Drug-drug interaction (DDI) studies in vivo

Published

March 18, 2026

The drug under investigation can be the object drug or the precipitant drug in the interaction.

NoteICH M12 terminology (2024)

ICH M12 (Step 4, May 2024) replaced the older “victim/perpetrator” terminology with object drug (the drug whose PK is affected) and precipitant drug (the drug causing the interaction).

Object drug study

Evaluates how another drug affects the PK of the drug under investigation.

  • Inhibitor/inducer dosed to steady state (or maximum inhibition); own drug given as a single dose.
  • Measures effect on own drug’s PK (AUC, Cmax).
  • Also assess impact on active metabolite formation and elimination.

Precipitant drug study

Evaluates how the drug under investigation affects the PK of other drugs.

  • Own drug dosed to steady state at maximum therapeutic dose; sensitive probe substrate given as a single dose.
  • Measures effect on probe’s PK.
  • Cocktail studies (e.g. Geneva expanded cocktail) can assess multiple CYP/transporter pathways simultaneously.
  • Probe sensitivity can be improved by measuring metabolite ratios (e.g. hydroxybupropion for CYP2B6, or pravastatin urine collection to isolate hepatic clearance from renal excretion).

Study design

  • Several designs are possible, including cross-over or parallel groups; single-dose or multi-dose administration.

Alternatives to dedicated clinical DDI studies

  • Endogenous biomarkers can provide early DDI signals for certain enzymes and transporters without a dedicated clinical study. No validated biomarkers currently exist for intestinal transporters (P-gp, BCRP, intestinal CYP3A).
  • Pharmacogenomics (e.g. CYP or transporter polymorphisms) can inform or replace DDI studies.
  • PBPK modeling may be accepted by regulators to waive certain clinical DDI studies, particularly for CYP-mediated interactions.