Abstract
Pharmacokinetic drug–drug interactions (DDIs) occur when a drug alters the absorption, transport, distribution, metabolism or excretion of a co-administered agent. The occurrence of pharmacokinetic DDIs may result in the increase or the decrease of drug concentrations, which can significantly affect the drug efficacy and safety in patients. Enzyme-mediated DDIs are of primary concern, while the transporter-mediated DDIs are less understood but also important. In this review, we presented an overview of the different mechanisms leading to DDIs, the in vitro experimental tools for capturing the factors affecting DDIs, and in silico methods for quantitative predictions of DDIs. We also emphasized the power and strategy of physiologically based pharmacokinetic (PBPK) models for the assessment of DDIs, which can integrate relevant in vitro data to simulate potential drug interaction in vivo. Lastly, we pointed out the future directions and challenges for the evaluation of pharmacokinetic DDIs.
Highlights
Drug–drug interactions (DDIs) can occur in patients undergoing polytherapy at pharmacokinetic (PK) and pharmacodynamic (PD) level, resulting in altered drug concentrations by either inhibiting or inducing the enzymes or transporters responsible for the disposition of that drug or producing agonistic or antagonistic effects [1]
If in vitro studies indicate a high-risk for PK-related DDIs, a mechanistic static model will be applied, estimating the ratios of concentration area under the curve (AUCi/AUC) for cytochromes P450 (CYPs)- and transporter-based inhibition or induction in the presence (AUCi) or absence (AUC) of the perpetrator
To give an in-depth understanding of how various interactions between victim and perpetrator are handled by the physiologically based pharmacokinetic (PBPK) modeling approach, here we summarized the key differential equations for different DDI mechanisms
Summary
Drug–drug interactions (DDIs) can occur in patients undergoing polytherapy at pharmacokinetic (PK) and pharmacodynamic (PD) level, resulting in altered drug concentrations by either inhibiting or inducing the enzymes or transporters responsible for the disposition of that drug or producing agonistic or antagonistic effects [1]. Both the PK and PD interactions may lead to reduced efficacy or increased toxicity in the clinic. The induction of transporters is most reported for P-gp [2]
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