A key drug development safety consideration is whether the drug candidate will interact with co-medications. Drug-drug interaction (DDI) studies are used to help assess this risk.
These studies quantify the impact of the drug candidate on key drug-metabolizing enzymes. The most studied metabolic enzymes are the cytochrome P450 (CYP) enzyme family members.
Recommended index substrates are drugs known to be metabolized by specific CYPs. Thus, these drugs serve as probes that can detect if the CYP is being induced or inhibited by the candidate drug.
| Enzyme | Sensitive index substrates unless otherwise noted |
| CYP1A2 | caffeine, tizanidine |
| CYP2B6(a) | – |
| CYP2C8 | repaglinide(b) |
| CYP2C9 | tolbutamide(c), S-warfarin(c) |
| CYP2C19 | lansoprazole(c,d), omeprazole |
| CYP2D6 | desipramine, dextromethorphan, nebivolol |
| CYP3A | midazolam, triazolam |
When designing clinical drug-drug interaction studies, a key consideration is whether measuring the metabolites of the probe substrates used is necessary. Measuring the products of metabolism may give further insights into how a drug interaction might affect safety or effectiveness. It can also provide more information about the mechanism of the interaction. Ultimately, all this information can help make sense of the DDI study results.
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) has published the final version of the harmonized drug-drug interaction (DDI) guideline (ICH M12). Check out this blog for our summary of the ICH M12 guidance and our recommendations on how it may impact your DDI package.
At Certara, our experts in clinical pharmacology, DMPK (drug metabolism pharmacokinetics), and PBPK (physiologically-based pharmacokinetic modeling) collaborate via our Center for Excellence in Drug Interaction Science to help our clients perform DDI risk assessments. The question of drug metabolite measurement in DDI studies was recently explored in an article by several authors from this center, published in the journal Metabolites.
The Certara Drug Interaction Database (DIDB) is the largest scientist-curated collection of qualitative and quantitative human in vitro and clinical (in vivo) information related to various extrinsic and intrinsic factors that can affect drug exposure. Using this database, studies with index substrates from the ICH M12 guideline for CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A were reviewed.
For each probe substrate, the frequency of metabolite measurements in the studies was calculated, and a correlation analysis between the change in the plasma exposure of the index substrates and marker metabolites was performed. In total, 3261 individual index DDI studies were available, and 45% of the studies measured at least one metabolite. For individual substrates, the frequency of metabolite measurement ranged from 11% to > 80%.
The analysis indicated that measuring metabolites for substrates like caffeine (CYP1A2), bupropion (CYP2B6), omeprazole (CYP2C19), and dextromethorphan (CYP2D6) enhanced sensitivity in detecting DDIs or reduced intrasubject variability. Including metabolite measurements for omeprazole can offer mechanistic insights into the effects of the interacting compound on both CYP3A4 and CYP2C19. However, for substrates like midazolam, measuring metabolites did not provide a clear benefit for interpreting the outcomes of drug interaction studies.
Therefore, some metabolites are worth measuring, and some aren’t. Knowing this distinction can help your team get the best ROI on your clinical pharmacology program.
Read the full article here
If you need help designing your DDI studies, our experts can help. You can email them at ddi@certara.com