Quick Definition
What is a Drug-Drug Interaction (DDI)?: A drug-drug interaction (DDI) is an alteration in the pharmacokinetics or pharmacodynamics of one drug caused by concurrent administration of another. Pharmacokinetic DDIs occur when one drug affects the absorption, distribution, metabolism, or excretion (ADME) of another — most commonly through inhibition or induction of CYP450 enzymes or transporter proteins.
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
SeamlessBio GmbH · Passau, Germany · info@seamlessbio.de
English 
Deutsch