Transporter Study Design FAQ

  • Transporters are a class of nearly 400 membrane proteins that act as nature’s “gatekeepers,” facilitating the movement of drugs and other substances into and out of cells. As such, transporters play a vital role in drug response and safety.

  • Drug transporters are involved in drug-drug interactions, pharmacology, toxicology, drug targeting and nutrient depletion. They play an essential role in the trafficking of endogenous compounds and xenobiotics throughout the body.

  • The two main kinds of drug transporter studies are inhibition studies and substrate studies. An inhibition study analyzes whether your drug/new chemical entity (NCE) inhibits the transport of co-administered medications (co-meds) that are known to be substrates of specific transporters. Inhibition of one or more transporter could cause drug-drug interactions in a clinical setting.  In such a case, your drug/NCE would be considered to be the perpetrator drug that alters the pharmacokinetics of the victim co-med.  A substrate study analyzes whether a drug/NCE is transported by any one of a number of specific transporters.  If your drug/NCE is a substrate of any of these transporters, it could potentially become a victim drug if the transporter(s) for which it is a substrate is/are inhibited, enhanced, or induced by co-meds or any endogenous ligands.

  • P-gp and BCRP should be investigated for both inhibition potential and substrate potential. OAT1, OAT3, OCT2 should be investigated for inhibition potential, and if renal elimination accounts for at least 25% of the AUC, then also for substrate potential. OATP1B1 and OATP1B3 should be investigated for inhibition potential, and if hepatic elimination accounts for at least 25% of the AUC, then also for substrate potential. 

  • The same as those recommended by the FDA, with the addition of OCT1 and BSEP for inhibition potential.

  • For more information please contact us to receive the following publications and guidance documents: 

    ITC2 Highlights

    EMA 2012 Final Guidance

    FDA 2012 Draft Guidance

    ITC2 2010 Transporter White Paper

  • In vitro drug transporter studies are recommended for drugs of all BCS classes. However, positive in vitro indications of your drug being a victim (but not a perpetrator) of DDI need not result in clinical trials, if the drug is BCS class I.

  • Typically the FDA asks for transporter DDI and clinical data at the end of phase 2 meeting. This is why it is critical to start the in vitro phase with plenty of lead time to follow-up on positives.

  • No, drug transporter studies are not required for IND filing. However, there may be good strategic, scientific, or even business reasons why drug transporter data is best generated pre-IND. The de-risking costs can pay for themselves in valuation improvements for programs seeking partners and investors.

  • Unless there are important reasons to do drug transporter studies pre-IND, such studies should be started around the time of the dose escalation studies during phase 1 clinical trials. This allows time for follow-ups on positives, including any resulting clinical trials that may be necessary, before the end of phase 2. If you have exclusion criteria among patients, even for phase 2 trials, then you should start in vitro drug transporter studies much earlier.

  • Ideally, you should have a good estimate of Cmax and the elimination route. Knowledge of the BCS class and bioavailability are also useful. At a minimum, you should have caco2 data and elimination studies in rats.

  • Not necessarily. If preclinical species are known to be good predictors of human disposition, then you can feel safe in extrapolating. But if preclinical species are conflicting or ambiguous, then you delay conducting substrate studies. In contrast, the inhibition studies can be started without knowing anything about human elimination, since the regulatory recommendations for inhibition studies do not depend on the elimination path.

  • Although there is considerable overlap in the elimination of drugs between preclinical species and humans, nothing can be predicted with certainty.

  • Yes, you need to have an estimate of Cmax in humans to begin studies.

  • No. Cold parent compound is sufficient. However, if you have hot compound available this makes the assay simpler and cheaper.

  • Positives resulting from a single concentration inhibition screens should be followed up with an IC50, if the IC50 is within 10x Cmax, then you will probably be required to perform a clinical trial with your drug as the perpetrator. Positives resulting from a substrate study need to be followed up with a clinical trial, with your drug as the victim.

  • Regulatory authorities will always err on the side of caution and assume that the positive results are the correct ones. For this reason, false positives can be an expensive problem.