Clinical Education Initiative [email protected] THE BASICS OF ARV DRUG INTERACTIONS Speaker: Christopher Nguyen, PharmD, AAHIVP 4/5/2017 The Basics of ARV Drug Interactions [video transcript] 00:00:07 - [Speaker] Okay, so these are my disclosures. 00:00:10 So today, in the 20 minutes, I'm just gonna do some basics of drug interactions. We'll look at some interaction mechanisms in ARV, seeded in anti-retro virals. You will understand some potential of drug classes, as far as interactions, and then look at some ways to prevent or manage ARV drug interactions. 00:00:36 This patient case I put in here, just to demonstrate the possibility of having drug interactions, due to polypharmacy. This was a patient of mine back in 2010 and when he came to me that was his regimen, Intelence, Isentress, and Selzentry, but more importantly these are the rest of his medications. 00:00:53 And it was a massive list that he came to me with. So I had to prune down quite a few of them. There's some duplications, there's some overkill, there's just a whole bunch of stuff, and this kinda demonstrates you know, how easy it is to rack up medications and then have interactions happen. 00:01:21 So, as we know, our patient population is aging and as they age, there's gonna be more multiple co- morbidities and we tend to rarely de-prescribe, we just add on medications, and so polypharmacy is pretty common and our patients are increasingly using herbals and alternative meds and over-the- counters, and so, those are the types of meds that we don't tend to see, and so all of this combined, can increase the risk for drug interactions. 00:01:56 This was a the Swiss study, the one study in that country, and this showed the prevalence of drug interactions in this cohort, between ARVs and co-medications. Most of them, as you can see tend to be, the light gray is the orange-flag interactions and what that means is interactions that may require dosing adjustments. Green flag ones, I'm sorry, the darker gray is the orange flag, the green-flag one are interactions where it may be clinically insignificant, where you can just monitor. And then there's very few red ones, specifically this was with oral Midazolam, where it's contra-indicated. And this cohort are with HIV specialists, and you can see the prevalence of drug interactions that still happen with HIV providers, let alone in a clinic, without a lot of HIV specialists, so it's something that we have to keep an eye on. 00:02:58, So let's talk mechanisms. So there's two main mechanisms, as far as drug interactions in general, not just in HIV. You have your pharmacodynamic interactions, and then pharmacokinetic drug interactions. 1 So the dynamic drug interactions is when two drugs kind of potentiates an effect in your body or the effects are cancel out each other. And then the pharmacokinetic drug interaction is when one drug alters the way the second drug is absorbed, distributed, metabolized, or excreted. 00:03:32 Okay, so pharmacodynamic, I've put some examples here. So for instance when you give zidovudine and gancyclovir together we see potentiation for marrow suppression or we can use that to our advantage for instance, zidovudine and gancyclovir when combined they have synergistic HIV activity. So that's pharmacodynamic. That mechanism tends to be not as common as pharmacokinetic interactions, which is the most common type. 00:04:04 And it can happen in any of the four areas of a drug's life, from when it enters your body to when it goes out. So absorption, distribution, metabolism, and excretion. So for instance, an absorption, you could have alterations in the GI dissolution and absorption. So the perfect example there is with PPIs and Lipradin. So that is a contraindication that is in the absorption phase. You can have alterations in protein binding which affects the distribution phase. I can't think of any HIV examples in here but for instance Warfarin and setra. They kind of compete for protein binding. Your most common mechanism is going to be in your metabolism base, specifically the cytochrome P450 isozymes, So that is where you're going to have your inhibition and induction of this isozyme which metabolizes the majority of our drugs. So that's where most of the ARV interactions will be. And then your alterations and urinary excretion, and that, an example would be dalutragibir and metformin. 00:05:25 So this gives you a distribution of the Cytochrome P450 isozyme and this is the most common drug interaction area or mechanism. So the major isozyme is going to be your CYP3A4 and 2D6. So that makes up a chunk of your drugs. And then you have your 2 Cs, so your 2C9 and 2C19. So those three that were 3A to 2D and the 2 Cs will make up the majority, and then the rest of them kind of sprinkled in in there. So the way I tell my students when I teach them interactions is that you have your substrates which are the drugs getting metabolized, because the isozyme in that is your victim, as far as drug interaction. So again the drugs that modulate three and four will be your perpetrators. This can be confusing sometimes for people including pharmacists so I'm going to go through them. So the inhibitors will increase the concentration of your substrate by reducing the metabolism of them. And the effect, overall effect is going to be increased toxicity. Increase in efficacy too but more so increase in toxicity is what we worry about. The inducers decrease the concentration of your substrate by increasing their metabolism. So the overall effect is going to be decreased efficacy. In general, if you have because sometimes, actually many times, you're just not going to have one interaction, you may have multiples. So if you have both of them there at the same time, in general, your inhibitors will win out. So the strength of the inhibition is going to be stronger. It's also quicker onset offset, so it's almost immediate, versus induction takes days to happen. So usually you want to look at the inhibitors a bit more closer than the inducers when you have both of them on board. With that said though, nowadays, at least 10% of all of our drugs are prodrugs, and scientists are making more and more prodrugs as we move forward, 2 to improve pharmacokinetics. And prodrugs will have the opposite effect. So the prodrugs are medications that are not active and they have to be metabolized into the active form or give off an active metabolite. So if you have a CYP inhibitor of a prodrug, it's going to be the opposite. You're going to have a decreased efficacy, and then if you have a CYP inducer of a prodrug you have increased toxicity. So you just kind of flip them when you have prodrugs. And then it gets more complicated when a drug gets shunted through several isozymes. So a great example, here I'll use both multiple isozyme and a prodrug, which is codeine. So codeine is a prodrug and 10% of it gets metabolized through CYP2D6 into morphine and that's your actual drug with analgesic properties. Codeine doesn't really have any analgesic properties. The rest of it, gets shunted through 384 in gluconagation, into inactive metabolites. So if you have CYP2D6 inhibitors, then your patients may not have any of the analgesic effect. If you have inducers on board they may have codeine toxicities. So it's kind of the opposite. At the same time, if you now are blocking 3A4 then the medications will go through the 2D6 more, and so now you're going to have more effect of the efficacy or the toxicity. So it can get complicated when you have prodrugs, and when you have a drug that gets metabolized through multiples of these isozymes. 00:09:38 So besides that, nowadays, more and more of these drug transporters are being recognized as important drug interaction areas in HIV, influencing pharmacokinetics, so you have P-gp which is going to be your biggy, P-glycoprotein. And this is an eflux pump, so drug comes in, it gets pumped out. And so when you block P-gp you get more drugs inside. When you induce P-gp you have less drugs because it's pumping it out more. And then you have other kidney transporters that we know are involved in HIV medication interactions, such as, MATE1 for cobicistat. And then OAT2 for doch aggravator, and stuff like MRP4 which is where your tenofovir interacts with your enzates. So you have a whole bunch of these different transporters that are now being more recognized as contributing to drug interactions. Next slide. 00:10:47 Okay, so a whole bunch of different factors contribute to whether a drug interaction is clinically significant and how bad it's going to be. So you have comorbidities, you have gender, age, the older patient is the more you will see the extent of it, body size and composition, and you have ethnicity which determines genetic polymorphism. So one of the isozymes for instance, the CYP 2D6, is a highly polymorphic isozyme so you can have ethnicities that without the drug interaction is already is effected by the 2D6 being working too much or not enough.