Update on DDI Guidances
Transporters, acting alone or in concert with metabolizing enzymes, can play an important role in modulating drug absorption, distribution, metabolism, and excretion, thus affecting the pharmacokinetics (PK) and/or pharmacodynamics (PD) of a drug. Clinically relevant drug-drug interactions (DDI) mediated by transporters are of increasing interest in drug development. The DDI guidance documents from regulatory agencies include various decision criteria that may be used to predict the need for in vivo assessment of transporter-mediated DDIs (tDDIs). Science and research continue to assess the prediction performances of various criteria, which form the base for updates in the regulatory guidelines. This presentation will focus on those areas pertinent to tDDIs that are different between the recently released FDA final in vitro and clinical DDI guidance (2020) and previous version (2017) and provide rationale for the changes. The presentation will also highlight some challenging issues in predicting in vivo tDDIs from in vitro data, aiming to foster an interactive discussion and promote further research in this field.
Prediction of P-gp-Mediated DDIs
New drugs are evaluated in in vitro bidirectional assays to determine whether they are a substrate and/or inhibitor of the P-glycoprotein (P-gp) transporter. Differences between cell lines and calculation methods can lead to variations in the computation of efflux ratios (ER) and IC50 values used to classify a drug as a P-gp substrate and inhibitor, respectively. Information was collected from the literature on ER and IC50 values generated with digoxin as the probe substrate using different cell lines (Caco-2, MDCK-MDR1, LLC-PK1-MDR1) and inhibition calculation methods (ER, net secretory flux, or secretory permeability). Ratios of inhibitor in vivo concentrations [I] to in vitro IC50 values were used to classify the drugs as in vitro inhibitors. Predictive performance was evaluated by comparing in vitro vs. in vivo classifications. Based on intestinal drug concentrations cut-off criteria ([I2]/IC50 ≥ 10), there were no differences in positive (PPV) or negative (NPV) predictive values based on cell line or calculation method for the drugs. Within this limited dataset, differences between cell lines or IC50 calculation methods do not seem to impact the PPV or NPV of criteria used to predict in vivo P-gp inhibition.
EMA Regulatory Processes
This presentation will provide an insight into the current regulatory requirements from the European Medicines Agency (EMA) concerning the drug transporters in drug development. The most relevant aspects of the respective EMA guidelines will be highlighted. Moreover, regulatory assessment processes will be illustrated with appropriate examples/cases involving drug transporter studies. The most commonly used in vitro approaches will be discussed from a regulatory perspective. In addition, EMA experiences with the respective in vivo and in silico transporter studies will be presented.
Transporters, acting alone or in concert with metabolizing enzymes, can play an important role in modulating drug absorption, distribution, metabolism, and excretion, thus affecting the pharmacokinetics (PK) and/or pharmacodynamics (PD) of a drug. Clinically relevant drug-drug interactions (DDI) mediated by transporters are of increasing interest in drug development. The DDI guidance documents from regulatory agencies include various decision criteria that may be used to predict the need for in vivo assessment of transporter-mediated DDIs (tDDIs). Science and research continue to assess the prediction performances of various criteria, which form the base for updates in the regulatory guidelines. This presentation will focus on those areas pertinent to tDDIs that are different between the recently released FDA final in vitro and clinical DDI guidance (2020) and previous version (2017) and provide rationale for the changes. The presentation will also highlight some challenging issues in predicting in vivo tDDIs from in vitro data, aiming to foster an interactive discussion and promote further research in this field.
Prediction of P-gp-Mediated DDIs
New drugs are evaluated in in vitro bidirectional assays to determine whether they are a substrate and/or inhibitor of the P-glycoprotein (P-gp) transporter. Differences between cell lines and calculation methods can lead to variations in the computation of efflux ratios (ER) and IC50 values used to classify a drug as a P-gp substrate and inhibitor, respectively. Information was collected from the literature on ER and IC50 values generated with digoxin as the probe substrate using different cell lines (Caco-2, MDCK-MDR1, LLC-PK1-MDR1) and inhibition calculation methods (ER, net secretory flux, or secretory permeability). Ratios of inhibitor in vivo concentrations [I] to in vitro IC50 values were used to classify the drugs as in vitro inhibitors. Predictive performance was evaluated by comparing in vitro vs. in vivo classifications. Based on intestinal drug concentrations cut-off criteria ([I2]/IC50 ≥ 10), there were no differences in positive (PPV) or negative (NPV) predictive values based on cell line or calculation method for the drugs. Within this limited dataset, differences between cell lines or IC50 calculation methods do not seem to impact the PPV or NPV of criteria used to predict in vivo P-gp inhibition.
EMA Regulatory Processes
This presentation will provide an insight into the current regulatory requirements from the European Medicines Agency (EMA) concerning the drug transporters in drug development. The most relevant aspects of the respective EMA guidelines will be highlighted. Moreover, regulatory assessment processes will be illustrated with appropriate examples/cases involving drug transporter studies. The most commonly used in vitro approaches will be discussed from a regulatory perspective. In addition, EMA experiences with the respective in vivo and in silico transporter studies will be presented.