A current buzz phrase in pharmaceutical research right now is “drug-drug interaction” or simply “drug interaction”. The definition of a drug-drug interaction has fluctuated over the last few years, not because of changes in research, but because of misconceptions in the research community. The US Food and Drug Administration (FDA) has published a draft guidance in September 2006 and you can download it for yourself (link). This guidance addresses what are called metabolic drug interactions (i.e. cases where Drug A affects the metabolism of Drug B). The guidance also recognizes that other drug interactions can occur (page 4 of guidance):
Furthermore, not every drug-drug interaction is metabolism-based, but may arise from changes in pharmacokinetics caused by absorption, distribution, and excretion interactions. Drug-drug interactions related to transporters are being documented with increasing frequency and are important to consider in drug development. Although less well studied, drug-drug interactions may alter pharmacokinetic/pharmacodynamic (PK/PD) relationships. These important areas are not considered in detail in this guidance.
In more simplistic terms, drug-drug interactions occur when the presence of Drug A affects the levels of Drug B in the body. These effects can increase or decrease the levels of Drug B. The current regulatory environment focuses on only metabolic drug interactions because they are the best understood, and easiest to evaluate. Other interactions (e.g. absorption, distribution, pharmacodynamic, transporters, etc.) are very difficult to evaluate because it is nearly impossible to isolate those processes in humans to allow for the conduct of a proper scientific experiment.
Therefore, let’s discuss metabolic drug interactions. I believe these can be separated into 2 broad categories:
- Inhibition
- Induction
With Inhibition, Drug A inhibits the metabolism of Drug B. If you refer back to my post on compartmental models, if you reduce the metabolism of Drug B (i.e. the body’s method of eliminating Drug B) then the levels of Drug B will rise. One example of this is the combination of fluoxetine (Drug A, an anti-depressant called Prozac) and dextromethorphan (Drug B, a cough suppressant).
| Drugs taken | Dextromethorphan levels |
|---|---|
| Dextromethorphan | Normal |
| Dextromethorphan + Fluoxetine |
High |
Thus the fluoxetine inhibits the metabolism of dextromethorphan which results in high dextromethorphan levels. And high levels of dextromethorphan can result in dizziness, drowsiness and hallucinations. This is why drug interactions are tested!
With induction, Drug A accelerates the metabolism of Drug B. This is the opposite of inhibition, the induction speeds up metabolism leading to lower drug levels. One example of this is the combination of rifampicin (Drug A, an antibiotic used to treat tuberculosis) and warfarin (Drug B, an anticoagulant called Coumadin).
| Drugs taken | Warfarin levels |
|---|---|
| Warfarin | Normal |
| Warfarin + Rifampicin |
Low |
Thus the rifampicin accelerates the metabolism of warfarin leading to lower warfarin levels in the blood. Low levels of warfarin may lead to blood clots that may cause death. In fact, warfarin levels are so sensitive to rifampicin, that this combination is prohibited on the warfarin drug label (link).
Now when you hear “drug-drug interaction”, I hope the first thoughts that come to your mind are:
- Change in metabolism
- Inhibition or induction
Reminding yourself of these two simple facts will help you conceptualize what is happening, and allow you to ask thoughtful questions. And, it might help detect someone who doesn’t know a thing about drug interactions!
Cancer treatments often use regimens of multiple drugs being administered simultaneously, thus raising their potential for DDIs. Indeed, DDIs that cause unmanageable, severe adverse effects have led to restrictions in clinical use and even drug withdrawals from the market. Read this case study to learn how pharmacometrics was used to assess the risk of a DDI for a new combination cancer treatment.
