AAPS-FDA Drug Transporters

The American Association of Pharmaceutical Scientists (AAPS) and U.S. Food and Drug Administration (FDA) co-sponsored the workshop “Drug Transporters in ADME: From the Bench to the Bedside,” held April 16-18, 2018 in Herndon, VA. There were twenty-six presentations covering numerous aspects of transporter science as well as poster sessions.

XenoTech took the opportunity to host a discussion on Tuesday over lunch. We outlined six drug transporter related questions typically faced when submitting a new drug for approval by the FDA and European Medicines Agency (EMA) and Pharmaceuticals and Medical Devices Agency (PMDA). The questions focused on the drug-drug interaction (DDI) guidance documents issued by the FDA in 2017, the EMA in 2013 and PMDA in 2017, and sparked some great conversations.

Based on the discussion, drug transporter interaction assays are typically being performed between phase I and phase II, but the timing can vary depending on the class of compound, indication and concomitant medications of the patient population. The majority of respondents also noted that, even though the guidance documents allow for alternative methods, they are using the outlined test systems and methods.

The 2017 DDI guidance from the FDA notes that, among other parameters, the non-specific binding of a drug to the incubation vessel should be evaluated, however, the impact on interpretation of the results is vague. The majority of attendees noted that inhibition parameters are based on the nominal concentration, although one respondent adjusts based on the free concentration.

In the 2013 DDI guidance from the EMA, it is noted that multiple inhibitors should be included as controls for inhibition studies (strong and less potent). This was a controversial topic, but the majority of respondents agreed multiple inhibitors should be included.

One problem facing researchers is solubility at the high concentrations needed for in vitro transporter inhibition assays to evaluate the cutoffs for clinical studies. One solution presented by a participating staff member from a regulatory agency was to evaluate the solubility in the relevant physiological buffer (e.g., intestinal fluid or blood) to put the in vitro solubility into perspective.

To wrap up the discussion, we polled attendees on possible transporters that may be added to the guidance documents. Only OCT1 rose to the level of possible inclusion in the standard panel. OCT1 has relevant clinical DDIs, multiple in vitro substrates and inhibitors and polymorphisms that can affect the PK and PD of substrates. However, researchers are often testing transporters that are not specifically stated in the guidance documents, as well. In fact, during a separate presentation at the workshop, a representative from the EMA stated that the agency is regularly requesting additional transporters beyond the standard panel.

Another focus of the workshop was to review the expected publications resulting from the Third Workshop on Membrane Transporters in Drug Development held in March 2017 and hosted by the International Transporter Consortium (ITC). There are approximately nine publications planned for November 2018 in the Journal of Clinical Pharmacology and Therapeutics. Key topics that will affect researchers investigating potential DDIs include: 1) papers on emerging transporters of clinical importance and 2) transporter polymorphisms in drug disposition and development. Several transporters are discussed, but OCT1 is recommended for addition to the standard panel of transporters. Other topics include: 3) biomarkers for investigating transporter function and DDIs, 4) commentary on metformin clinical DDI study design, 5) comparison of dabigatran etexilate and digoxin as clinical probes for P-gp inhibition, 6) advancing predictions of tissue and intercellular drug concentrations, 7) disease associated changes in drug transporters, 8) molecular modeling of drug-transporter interactions, and 9) a commentary on the in vitro BSEP inhibition and the prediction of DILI.

The International Transporter Consortium is “comprised of scientists from academia, industry and regulatory agencies around the world. We seek to advance our understanding of transporter biology to develop drugs with the goal of improving human health.” For more information, visit: https://www.itc-transporter.org/.

For more information on regulatory DDI guidance, you may be interested in listening to Dr. Brian Ogilvie’s recent webinar reviewing the 2017 DDI guidance from the FDA and his follow-up webinar and poster, co-presented by Dr. Andrew Parkinson, on the differences between the FDA, EMA and PMDA guidance documents.

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