What is a Drug-Drug Interaction (DDI)?

Transporter vs enzyme DDIs

Enzyme-mediated DDIs (CYP450) affect drug metabolism — chemical transformation into metabolites. Transporter-mediated DDIs affect drug transport across membranes — intestinal absorption (P-gp, BCRP), hepatic uptake (OATP1B1/1B3), renal secretion (OCT2, OAT1/3, MATE1/2-K), biliary excretion (BSEP, MRP2). The most complex DDIs involve both mechanisms simultaneously.

Regulatory DDI assessment package

Before first-in-human: in vitro DDI assessment for CYP450 inhibition (reversible and time-dependent) for CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4; CYP induction (1A2, 2B6, 3A4); and transporter substrate/inhibitor for P-gp, BCRP, OATP1B1/1B3, OCT2, OAT1/3, MATE1/2-K, with BSEP and MRP2 additionally recommended.

Key Facts

• Two main mechanisms: pharmacokinetic DDI (ADME alteration) and pharmacodynamic DDI (additive/synergistic/antagonistic effects)
• Most clinically significant DDIs are pharmacokinetic — mediated by CYP450 enzymes and transporters (P-gp, BCRP, OATP1B1/3, OCT2, OAT1/3)
• Inhibition DDI: victim drug exposure increases (AUC rises) → toxicity risk. Induction DDI: exposure decreases → efficacy loss
• Clinically significant threshold: >2-fold change in victim drug AUC is generally considered significant by FDA/EMA
• FDA 2020 DDI Guidance and ICH M12 (2022) define which enzymes and transporters must be assessed for all NMEs before IND
• IVIVE: IC50 from in vitro assay + clinical Cmax → R value or AUC ratio → predicts clinical significance

Further Reading

• What is ADME?
• FDA & EMA Mandatory Transporters for IND
• What is ABC Transporter?
• In Vitro Drug Metabolism Guide

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