Highlights from the 2013 AAPS Workshop on Drug Transporters in ADME (by Kent Grindstaff, PhD)
March 26, 2013
The 2013 AAPS Workshop on Drug Transporters in ADME:
From the Bench to the Bedside once again provided a great opportunity to review the current state of the transporter field and its impact on drug development. Presentations by Academic, Industry, and Regulatory Agency participants underscored advances made over the past few years in the transporter field and highlighted challenges that still lay ahead. While recognition of transporters as key determinants of absorption, distribution, excretion, and even metabolism for xenobiotics is widely accepted, how we address these interactions and the implications on drug safety continue to evolve.
HIGHLIGHTS FROM THE 2013 AAPS WORKSHOP:
PHYSIOLOGICAL ROLE OF TRANSPORTERS: INTERACTIONS WITH DRUG MOLECULES
Creatinine-drug Interactions Involving Renal Transporters
Alex Sparreboom, Ph.D., St. Jude Children’s Research Hospital
- Highlighted the importance of properly interpreting serum creatinine and creatinine clearance as markers of renal function.
- Addressed drug interactions that lead to an increase in serum creatinine without affecting glomerular filtration rate.
- Provided evidence for role of organic cation transporters (OCT1 and OCT2) in creatinine clearance.
Hepatic Clearance Prediction from In Vitro Drug Metabolism and Transport Data: A New Perspective for Accessing Drug-drug Interactions
Gian Camenisch, Ph.D., Novartis Pharmaceuticals Cooperation
- Emphasized the interplay of uptake, metabolism, biliary secretion, and sinusoidal efflux in hepatic clearance.
- Demonstrated improved correlation in existing model for hepatobiliary clearance upon integration of transporter-mediated processes.
CURRENT STATE OF THE ART: TRANSPORTER ASSAYS
Transporters in Discovery: Progress with Development of Tools and their Applications
Matt Soars, Ph.D., Bristol-Myers Squibb Company
- General overview of in vitro tools available to address transporter interactions.
- Stressed importance of rigorous characterization of transporter models and the need to understanding their utility and limitations.
- Use of appropriate transporter study design for informed decision-making in both early-stage discovery and development.
TRANSPORTERS IN TRANSLATIONAL MEDICINE
Metformin PK/PD following Ablation of both Renal and Hepatic OCT or MATE Transport: Implications to Interpretation of Metformin Drug Interactions in Humans
Maciej J. Zamek-Gliszczynski, Ph.D., Eli Lilly and Company
- Evidence for altered metformin pharmacodynamics (PD) in absence of corresponding changes in systemic pharmacokinetics (PK) due to altered OCT and/or MATE transporter function.
- Emphasized importance of PK and PD measurements for metformin drug-drug interaction studies since systemic PK alone is insufficient address potential changes hepatic distribution.
INTRACELLULAR CONCENTRATIONS OF DRUG AND METABOLITES: MEASUREMENT, INTERPERTATION, AND IMPLICATIONS
Assessment of Intracellular Unbound Concentrations: Implications for Hepatic Efflux of Drugs and DDIs
Kim Brouwer, Pharm.D., Ph.D., University of North Carolina
- Highlighted importance of determining not only disposition but also intracellular unbound drug concentrations when evaluating DDIs and drug-induced toxicity.
- Presented method for estimating unbound hepatocellular concentration of drugs. Intravital Multiphoton Microscopy as a Tool for Evaluating Drug Parmacokinetics and Pharmacodynamics
Kenneth Dunn, Ph.D., Indiana University
- Use of in vivo imaging technique to address the distribution of drugs on a subcellular level in real-time.
- Ability to access the effect of drugs on transport mechanisms and dissect uptake and elimination processes.
REGULATORY PERSPECTIVES ON TRANSPORTER DDIs IN DRUG DEVELOPMENT FDA
Recommendation on Transport DDIs and Emerging ITC Transporters
Lei Zhang, Ph.D., U.S. Food and Drug Administration
- Stressed importance of transporters in ADME and thus their potential affect on PK and/or PD.
- Emphasized the increasing number of New Chemical Entities (NCEs) with transporter information of their label since 2007.
- Consider adding MATE1 and MATE2K to OCT2 decision table.
The European Regulatory Position on Transport DDIs
Eva Gil Berglund, Ph.D., Medical Products Agency
- Reviewed recommendations in 2012 EMA guidance on DDIs.
- Stressed importance of discussing rational for selecting specific transporter models in submission.
- Emphasized need to evaluate transport interactions of major metabolites.
- Addressed value in using multiple transporter models to confirm transporter interactions.
- Discussed importance of identifying specific transport pathway for actively eliminated drugs.
SOLVO had 3 posters at the workshop
Seeking the Optimal BCRP (ABCG2) Probe
Márton Jani, Erzsébet Beéry, Emese Kis, Ildikó Makai, István Sziráki, Franciska Erdő, Annamária Bui, Tasha K. Ritchie, and Péter Krajcsi Solvo Biotechnology
Optimization of cellular uptake assays for the determination of test compound interactions with OAT1 (SLC22A6)
Erzsébet Beéry, Ildikó Makai, Csilla Ambrus, Viktoria Juhasz, Eszter Patakine Illes, Tasha K. Ritchie, Rémi Magnan, Márton Jani, Péter Krajcsi Solvo Biotechnology
Chlorothiazide is a substrate for the human uptake transporters OAT1 and OAT3
Joe K. Zolnerciks , Viktória Juhász, Erzsébet Beéry, Zoltán Nagy, Annamária Bui, Éva Molnár, Rémi Magnan, Márton Jani, Tasha K. Ritchie, William W. Johnson, Kent Grindstaff, Eric Wexler and Péter Krajcsi Solvo Biotechnology
Next entry: SOLVO partners with AIT to represent its small-animal Molecular Imaging Services worldwide
Previous entry: New BCRP Probe Substrates
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