AM: Hello and welcome. My name is Axel Merseburger and I’m sitting here in Baveno, Italy, with my dear colleague, Professor Romano Danesi from Pisa, Italy. We are here at the Prostate Cancer Current Treatment Practices meeting to really go into practice practical aspects on how to treat this deadly disease. I’m very delighted to have you here as an expert, maybe you can find some words of your background, what is your daily job?
RD: Thank you, Axel, thank you so much for this discussion. My job is clinical pharmacology so my daily job is to help clinicians in the definition of the potential drug interactions. This job is just to avoid the risk of toxicity associated with multi-drug treatment which is very common in daily practice. Drug interactions are very common because on average patients can take up to seven different drugs and, for these reasons, there are potential interactions at liver function and also renal function. So the problem is viable and should be addressed with professional relevance.
AM: Romano, thank you. This is what we heavily discussed over the last couple of days here in Baveno. Could you help me, starting off with some definitions on pharmacokinetics, so just to give me some advice as a urologist or medical oncologist what the definitions are?
RD: Yes, Axel. Well, considering that most of the drugs are given by the oral route the first problem is the drug interaction at the level of absorption. We used to give to patients proton pump inhibitors to protect the stomach from over-secretion and this is the first point of interaction because many proton pump inhibitors can reduce the absorption or modify the absorption of orally administered drugs. The second level of interaction is the absorption at the intestine level because, for instance, food can interact with the absorption of drugs and also drugs like iron or antacids can interact with the absorption of many drugs. So also at that level we should be aware that drug interaction can reduce the absorption and reduce the amount of drug delivered to the disease. The third level of interaction is, of course, at the liver level. In the liver a drug can be metabolised and metabolised the liver to the bile route in order to be excreted by the intestine or released back to the blood and at that level it can be cleared by the kidneys. So if we administer two or more drugs together we can have an interaction on the drug metabolism system and also the proton pump inhibitors can also affect the drug metabolism. So we have many different steps in which you can have a substantial difference in drug concentrations due to drug interaction again.
AM: Thank you. So when it comes to daily clinical practice, Romano, what is your advice for the novel substances? We have a lot, we have enzalutamide, we have abiraterone, we have radium-223, we have still docetaxel, cabazitaxel and all those novel substances, really, delivering overall survival benefit and therefore are very important within the treatment armamentarium of deadly prostate cancer. So what is your advice? Should we consult you more often as experts, or your department, colleagues from the department as experts on how to treat or can we still continue to treat ourselves? What is, for example, your caution for enzalutamide, abiraterone or what should be taken care of the most?
RD: Well I think the best approach is to collaborate and to interact with each other because there are many interactions, that’s for sure, the problem is to select which interaction is clinically relevant for the patient. So the basic idea is that for complex diseases and for chronic treatments the interaction between the clinician and the pharmacologist is important in order to improve our ability to deliver the best treatment. In terms of novel drugs and metabolic profile of each drug, we know from the literature that, for instance, enzalutamide is released by the kidney up to 70% of the dose administered to the patient while abiraterone is eliminated by the liver up to 70%. So these two drugs are very different in terms of elimination and this could be important for the single patient in which you have reduction of kidney activity, kidney clearance or function, and the same for enzalutamide or abiraterone towards the liver activity of elimination. So that’s the first point. So these two drugs are very different and also they are very different in terms of metabolism because, in particular, enzalutamide is metabolised by different enzymes in the liver and also can induce the activity of selected enzymes and inhibit other enzymes. So the profile is complex and the clinician should be aware of these potential drug interactions and collaboration and exchange of ideas and suggestions is very important.
AM: So we have to work on our education in this field. I also had this impression while being here at this excellent meeting and when looking at the patients, the men with CRPC, most of them like to drink a glass of wine or a beer for a good dinner, so how does this daily alcohol input affect those novel treatment options? Does it have an effect, do we have to advise our patients on how much alcohol intake? Because this is a question that often comes from the patient – ‘Doctor, my wife told me I cannot eat red meat any more, no alcohol, no cigarettes.’ So from your standpoint how should we advise our patients?
RD: Well it is always very good to avoid cigarettes, of course. Smoking is dangerous.
AM: I agree, as a urologist.
RD: And particularly smoking is a strong inducer of liver metabolism. But concerning alcohol intake, at low doses the alcohol intake is a modest inducer of enzyme drug metabolism.
AM: So that means, if I can interrupt you there, that means the drug works more active?
RD: Well it depends because we have some drugs that are pro drugs so if you induce metabolism you increase the amount of active drug delivered into the circulation.
AM: So for the specific drugs abiraterone, enzalutamide, a glass of wine in the evening, what does it do? Sorry to pinpoint you there.
RD: Yes, that’s a good point. Theoretically since abiraterone needs to be metabolised to reach activity because it’s abiraterone acetate and acetate should be removed by esterases, so if you increase metabolism you increase the activity of the drug because it is converted to the active metabolite. On the contrary, enzalutamide, when metabolised, gives to a number of inactive metabolites so the increase in enzalutamide metabolism can reduce, potentially, but of course it should be proven in the clinic, but potentially can reduce the activity of the drug.
AM: OK. So Romano, thank you very much for your insight, your update, your education. I have learned a lot here with you at ecancer. Thank you very much. Thank you for listening to us and have a good day.
RD: Thank you.