Typical clinical study designs to determine if the NME is an inhibitor or inducer of a specific P450 enzyme a

Order of Drug Administration and Data Collected

1. Administer probe compound as an SDb regimen; collect PK information 1. Safe and well tolerated with minimal pharmacodynamic effects, allowing for adequate sensitivity in detecting effects on the activity of the relevant P450 pathway; common referenced doses
2. Administer NME as an MDc regimen until steady-state achieved (for inhibition) or at least 5 days for induction to occur (this may extend to 10-14 days, depending on the properties of the NME) 2. For inhibition: standard (relevant therapeutic dose) or highest approved dose (or highest dose in clinical development)d; for induction: highest dose
3. Administer probe compound as an SD + NME on the last few days (≈5 half-lives of NME) or last day (if half-lives of the two compounds are similar), collect PK information for the probe
3. Same as in 1., dosing of the NME should continue until the PK information of the probe is collected
  • a This type of induction study is not mandatory, in particular, if the NME is both a substrate and an inducer of a given P450 pathway, evidence of auto-induction from a multiple oral dose study may be sufficient.

  • b Single dose (SD), e.g. oral midazolam for CYP3A, if the NME is an inhibitor or inducer of several P450s, it is possible to combine several probe substrates in a cocktail to reduce the studies.

  • c Multiple dosing (MD) may be especially needed if a metabolite of the NME is a P450 inhibitor or if there is dose accumulation (e.g., >2-fold) with NME MD.

  • d If the NME has a potentially narrow therapeutic index, then a low but clinically relevant dose may be appropriate.