College of Pharmacy

7 Greenhouse Road Kingston, RI 02881

pharmcol@etal.uri.edu – Office: 401.874.2761 Fax: 401.874.2181

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drugtransporters

July 31st – August 2nd, 2017

8:00 am – 5:00 pm

 

“I found the course very educational and I really appreciated the open discussion and willingness of the teacher to share real life experiences”

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testThe workshop will take place at the College of Pharmacy building on the URI Kingston Campus.

7 Greenhouse Road,
Kingston, RI 02881

Free parking will be available on campus, full information on parking will be provided to registered participants closer to the dates of the workshop.

Course Scope and Description

agenda2

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Several factors led to the recent emphasis on the field of transporters and their impact on drug absorption and disposition. Pharmaceutical industry continues to have keen interest in optimizing the physicochemical space of NCEs and minimizing their Cytochrome P-450 (CYP)-mediated metabolic liability. This led to the increasing selection of compounds that are both hydrophilic and polar in nature. Such chemical space inherits low passive permeability and metabolic clearance characteristics, and more importantly have potential contribution of transporters to their disposition in man. This paradigm shift presents the research community with a more difficult chemical space for addressing drug absorption and predicting pharmacokinetics and tissue distribution. Appropriate understanding of transporters and in vitro and in silico tools that characterize their contribution to drug absorption, disposition and toxicity is key for the success of the pharmaceutical industry. Additionally, the US FDA, EMA and other regulatory agencies provided new guidance on approaches to assess the liabilities of transporter-mediated drug-drug interaction (DDI), efficacy and organ toxicity for new chemical entities (NCEs) with special emphasis on certain transporters with considerable knowledge in the clinic.

*This program is not accredited for Pharmacy CME/CE*

Day 1

Introduction

  • Why transporters and why now?
  • Transporter classification based on energy requirement
  • Extended clearance classification system [ECCS] and its utility in predicting drug clearance

Intestinal Transporter

  • Introduction to oral bioavailability
  • Impact of efflux transporters on oral bioavailability and Fa
  • Impact of influx transporters on oral bioavailability and Fa and case examples

BBB Transporters

  • Introduction
  • Impact of efflux transporters on drug brain penetration
  • Impact of influx transporters on drug brain penetration
  • Preclinical models to assess brain penetration

Renal Transporters

  • Introduction
  • Physicochemical factors that affect renal drug elimination
  • Impacts of Organic Cation Transporter 2 (OCT2) on renal elimination
  • Impacts of Organic Anion Transporter 1 and 3 (OAT1 and OAT3) on renal elimination
  • The emerging role of Multidrug and toxin extrusion protein 1 (MATE1) and OAT2 in renal elimination

Hepato-biliary Transporters

  • Introduction
  • Physicochemical properties that affect drug biliary elimination
  • The impacts of Organic Anion Transporting Polypeptide 1B1, 1B3, 2B1, and NTCP on drug disposition
  • The impacts of Organic Cation Transporter 1 (OCT1) on drug disposition: Metformin as a case study

 

Day 2

 

In vitro Approaches to Assess Transporter Impact on Drug Disposition

  • Assays using immortalized human cells
  • Assays using Recombinant System and Membrane Vesicles for kinetics parameters
  • “Bottom up” and “top-down” approaches to assess transporter liabilities

In vivo Approaches to Assess Transporter Impact on Drug Disposition

  • Renal and biliary recovery and clearance calculation in preclinical species
  • Applications of chemical knockout preclinical models for transporter related drug disposition
  • Gene modified models for the contribution of transporter to drug disposition
  • Cynomolgus Monkey as a Potential Model to Assess Drug Interactions: Application and Limitations
  • In vitro/in vivo scalars for human PK prediction
  • Biomarkers Informing Transporter DDI

Impact of metabolic disease and hormones on transporter expression and disposition

  • Metabolic stress as a regulator of transporter expression
  • Impact of liver disease on transporter expression and drug toxicity
  • Impact of metabolic disease on transporter expression in extra-hepatic tissues
  • Regulation of transporter expression during pregnancy
  • Transporter expression in a model of gestational diabetes
  • Disease impact on drug pharmacokinetics and disposition

 

Day 3
Prediction of Drug Interactions Day

Static Models to Predict Human Hepatic, Renal, and Intestinal Clearance and DDI

  • Transporter-enzyme interplay and the extended clearance concepts
  • Prediction of hepatic transporter mediated clearance
  • Principles of drug-drug interactions
  • Extended net effect model to project hepatic transporter-mediated DDI
  • Static models to project intestinal transporter-mediated DDI
  • Static models to project renal transporter-mediated DDI

Introduction to FDA Guidance on Transporter Mediated DDI

  • P-gp and BCRP transporter DDI regulation
  • Renal transporter DDI regulation
  • Hepatic transporter DDI regulation
  • Considerations of other emerging transporters: MATE, MRP2, OAT2 and BSEP
  • Clinical Trials for transporter-mediated DDIs: The Principals

Dynamic Models to Predict Human Hepatic and Renal Clearance and DDI (MV)

  • Principles of Dynamic models for projecting transporter mediated Drug-Drug Interactions
  • Dynamic models to project transporter mediated DDI

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