Newsletter Volume 33, Number 1, 2018


 写真:Thomas Ebner, Ph D

Comment for Best poster presentation award of JSSX meeting 2017

Boehringer Ingelheim Pharma GmbH & Co KG,
Biberach, Germany
Thomas Ebner, Ph D

Our poster entitled “Probe-drug cocktails to assess transporter activity in humans: Concept, probe selection and pharmacokinetic evaluation” covers the background and results of an innovation project at Boehringer Ingelheim. The idea of this project was born by the problems of variable data of in vitro assays on drug transporters and the need to conduct many clinical drug-drug interaction trials that are triggered by conservative guidelines of regulatory agencies. First concepts of a such a probe drug cocktail approach date back to spring 2012 when the first Boehringer-Ingelheim Drug Transporter Symposium was held at Kobe Pharma Research Institute of Nippon Boehringer Ingelheim. Since then this project gained momentum and received strong support within Boehringer Ingelheim and by many distinguished experts in the field of drug transporters. It was our goal to provide a new tool for the assessment of transporter-based drug-drug interactions to be implemented in the process of drug development.

When the project was first discussed in 2012 we encountered many difficult questions: Which and how many test drugs should be selected? Which transporters should be investigated? Which studies and clinical trials are required to validate this cocktail? Should the probe-drug cocktail address only transporter-based drug-drug interactions or should cytochrome P450-based rug-drug interaction be included? Because at that time no other drug transporter probe-drug cocktail was described, we had to do some pioneering work. First we formed a project group with members of experts in the field of drug transporters of all three development sites of Boehringer Ingelheim that are located in Biberach an der Riss (Germany), Ridgefield (Connecticut, USA) and Kobe (Japan). After several rounds of internal discussion we developed a concept of a four component drug transporter probe-drug cocktail. We wanted to have a practical tool that would be widely applicable. Therefore, we chose well-established drugs for our cocktail: Metformin, Digoxin, Furosemide and Rosuvastatin. These drugs are considered as safe for single dosing and are widely available around the world. We also selected conventional dose size so no pharmaceutical manufacturing of special formulations is needed. The biggest hurdle of a drug transporter probe-drug cocktail is the fact that there are no drugs available for testing in human that are specifically transported by a single transporter. This is different to probe-drug cocktails for cytochrome P450 enzymes, for which very specific probe-drugs are available. So we had to make compromises in the selection of probe drugs. Rosuvastatin, for example, is a substrate not only for several OATP transporters, but also for BCRP and NTCP. On the other hand, Rosuvastatin is a sensitive probe-drug that is well suited to investigate drug-drug interactions that are based on the inhibition of hepatic uptake by OATPs. It is also safe and widely used. These are some reasons why we selected Rosuvastatin. Basically, we wanted a probe drug cocktail that would cover some very important processes of drug absorption and drug disposition: 1) Intestinal absorption ad effects of intestinal efflux transporters such as P-gp and BCRP; 2) Uptake into the liver by hepatic uptake transporters such as OATP1B1 and OATP1B3; 3) Excretion by the kidney by transporters that contribute to renal elimination such as OAT and OCT.

The next step was to assess the possibility that the four probe drugs could interact with each other, this means the issue of mutual interaction. A thorough review of published data was done and a series of in vitro studies was performed to assess the transporter properties of furosemide. For this compound a few data were not available from published literature. We could confirm that furosemide was a good substrate for OAT and could show that there was some lower extent of active transport by BCRP, MRP2, OATP1B1 and OATP1B3. When we concluded these investigations, the results were presented at the second Boehringer-Ingelheim Drug Transporter Symposium in Biberach an der Riss in 2015 and were published in the same year in the Journal of Pharmaceutical Sciences. In hit year we also obtained the results of the first clinical trial that was conducted to investigate the possibility of mutual interactions between the four cocktail components. Surprisingly, there was an increase of the exposure of Rosuvastatin when it was dosed as a cocktail component compared to when it was dosed alone without concomitant probe drugs. The effect was not big but the exposure of Rosuvastatin was increased and was outside the formal bioequivalence criteria. In subsequent clinical trials the problem was addressed. Eventually, a modified probe-drug cocktail was identified that used lower dosed of Furosemide and Metformin that was free of mutual interaction in a clinical trial. Currently, another clinical validation trial is ongoing that investigates the effect of known potent inhibitors of drug transporters on the probe-drug cocktail. In this trial we also want to assess possible effects of potent inhibitors of drug transporters on endogenous components that may serve as biomarkers for transporter drug-drug interactions.

Working on this project has been very satisfying to me. This is because it involved excellent discussions and many productive meetings with so many colleagues from within Boehringer Ingelheim who work in Japan, Germany and the USA. So this was a truly global project. There were also many discussions with distinguished experts in the field of drug transporters who were invited as external consultants. These experts included among others Mikko Niemi, Peter Swaan, Martin Fromm, Cathleen Giacomini, and Richard Kim. It was also very stimulating that we encountered big interest for our project when the data were first presented to the scientific community at various occasions. The value of such an approach was also underlined by the point that there have been published at least three other drug transporter probe-drug cocktails by other groups from academia or the pharmaceutical industry. My colleagues and I are very proud on this achievement and to have opened a new field for the assessment of transporter-based drug-drug interactions and are grateful for support received by Boehringer Ingelheim and the positive and motivating discussion with our peer scientist at meetings and conferences.

Personally, I want to say thank you to the colleagues who were the key contributors to the “Cocktail Team” at Boehringer Ingelheim: Naoki Ishiguro, Mitchell Taub, Peter Stopfer, Thomas Giessmann, Fabian Müller, Ashish Sharma, Heike Zimdahl-Gelling and Sabrina Wiebe.