulation of P450s by Endocrine Factors
References: Constitutive Regulation of P450s by Endocrine Factors Meyer UA. Endo-xenobiotic crosstalk and the regulation of cytochromes P450. Drug Metab Rev 39:639-46, 2007. Waxman DJ and O Connor C. Growth
More informationCurrent 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 informationDMD Comparison of Different Algorithms for Predicting Clinical Drug-Drug. Interactions, Based on the Use of CYP3A4 in Vitro Data;
DMD This Fast article Forward. has not been Published copyedited on and formatted. April 30, The 2009 final as version doi:10.1124/dmd.108.026252 may differ from this version. Comparison of Different Algorithms
More informationThe Application of Physiologically Based Pharmacokinetic Modeling to Predict the Role of Drug Transporters: Scientific and Regulatory Perspectives
Supplement Article The Application of Physiologically Based Pharmacokinetic Modeling to Predict the Role of Drug Transporters: Scientific and Regulatory Perspectives The Journal of Clinical Pharmacology
More informationStrategies for Developing and Validating PBPK Models for Extrapolation to Unstudied Population
Strategies for Developing and Validating PBPK Models for Extrapolation to Unstudied Population Nina Isoherranen Department of Pharmaceutics University of Washington Processes driving drug disposition are
More informationEfficient 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 informationPrediction of in vivo hepatic clearance and DDI of OATP substrates: Comparison of different in vitro approaches. Yuichi Sugiyama
Prediction of in vivo hepatic clearance and DDI of OATP substrates: Comparison of different in vitro approaches. Yuichi Sugiyama Sugiyama Laboratory, RIKEN Innovation Center, RIKEN, Research Cluster for
More informationPBPK 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 informationCaveat: 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 informationPrediction 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 informationImportance 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 informationMechanisms and Predictions of Drug-Drug Interactions of the Hepatitis C Virus 3-Direct Acting
Title Page Mechanisms and Predictions of Drug-Drug Interactions of the Hepatitis C Virus 3-Direct Acting Antiviral (3D) Regimen: Paritaprevir/Ritonavir, Ombitasvir and Dasabuvir Mohamad Shebley, Jinrong
More informationExploiting 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 informationWelcome 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 informationHepatic Transporter Proteins involved in Bile Formation
Bile salt synthesis Hepatic Transporter Proteins involved in Bile Formation Basolateral membrane transporter proteins fx: NTCP uptake of bile salts OATP bulky organic anions Canalicular membrane transporter
More informationUsing virtual populations to solve drug development problems. Iain Gardner Head of Translational DMPK Science SIMCYP
Using virtual populations to solve drug development problems Iain Gardner Head of Translational DMPK Science SIMCYP Prediction of human PK (PD) in virtual individuals In vitro system In vitro CLu int Scaling
More informationWhat 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 informationWhen does the rate-determining step in the hepatic clearance of a drug switch from
When does the rate-determining step in the hepatic clearance of a drug switch from sinusoidal uptake to all hepatobiliary clearances? Implications for predicting drug-drug interactions Gabriela I. Patilea-Vrana
More informationCritical 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 informationModeling, Prediction, and In Vitro In Vivo Correlation of CYP3A4 Induction
DMD This Fast article Forward. has not been Published copyedited and on formatted. July 31, The 2008 final as version doi:10.1124/dmd.108.020602 may differ from this version. DMD #20602 Modeling, Prediction,
More informationPhysiologically Based Pharmacokinetic Model of the CYP2D6 Probe Atomoxetine: Extrapolation to Special Populations and Drug-Drug Interactions s
Supplemental material to this article can be found at: http://dmd.aspetjournals.org/content/suppl/2017/08/31/dmd.117.076455.dc1 1521-009X/45/11/1156 1165$25.00 https://doi.org/10.1124/dmd.117.076455 DRUG
More informationClinical 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 informationExamining 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 informationCryo 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 informationIn Vitro In Vivo Extrapolation (IVIVE): Why It Is Not As Easy As You May Think
EMA Workshop on MPS - 2017 In Vitro In Vivo Extrapolation (IVIVE): Why It Is Not As Easy As You May Think Amin Rostami Professor of Systems Pharmacology University of Manchester, UK & Chief Scientific
More informationDRUG-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 informationBrainteaser NK-1 receptor antagonists
Brainteaser K-1 receptor antagonists 96 Strategies: Lower overall lipophilicity of compound - find areas of the molecule where logd can be lowered Identify and block sites of metabolism major site of metabolism
More informationBuilding 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 informationPhysiologically-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 informationSimulation and Prediction of the Drug-Drug Interaction Potential of Naloxegol by Physiologically Based Pharmacokinetic Modeling
Citation: CPT Pharmacometrics Syst. Pharmacol. (2016) 5, 250 257; VC 2016 ASCPT All rights reserved doi:10.1002/psp4.12070 ORIGINAL ARTICLE Simulation and Prediction of the Drug-Drug Interaction Potential
More informationDMPK. 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 informationApplication of Physiologically Based Pharmacokinetic Modeling in. Understanding Bosutinib Drug-Drug Interactions: Importance of Intestinal
TITLE: Application of Physiologically Based Pharmacokinetic Modeling in Understanding Bosutinib Drug-Drug Interactions: Importance of Intestinal P-Glycoprotein AUTHORS: Shinji Yamazaki, Cho-Ming Loi, Emi
More informationLeslie 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 informationHTPK: 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 informationPrediction of CYP3A-Mediated Drug-Drug Interactions Using Human Hepatocytes Suspended in Human Plasma S
Supplemental material to this article can be found at: http://dmd.aspetjournals.org/content/suppl/20/0/06/dmd.0.036400.dc 0090-9556//3904-59 602$20.00 DRUG METABOLISM AND DISPOSITION Vol. 39, No. 4 Copyright
More informationSupplemental Information
Supplemental Information Article Title:The Proton Pump Inhibitor, Omeprazole, but not Lansoprazole or Pantoprazole, is a Metabolism-Dependent Inhibitor of CYP2C19: Implications for Co-Administration with
More informationInhibition 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 informationModel-Informed Drug Development (MIDD) for Ixazomib, an Oral Proteasome Inhibitor
Model-Informed Drug Development (MIDD) for Ixazomib, an Oral Proteasome Inhibitor Neeraj Gupta, Michael J. Hanley, Paul M. Diderichsen, 2 Huyuan Yang, Yeamin Huh, Alice Ke, 4 Zhaoyang Teng, Richard Labotka,
More informationDose Response Approaches for Nuclear Receptor Mediated Modes of Action Workshop Preliminary Report
Dose Response Approaches for Nuclear Receptor Mediated Modes of Action Workshop Preliminary Report Workshop Organizing Committee 2 Major Goals of the Workshop Determine whether the biology of nuclear receptors
More information3. P450 Drug Metabolism DDIs: Induction
35 3. P450 Drug Metabolism DDIs: Induction General Introductiona and Definition of a DDI: A drug-drug interaction (DDI) occurs when two drugs, each of which is safe and efficacious alone at their respective
More informationEvaluation 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 informationPREDICTING PHARMACOKINETICS FOLLOWING TOPICAL APPLICATION USING NON-ANIMAL METHODS IAN SORRELL, MI-YOUNG LEE, RICHARD CUBBERLEY
PREDICTING PHARMACOKINETICS FOLLOWING TOPICAL APPLICATION USING NON-ANIMAL METHODS IAN SORRELL, MI-YOUNG LEE, RICHARD CUBBERLEY UNILEVER APPLICATIONS KINETICS Need for estimates of local and systemic concentrations
More informationCurrent 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 informationEvaluation of P450 Inhibition and Induction by Artemisinin Antimalarials in Human Liver Microsomes and Primary Human Hepatocytes
1521-009X/12/4009-1757 1764$25.00 DRUG METABOLISM AND DISPOSITION Vol. 40, No. 9 Copyright 2012 by The American Society for Pharmacology and Experimental Therapeutics 45765/3788434 DMD 40:1757 1764, 2012
More informationPhysiologically Based Pharmacokinetic Model to Assess the Influence of Blinatumomab-Mediated Cytokine Elevations on Cytochrome P450 Enzyme Activity
Citation: CPT Pharmacometrics Syst. Pharmacol. (2015) 4, 507 515; VC 2015 ASCPT All rights reserved doi:10.1002/psp4.12003 ORIGINAL ARTICLE Physiologically Based Pharmacokinetic Model to Assess the Influence
More informationApplication of a Physiologically Based Pharmacokinetic Model to Predict OATP1B1-Related Variability in Pharmacodynamics of Rosuvastatin
Original Article Citation: CPT Pharmacometrics Syst. Pharmacol. (), e; doi:./psp.. ASCPT All rights reserved -/ Application of a Physiologically Based Pharmacokinetic Model to Predict OATPB-Related Variability
More informationStereoselective inhibition of CYP2C19 and CYP3A4 by fluoxetine and its metabolite:
DMD Fast This article Forward. has not been Published copyedited on and June formatted. 19, The 2013 final version as doi:10.1124/dmd.113.052639 may differ from this version. Stereoselective inhibition
More informationBiopharmaceutics 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 informationAssessing the role of hepatic uptake in drug clearance - Pharmacokinetic and experimental considerations
Assessing the role of hepatic uptake in drug clearance - Pharmacokinetic and experimental considerations Peter Webborn ISSX Short course Toronto 2013 1 Defining the why, when and how of Transporter studies
More informationPharmacologic 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 informationPursuing 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 informationBiopharmaceutics 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 informationEvaluation of clinical drug interaction potential of clofazimine using static and dynamic
TITLE PAGE Evaluation of clinical drug interaction potential of clofazimine using static and dynamic modeling approaches Ramachandra Sangana, Helen Gu, Dung Yu Chun, and Heidi J. Einolf Novartis Healthcare
More informationApplication of PBPK Modeling and Simulations in Drug Development
Application of PBPK Modeling and Simulations in Drug Development Ping Zhao Division of Pharmacometrics Office of Clinical Pharmacology Office of Translational Sciences Center for Drug Evaluation and Research
More informationInvestigating 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 informationTransporter-mediated disposition, clinical pharmacokinetics and cholestatic potential of glyburide and its primary active metabolites
Transporter-mediated disposition, clinical pharmacokinetics and cholestatic potential of glyburide and its primary active metabolites Rui Li, Yi-an Bi, Anna Vildhede, Renato J. Scialis, Sumathy Mathialagan,
More informationExamination of the Human Cytochrome P4503A4 Induction Potential of PF , an Irreversible Myeloperoxidase Inactivator: Integration of
Examination of the Human Cytochrome P4503A4 Induction Potential of PF- 06282999, an Irreversible Myeloperoxidase Inactivator: Integration of Preclinical, In Silico, and Biomarker Methodologies in the Prediction
More informationCombination therapy with simeprevir and TMC647055/low dose ritonavir: dose anticipation using PBPK modeling and dose optimization in healthy subjects
Combination therapy with simeprevir and TMC647055/low dose ritonavir: dose anticipation using PBPK modeling and dose optimization in healthy subjects MC. Rouan, J. Snoeys, S. Ouwerkerk-Mahadevan, R. Verloes,
More informationIdentification of influential proteins in the classical retinoic acid signaling pathway
Ghaffari and Petzold Theoretical Biology and Medical Modelling (2018) 15:16 https://doi.org/10.1186/s12976-018-0088-7 RESEARCH Open Access Identification of influential proteins in the classical retinoic
More informationPhysiologically Based Pharmacokinetic Model of Mechanism-Based Inhibition of CYP3A by Clarithromycin
0090-9556/10/3802-241 248$20.00 DRUG METABOLISM AND DISPOSITION Vol. 38, No. 2 Copyright 2010 by The American Society for Pharmacology and Experimental Therapeutics 28746/3550645 DMD 38:241 248, 2010 Printed
More informationEffects 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 informationOpinion on. Classification of Musk ketone
EUROPEAN COMMISSION HEALTH & CONSUMER PROTECTION DIRECTORATE-GENERAL Directorate C - Public Health and Risk Assessment C7 - Risk assessment SCIENTIFIC COMMITTEE ON HEALTH AND ENVIRONMENTAL RISKS SCHER
More informationErik 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 informationSupplemental 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 informationA study on pharmacokinetics of bosentan with systems modeling, Part 1: translating systemic plasma concentration to liver exposure in healthy subjects
A study on pharmacokinetics of bosentan with systems modeling, Part 1: translating systemic plasma concentration to liver exposure in healthy subjects Rui Li, Mark Niosi, Nathaniel Johnson, David A. Tess,
More informationHepatic Drug-Metabolizing Enzyme Induction and Implications for Preclinical and Clinical Risk Assessment
Toxicologic Pathology, 38: 799-809, 2010 Copyright # 2010 by The Author(s) ISSN: 0192-6233 print / 1533-1601 online DOI: 10.1177/0192623310375099 Hepatic Drug-Metabolizing Enzyme Induction and Implications
More informationMuhammad Fawad Rasool Feras Khalil Stephanie Läer
Clin Pharmacokinet (2015) 54:943 962 DOI 10.1007/s40262-015-0253-7 ORIGINAL RESEARCH ARTICLE A Physiologically Based Pharmacokinetic Drug Disease Model to Predict Carvedilol Exposure in Adult and Paediatric
More informationEVALUATION 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 informationRole of CYP3A4 in kinase inhibitor metabolism and assessment of CYP3A4 activity
Review Article Role of CYP3A4 in kinase inhibitor metabolism and assessment of CYP3A4 activity Gerd Mikus, Kathrin Isabelle Foerster Department of Clinical Pharmacology and Pharmacoepidemiology, University
More informationPharmacokinetic 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 informationEvaluation of the Interplay between Uptake Transport and CYP3A4 Induction in Micropatterned Cocultured Hepatocytes s
Supplemental material to this article can be found at: http://dmd.aspetjournals.org/content/suppl/2016/09/21/dmd.116.072660.dc1 1521-009X/44/12/1910 1919$25.00 http://dx.doi.org/10.1124/dmd.116.072660
More informationSimulation of Clinical Drug-Drug Interactions from Hepatocyte CYP3A4 Induction Data and Its Potential Utility in Trial Designs
0090-9556/11/3907-1139 1148$25.00 DRUG METABOLISM AND DISPOSITION Vol. 39, No. 7 Copyright 2011 by The American Society for Pharmacology and Experimental Therapeutics 38067/3692984 DMD 39:1139 1148, 2011
More informationProteomic 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 informationUse of Immortalized Human Hepatocytes to Predict the Magnitude of Clinical. Drug-Drug Interactions Caused by CYP3A4 Induction ξ
DMD This Fast article Forward. has not been Published copyedited and on formatted. July 12, The 2006 final as version doi:10.1124/dmd.106.010132 may differ from this version. DMD #10132 Use of Immortalized
More informationAn Evaluation of the Dilution Method for Identifying Metabolism-Dependent Inhibitors of Cytochrome P450 Enzymes
9-9556/11/398-137 1387$25. DRUG METABOLISM AND DISPOSITION Vol. 39, No. 8 Copyright 211 by The American Society for Pharmacology and Experimental Therapeutics 38596/3724 DMD 39:137 1387, 211 Printed in
More informationDrug disposition classification systems: A comparative review of BDDCS, ECCS and ECCCS
Novartis Drug disposition classification systems: A comparative review of BDDCS, ECCS and ECCCS Birk Poller, Gian Camenisch - Novartis SOLVO - Meet The Experts Transporter Conference April 26, 2018 Drug
More informationHepatic 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