Managing Digoxin DDI by the P-gp IC50 working group & Practical methods to assess role of hepatic uptake transporters

Date: October 11 2012
Presenter(s): Caroline A. Lee, PhD

Managing Digoxin DDI by the P-gp IC50 working group & Practical methods to assess role of hepatic uptake transporters Webinar presented on October 11st, 2012 by Caroline A. Lee, PhD

Summary of the presentation

In 2008, P-glycoprotein (P-gp) IC50 variability working group was established following the first International Transporter Consortium workshop. Wide variability in IC50 values for each of the inhibitors across all test systems and equations were observed. Applying Principle Components and Variance Component Analyses, the variability in IC50 values was found associated to lab-to-lab differences rather than to systematic differences between the P-gp expression systems. In the current FDA draft guidance on drug interactions (DDIs), a compound that inhibits P-glycoprotein (P-gp) may require a follow-up clinical DDI study with digoxin when in vitro \[I\]/IC50 value is > 0.1 or [I2]/IC50 value is > 10. This cutoff does not incorporate IC50 variability. Receiver operating characteristic (ROC) analysis was utilized to refine in vitro cutoff values of I/IC50 = 0.03 and I2/IC50 = 45. This new cutoff was evaluated against an assembled database of results from clinical digoxin DDI studies (n=104 cases). Using this new cutoff, fewer false positives (FPs) and greater accuracy were obtained when compared to results generated using the recommendations in the current FDA draft guidance. Additionally, a 95% confidence interval test was developed to further guide decision-making to conduct a clinical digoxin study.

The presentation will focus on the development of the refined in vitro cutoff values and its application. Organic anion polypeptide transporters (OATP) are responsible for the basolateral uptake of xenobiotics in various tissues such as the gastrointestinal tract, liver, kidney and brain. Clinical significance of these transporters are largely associated with hepatic uptake either in the disposition of the drug or drug interactions (DDI). Classical substrates for the OATPs are drugs with carboxylic moieties such as statins, fexofenadine and repaglinide as well as non-carboxylic drugs as bosentan, glyburide, and saquinavir. Unlike efflux transporters, OATPs can be a rate limiting step in the uptake of a drug into the liver, thereby modulating drug exposure to metabolizing enzymes and efflux transporter. As such, pronounce victim exposure changes have been reported when OATPs are involved in drug disposition along with metabolism and efflux. In drug discovery and development, appropriate characterization of passive and active contributions toward hepatic transporter uptake is critical in order to attribute contribution to OATPs as well as to predict potential DDIs. If active transport is identified (active component >70%) then further investigation in OATP over-expressed cell lines is warranted to identify specific isoform(s) involved. Moreover, depending on the OATP transporter involved, potential liabilities with polymorphisms may also require follow up investigations. The presentation will focus on practical evaluation of hepatic uptake transporters in drug development and clinical relevance.

Caroline A. Lee is a graduate from the department of Pharmaceutics, University of Washington. Following graduate school, she went to Glaxo as an industrial postdoctoral fellow. As a post-doc, Caroline worked on the co-expression of human cytochrome P450, P450 reductase and cytochrome b5 to produce functional enzyme utilizing the baculovirus/insect cell system. In 1996, she joined Agouron Pharmaceuticals, Inc. as a Research Scientist in the DMPK group. She worked on Viracept, Agouron’s only marketed medicine for HIV (HIV Protease Inhibitor). Agouron was acquired by Warner Lambert and then by Pfizer. With Pfizer, Caroline established a high throughput ADME screening group, providing permeability and P-gp transport information, metabolic stability and CYP mediated drug interaction support to La Jolla’s drug discovery programs. Due to re-organization and centralization of high throughput ADME screening, her group then provided mechanistic enzymology and transporter support to address difficult issues in drug discovery and fulfilling IND or NDA requirements to support filings. In the past several years, she has been involved in various transporter initiatives including contributing author to the PhRMA/DIA Transporter White Paper and leading a Pharmaceutical industry driven project to evaluate the variability in P-gp IC50 and refining appropriate universal in vitro cutoff values to better predict digoxin related DDIs. She is currently working as a consultant in the areas of DM/PK & Transporters.

Literature References provided by Caroline A. Lee, PhD

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