DAAs drug-drug interaction

Every time we are facing an innovation, we have to be prepare to deal with the issues arising from the novelty. In the pharma field, dealing with complex regimes treating chronic conditions is drug-drug interactions.
In order to define the state of the art of the pharmacological interactions of the new protease inhibitors against HCV I have met David Back, Professor of Pharmacology at the University of Liverpool, one of the leading scientist in this field. Last February professor Back was invited in Rome by the faculty of the Associazione Italiana Studio Fegato for the AISF annual meeting.
The common feeling is that we are at the beginning of a new era also for the drugs against hepatitis C….
“Drug-drug interactions definitely represents a challenge for us, with the new directly-acting antivirals.
We have understanding of telaprevir and boceprevir that there are going to be a number of clear drug interactions that we will have to be watching for. This is because both of those drugs are potent inhibitors of one of the key enzymes for the way that drugs are handled in the body, cytochrome P453A. To a greater or a lesser extent, drugs that are metabolized by that enzyme are going to show drug interaction: that is the area that we are going to be concerned about.

During your speech at the 45th AISF Annual meeting you listed the different drug interactions for the two new drugs we are going to have in the clinical practice. We can start with telaprevir… With telaprevir there are a number of drug interactionstudies which have been done which have shown the potential problems that we face. So, for example, with immunosuppressants, which are key for transplant patients, the magnitude of the interaction with both cyclosporine and tacrolimus is such that we are going to have really careful management of dosing for those particular drugs. In one sense, what we would like to say, where there is a large interaction, is let’s use alternatives, but there are challenges because often there are no clear alternatives that we can use and so, we have to manage those interactions.

From an HIV background, which is where I come from, we are used to managing interactions in HIV. The challenge for hepatologists is to be able to think differently, because with peginterferon and ribavirin there are virtually no clinically relevant drug interactions, one or two at the most. With the DAAs, there are going to be a number, and there are going to be some comeds that are contraindicated, there are going to be some that we will have to be very cautious.
With telaprevir I highlighted some of the key areas that we are concerned about, where there will be contraindications, often with some cardiovascular drugs, and there will be others where we will have to manage those interactions with caution, starting with dose modification and then titrating to effect.

And with boceprevir?

Boceprevir has an additional way that the body gets rid of it. So, there is an enzyme called aldoketoreductase, which also handles boceprevir, metabolizes boceprevir, but it’s not going to rule out drug interactions at all. So, although the magnitude of the interaction with immunosuppressants is slightly less and with midazolam, for example, and with some of the statins, it still means that there are going to be contraindications for boceprevir, and there are going to be the areas that we’ll have to start with a dose, the lowest dose that we can, and gradually titrate to the effect. We are on a steep learning curve, we have a limited number of drug interaction studies done, what we now need to do is to begin to understand those drugs that we can’t do studies with, but we are going to have to use in our patients and that’s where I think pharmacologists, discussing with hepatologists and getting groups of people together to really understand how we can best manage the patients.

Taking into account also the HIV coinfection…

HIV coinfection is a specific issue. So, for example, just two weeks ago Merck issued a statement based on pharmacokinetic data for boceprevir, where the magnitude of the interaction of the HIV drugs with the HCV boceprevir drug meant that the extent of that interaction would rule out, being able to coprescribe atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, key drugs, key protease inhibitors for HIV, with boceprevir. So, what we need to then understand is which HIV drugs can we use in coinfected patients, and at the moment a drug like raltegravir has limited interactions, efavirenz is probably going to be a drug that we can use maybe with some dose modification, which has happened with telaprevir, but again: we are on that steep learning curve, we got new data and we now have to under stand how with the new data we can best use the drugs in coinfected patients.

And there is another issue that covers both drugs that are methadone interactions, because we have a lot of patients with HCV that have a story of intravenous drug use.

Yes, so methadone, that’s a key interaction: the good news I think with methadone is that, although there is a change in the exposure of methadone which would initially lead us to think you’d need to modify doses and cause changes in the stable dosing that one would use. In fact, because of some complication of protein binding which I won’t go into in detail, it seems that we don’t need to modify methadone with telaprevir, whether we do with boceprevir at this moment is not clear, but I suspect not. My understanding from the data we have is that methadone we can use pretty much without any dose modification.

As you have already done and established in the HIV field, you are running a website that could be a good help for the clinical practice.

I think it’s critical that we have the information available, so we have set up a website for hepatitis drug interactions which is populated with all the new information that comes from conferences, papers and with an expert editorial board inputting into the website.
What we are going to try to do is to make sure that it is as comprehensive as possible. One of the questions that arose during the discussion after my talk is “can you tell us which drugs we can’t use?”, and what we hope to do with the website is to give clear guidance as to which drugs are not to be used and what alternatives, where there is contraindications, what alternatives can we use in our patients and by doing that we hope that this will be a useful resource for the community. We can’t remember all drug interactions, I work in drug interactions, I can’t remember them, I need help and I need resources.
So, we have a website and from the website you can download for the iPad and for Android resources and iPhone resources, so it’s something that will be useful we hope.

As we said at the beginning of this conversation, we are at the beginning of a new era for hepatitis C treatments, with an impressive pipe line of new drugs.

How can you explain the reason why so many drugs in so small portion of time for hepatitis C? When you look at the pipeline and you see some people quote 60, 70, 80, 90 new drugs in that pipeline, it’s an exciting field to be in. When one considers 170 million people with HCV coinfection, clearly there is a huge potential and we know that we can cure this disease as well. We have started the process with the two new DAAs, we are going to get better drugs, we are going to get drugs that are easier to use. I mean what we are using at the moment, the drugs three time a day in high doses: we want to go to once-daily drugs and potentially then to remove pegylated interferon and ribavirin and those sort of issues are big issues for discussion at the present time and in clinical trial.

The numbers of people affected by this virus maybe is not enough to explain so many drugs because, for instance, for hepatitis B infection affects more people around the world…

Sure. I guess that, I am not from a pharmaceutical background, but when one looks at the pharmaceutical companies and realizes that virtually all the companies now have a big program in HCV with new drugs…we know that some drugs are going to fall by the wayside, that’s the nature of pharmaceutical company development, but I do think it’s an exciting pipeline with an exciting potential for us to really revolutionize the way that we treat hepatitis C. Given the drug interactions which I have described for the two, telaprevir and boceprevir, hopefully we are going to get drugs where we don’t have so many drug interactions and the usefulness would therefore be I think even greater.

Articolo presente in – HAART and correlated pathologies n. 14

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