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DDI Assessment Strategies
Transporter mediated drug-drug interaction assessments (tDDI) are performed to determine whether a compound can cause a drug interaction and also whether that compound can fall victim to a drug interaction.
DDI Victims: Vulnerable Substrates
A drug that relies on a transporter to mediate its disposition can become unsafe because inhibition can lead to increased absorption, decreased elimination or distribution into an off-target organ.
Many factors determine if a substrate drug will be a DDI victim such as whether it relies on a given transporter significantly for disposition, if it has limited passive permeability, low solubility and a narrow therapeutic index.
Because of these factors, substrate assessments are typically done on a case by case basis depending on the chemical structure, organs of elimination and physicochemical properties.
DDI Perpetrators: Inhibitors
Because many drugs rely on transporters to control their disposition, inhibiting them can cause drug levels to become dangerously high.
Both substrates and non-substrates of the transporter can be inhibitors. Inhibitors can have quite different chemical structures than substrates. The cellular localization of the seven FDA transporters causes them to be exposed to all compounds during absorption and systemic circulation regardless of whether they pass through that organ.
Because of these factors, the safest strategy is to assess NCEs for the inhibition of all seven FDA transporters.
Recommended DDI Assessment Study Design
Many customers choose to start with the full OptiProfile-Essential™ inhibition panel screen for all seven FDA transporters.
If significant inhibition is observed for a given transporter, the OptiDDI-IC50™ kinetic study is performed as a follow up to determine the IC50 inhibition constant.
When a substrate assessment is warranted, the OptiDDI-Substrate™ screen is performed. If the compound is found to be a substrate, full dose response curves can be completed as follow up studies to determine if transport can be saturated and the kinetic properties Km and Vmax.
Transporter mediated drug-drug interaction assessments (tDDI) are performed to determine whether a compound can cause a drug interaction and also whether that compound can fall victim to a drug interaction.
DDI Victims: Vulnerable Substrates
A drug that relies on a transporter to mediate its disposition can become unsafe because inhibition can lead to increased absorption, decreased elimination or distribution into an off-target organ.
Many factors determine if a substrate drug will be a DDI victim such as whether it relies on a given transporter significantly for disposition, if it has limited passive permeability, low solubility and a narrow therapeutic index.
Because of these factors, substrate assessments are typically done on a case by case basis depending on the chemical structure, organs of elimination and physicochemical properties.
DDI Perpetrators: Inhibitors
Because many drugs rely on transporters to control their disposition, inhibiting them can cause drug levels to become dangerously high.
Both substrates and non-substrates of the transporter can be inhibitors. Inhibitors can have quite different chemical structures than substrates. The cellular localization of the seven FDA transporters causes them to be exposed to all compounds during absorption and systemic circulation regardless of whether they pass through that organ.
Because of these factors, the safest strategy is to assess NCEs for the inhibition of all seven FDA transporters.
Recommended DDI Assessment Study Design
Many customers choose to start with the full OptiProfile-Essential™ inhibition panel screen for all seven FDA transporters.
If significant inhibition is observed for a given transporter, the OptiDDI-IC50™ kinetic study is performed as a follow up to determine the IC50 inhibition constant.
When a substrate assessment is warranted, the OptiDDI-Substrate™ screen is performed. If the compound is found to be a substrate, full dose response curves can be completed as follow up studies to determine if transport can be saturated and the kinetic properties Km and Vmax.