What is a Drug-Drug Interaction (DDI)?

A drug-drug interaction (DDI) occurs when one drug alters the pharmacokinetics or pharmacodynamics of another drug administered concurrently. Transporter-mediated DDIs — where one drug inhibits a transport protein that another drug depends on for absorption or excretion — are among the most clinically significant and require regulatory assessment during drug development.

Transporter-Mediated DDIs

When a drug inhibits P-gp in the intestinal wall, co-administered P-gp substrates are absorbed in higher quantities, increasing plasma concentrations and potentially causing toxicity. Similarly, inhibition of MRP2 or BSEP in the liver can impair bile acid secretion, leading to cholestasis and drug-induced liver injury (DILI). Regulatory agencies require in vitro DDI assessment for new drugs before clinical studies.

Regulatory Framework

The FDA Guidance on DDIs (2020), EMA DDI Guidelines, and ICH M12 specify the transporters that must be evaluated: P-gp, BCRP, OCT1, OCT2, OAT1, OAT3, OATP1B1, OATP1B3, MATE1, MATE2-K, and BSEP. Vesicle-based assays and cell-based inhibition assays are the accepted in vitro methods.

Avoiding DDI-Related Drug Failures

Early in vitro DDI screening significantly reduces the risk of late-stage clinical failures. A well-designed DMPK cascade — including ATPase, vesicle, and cell-based assays — provides the data needed for informed go/no-go decisions.

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