Читать книгу Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations - Sheila Annie Peters - Страница 56

In vitro data are associated with uncertainty due to knowledge gaps in system parameters or scalars. The data may also vary considerably between laboratories due to differences in donors and assays. When an NCE is a perpetrator of drug interaction, the unbound drug concentration at the site of interaction is uncertain, if the compound is a transporter substrate and/or highly bound to plasma proteins. This is especially true for efflux transporter inhibition or for CYP induction, where the driving concentrations are intracellular drug concentrations. The uncertainty in driving concentrations are even higher when these processes occur in the gut. In early development, the therapeutic dose of the perpetrator NCE drug is not identified and can add to the uncertainty in the DDI risk assessment. Sources of uncertainty are listed below:

NCE as victim

 Contribution of gut for CYP3A and UGT substrates, fg;

 Fraction metabolized, fm

 fm,CYP

NCE as perpetrator

 In vitro interaction parameters (Ki, kinact, KI, EC50 )

 In vivo relevance of transporters in determining the intracellular concentrations of inhibitors that are substrates for uptake and/or efflux transporters

 Protein binding of highly plasma‐bound drugs

 Final dose