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

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 In the current FDA draft guidance on drug interactions (DDIs), a compound that inhibits P-glycoprotein (P-gp) may require a follow-up clinical DDI study with digoxin when in vitro \[I\]/IC50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and greater accuracy were obtained when compared to results generated using the recommendations in the current FDA draft guidance.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.

Literature References provided by Caroline A. Lee, PhD

P-gp IC50 Final report out (1) Agarwal, S., Arya, V. & Zhang, L. Review of P-gp Inhibition Data in Recently Approved New Drug Applications: Utility of the Proposed [I1\]/IC50 and [I2]/IC50 Criteria in the P-gp Decision Tree. Journal of Clinical Pharmacology (2012). (2) Cook, J.A. et al. Refining the in vitro and in vivo critical parameters for P-glycoprotein, [I\]/IC50 and [I2]/IC50, that allow for the exclusion of drug candidates from clinical digoxin interaction studies. Molecular Pharmaceutics 7, 398-411(2010). (3) Fenner, K.S. et al. Drug-drug interactions mediated through P-glycoprotein: clinical relevance and in vitro-in vivo correlation using digoxin as a probe drug. Clin Pharmacol Ther 85, 173-81 (2009). (4) Giacomini, K.M. et al. Membrane transporters in drug development. Nat Rev Drug Discov 9, 215-36 (2010). (5) Zhang, L., Zhang, Y.D., Strong, J.M., Reynolds, K.S. & Huang, S.M. A regulatory viewpoint on transporter-based drug interactions. Xenobiotica 38: 709-24 (2008). (6) Acharya, P., O'Connor, M.P., Polli, J.W., Ayrton, A., Ellens, H. & Bentz, J. Kinetic identification of membrane transporters that assist P-glycoprotein-mediated transport of digoxin and loperamide through a confluent monolayer of MDCKII-hMDR1 cells. Drug Metabolism and Disposition 36: 452-60 (2008). (7) Taub, M.E. et al. Digoxin is not a substrate for organic anion-transporting polypeptide transporters OATP1A2, OATP1B1, OATP1B3, and OATP2B1 but is a substrate for a sodium-dependent transporter expressed in HEK293 cells. Drug Metabolism and Disposition 39: 2093-102 (2011). (8) FDA. Guidance for Industry Drug Interaction Studies Study Design, Data Analysis, and Implications for Dosing and Labeling. Draft Guidance (2012). Hepatic Uptake Transporter References: (9) Hagenbuch, B. & Gui, C. Xenobiotic transporters of the human organic anion transporting polypeptides (OATP) family. Xenobiotica 38: 778-801 (2008). (10) Hinton, L.K., Galetin, A. & Houston, J.B. Multiple inhibition mechanisms and prediction of drug-drug interactions: status of metabolism and transporter models as exemplified by gemfibrozil-drug interactions. Pharmaceutical Research 25: 1063-74 (2008). (11) Hirano, M., Maeda, K., Shitara, Y. & Sugiyama, Y. Drug-drug interaction between pitavastatin and various drugs via OATP1B1. Drug Metabolism and Disposition 34: 1229-36 (2006). (12) Kalliokoski, A., Backman, J.T., Kurkinen, K.J., Neuvonen, P.J. & Niemi, M. Effects of gemfibrozil and atorvastatin on the pharmacokinetics of repaglinide in relation to SLCO1B1 polymorphism. Clin Pharmacol Ther 84: 488-96 (2008). (13) Niemi, M., Pasanen, M.K. & Neuvonen, P.J. Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev 63: 157-81 (2011). (14) Noe, J., Portmann, R., Brun, M.E. & Funk, C. Substrate-dependent drug-drug interactions between gemfibrozil, fluvastatin and other organic anion-transporting peptide (OATP) substrates on OATP1B1, OATP2B1, and OATP1B3. Drug Metabolism and Disposition 35: 1308-14 (2007). (15) Parker, A.J. & Houston, J.B. Rate-limiting steps in hepatic drug clearance: comparison of hepatocellular uptake and metabolism with microsomal metabolism of saquinavir, nelfinavir, and ritonavir. Drug Metabolism and Disposition 36: 1375-84 (2008). (16) Poirier, A. et al. Design, data analysis, and simulation of in vitro drug transport kinetic experiments using a mechanistic in vitro model. Drug Metabolism and Disposition 36: 2434-44 (2008).