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 | Dose |
|---|---|
| 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.