A8 IDENTIFICATION AND EVALUATION OF CLINICAL SUBSTRATES OF ORGANIC ANION TRANSPORTING POLYPEPTIDES 1B1 AND 1B3

Savannah J. McFeely , University of Washington, Department of Pharmaceutics, Seattle, WA
Tasha K. Ritchie , Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA
Jingjing Yu , Pharmaceutics, University of Washington, Dept. of Pharmaceutics, Seattle, Washington
Eva Gil Berglund , ES2, Medical Products Agency, Uppsala, Sweden
Anna Nordmark , Medical Products Agency, Uppsala, Sweden
Isabelle Ragueneau-Majlessi , Department of Pharmaceutics, University of Washington, Seattle, WA
Organic anion transporting polypeptides (OATP) 1B1 and 1B3 facilitate the uptake of drugs and endogenous compounds into the liver. In recent years, the impact of these transporters on drug-drug interactions (DDIs) has become a focus of research, and the evaluation of their role in drug disposition is recommended by regulatory agencies worldwide1–4. While sensitive substrates of OATP1B1/1B3 have been identified in the literature and probe drugs have been proposed by some regulatory agencies, there is no general consensus on the ideal in vivo substrate for clinical DDI studies as analysis may be confounded by contributions from other metabolic and/or transport pathways. The aim of this work was twofold: to provide a thorough analysis of the available in vitro and in vivo data regarding OATP1B1/1B3 substrates and, from the identified substrates, propose the most sensitive and selective as probe markers of OATP1B1/1B3 activity. Using in vitro, clinical and pharmacogenetic (PGx) data available from the University of Washington Drug Interaction Database (www.druginteractioninfo.org), a total of 178, 37 and 88 substrates were initially analyzed, respectively. The in vitro dataset was reduced to 82 prospective substrates using the criteria of Km ≤ 10 µM and/or uptake ratio ≥ 2, while the clinical data set was reduced to 33 substrates based on the criteria of ≥ 20% inhibition observed. The PGx data set was filtered to 31 substrates using studies where a single SLCO1B1 or SLCO1B3 variant was studied and shown to have an effect on drug exposure. A total of 36 compounds identified using all three datasets were further investigated as possible clinical substrates – 33 drugs, two endogenous compounds (coproporphyrin I and III), and one molecular imaging probe. Of note, a significant number of substrates from the in vitro dataset had no clinical data available to evaluate the relevance of OATP1B1/1B3 in vivo. Of the 33 drugs selected, four showed high sensitivity, with observed AUC ratios > 5-fold following administration of a single dose of rifampin, a recommended inhibitor of OATP1B1/1B3, namely asunaprevir (AUC ratio of 14.8), atorvastatin (12.0), grazoprevir (10.2; component of the combination drug Zepatier), and pitavastatin (6.7). However, except for pitavastatin, these sensitive substrates are also significantly metabolized by CYP3A. Seven drugs showed moderate sensitivity with AUC ratios between 2- and 5-fold when co-administered with rifampin, including rosuvastatin (AUC ratio of 4.7), pravastatin (4.6), and fimasartan (4.3). It is worth noting that most of the substrates identified in this extensive analysis are also substrates of drug metabolizing enzymes and other transporters, highlighting the current challenge of finding a selective probe marker to study the impact of new molecular entities on OATP1B1/1B3 activity in vivo.

References:

1. The International Transporter Consortium. Membrane transporters in drug development. Nat. Rev. Drug Discov. 9, 215–236 (2010).

2. U.S. Food and Drug Administration. FDA guidance for industry on Drug Interaction Studies. (2012).

3. European Medicines Agency. Guideline on the Investigation of Drug Interactions. (2013).

4. The Ministry of Health, Labor and Welfare (MHLW), Japan. Drug interaction guideline for drug development and labeling recommendations. (2014).