Drug interaction is an important topic. For example, at the ARAMIS trial, 98% of the patients took at least one co-medication in addition to the study treatment. A lot of these co-medications are metabolized by cytochrome P450 enzymes. Usually abbreviated as CYP enzymes. And therefore, we investigate first in vitro if there is an effect of darolutamide on these CYP enzymes and we could show that there is no clinically relevant effect in vitro and extend that a bit by modeling data which are done according to the guidelines of the health authorities. And that was about the inhibitory effect, but there could be an inducing effect. As we know from the other androgen receptor antagonist that they have a strong inducing effect on the CYP enzymes. We checked it as well and there was at least a potential that also darolutamide could have an effect and so we initiated a Phase I study to investigate what was the most sensitive substrate, which is midazolam and it’s best investigated, I would say, because it is a very sensitive CYP3A4 substrate. And in that trial we could show that there was just a slight effect on the blood concentrations, which was less than 30% and distinctly less than what is shown for the other androgen receptor inhibitors.
We also investigated then transporters, because in vitro the darolutamide showed also a slight effect on P-gp which is a transporter located in the intestinal wall. And you can imagine if it’s an oral drug, you have high concentrations and there could be effects as well. And we did that in the same Phase I study and could show not at all any effect on the specific P-gp substrate.