Antiretroviral Pharmacology: An Expert Interview With David M. Burger, PharmD, PhD

Antiretroviral Pharmacology: An Expert Interview With David M. Burger, PharmD, PhD With the large number of antiretroviral regimens now available for the treatment of HIV, clinical pharmacology has become one of the most critical areas of AIDS research. journalArticle ethnopharmacology,tubercuolsis, tuberculosis, pharmacology clinical, dual protease inhibitor treatment, pharmacology, antiretroviral resistance,inhibitor,antiretrovirals,df, Efavirenz,tx,efavirinz,inhibitior, antiretroviral therapy,Antiretrovirals - Protease Inhibitors,tuburculosis,antiretroviral,tb,regimens,inhibitors,tuberculous, tenofovir disoproxil fumarate,inhibiter,tubercolosis,consumption Disclosure: Mark Wainberg, PhD, has disclosed that he has received grants for clinical research from GlaxoSmithKline and Bristol-Myers Squibb. Disclosure: David M. Burger, PharmD, PhD, has disclosed that he has received grants for clinical research and educational activities from Gilead (Viread and Emtriva). He has received grants for clinical research from Roche, Abbott, Merck, Bristol-Myers Squibb, and GlaxoSmithKline. Dr. Burger has received grants for educational activities from Abbot, Merck, Boehringer Ingelheim, Bristol-Myers Squibb, and GlaxoSmithKline. He has served as an advisor or consultant for Roche, Merck, Bristol-Myers Squibb, and GlaxoSmithKline. Medscape Medscape HIV/AIDS 07/27/2004 10 2 Editor's Note: With the large number of antiretroviral drug combination regimens now available for the treatment of HIV infection, clinical pharmacology has become one of the most critical areas of AIDS research. Investigators within this subspecialty generate data on antiretroviral pharmacokinetics, pharmacodynamics, and drug interactions that provide a foundation upon which viable antiretroviral therapy regimens are built.Dr. Mark Wainberg, Director, McGill University AIDS Centre, McGill University, Montreal, Quebec, Canada, and former president of the International AIDS Society, spoke with Dr. David Burger, Hospital Pharmacist, Associate Professor of Clinical Pharmacology; University Medical Centre, Nijmegen, The Netherlands, on the latest on HIV pharmacology from the XV International AIDS Conference in Bangkok, Thailand.Dr. Wainberg: I'm here with Dr. David Burger of The Netherlands who chaired the session on pharmacology at today's XV International AIDS Conference in Bangkok. Dr. Burger, why don't you tell us some of the highlights of the data presented at today's session?Dr. Burger: The first interesting presentation was the tipranavir drug interaction study of multi-protease inhibitor (PI)-resistant patients, in which tipranavir was added [to regimens] as well as a second boosted PI.[1] Quite surprisingly, they saw a decrease in the plasma levels of the second boosted PI. The extent of the drug interaction was at least 50% with amprenavir and lopinavir, and it was more than 80% with saquinavir. The main message from that study is that if people are going to use tipranavir in this setting, they should be looking for drug interactions with the second PI. At this moment, there is no recommendation to combine tipranavir with other PIs until we have more information on dosing and related issues.Dr. Wainberg: That's fascinating. Any idea of mechanism?Dr. Burger: Tipranavir is a known enzyme inducer, and that's why a higher dose of ritonavir (200 mg) was used as a booster; it was ritonavir 100 mg with the other PIs. But apparently this enzyme-inducing effect is relevant for the other PI [concurrently] administered with tipranavir.Dr. Wainberg: Well it certainly means that we have to think twice before using a double-boosted-PI approach with tipranavir, but on the other hand we want to point out that the resistance profile for this agent is looking great right now, and we still have hopes that it will be an excellent PI in salvage regimens.Dr. Burger: But the benefit of the second PI, if drug levels are this reduced, will be limited.Dr. Wainberg: What else did you learn today?Dr. Burger: The in vitro study of possible interactions with tenofovir.[2] We've seen some virologic failures in triple-nucleoside regimens given once daily. One of the possible mechanisms for these virologic failures has been drug interactions, either in plasma or intracellular. Data showed that these interactions did not exist, and that there is no antagonism between tenofovir and these drugs, as has been suggested. We are looking at these virologic failures for possible explanations, but there are no pharmacologic explanations that we saw.Dr. Wainberg: Well so far there are not. It's possible that we're not at the end of this story. Personally, I think nucleoside pools could turn out to play a role, but I agree that we need more research before we know for sure.Dr. Burger: Another important presentation today was a South African study of the potential effect of fluconazole on nevirapine plasma levels.[3] We see more and more patients in developing countries treated with nevirapine-containing regimens. We also know that fluconazole is frequently used in these populations. So far we have had no idea that there was any drug interaction between these 2 agents, but today we saw very important data that drug levels of nevirapine might be doubled by the addition of fluconazole, and that might lead to more nevirapine-associated toxicity. The major problem of the study as presented today is that the investigators couldn't make an interpatient comparison, and they only compared treated patients with historical controls of nevirapine who used without fluconazole. That was probably a different study population. We're not quite sure if the interaction is as it was presented today, but if people are going to use this, they should be monitoring for nevirapine toxicity and a possible drug interaction.Dr. Wainberg: What about half-life of nevirapine as it pertains to this? Is that going to be a potential issue?Dr. Burger: Yes, certainly.Dr. Wainberg: So the potential to select for resistance will also be important in this context.Dr. Burger: The other important pharmacology session that I wanted to highlight was in the tuberculosis session. It was a randomized trial of efavirenz 600 mg vs 800 mg in tuberculosis patients who used rifampin.[4] It is known that rifampin decreases the efavirenz plasma levels. For that reason, there is the official clinical recommendation to increase the dose from 600 mg to 800 mg per day, but there has never been a randomized clinical trial demonstrating that you really need that dose increment with rifampin in the setting of Asia or Africa, where patients usually have a lower body weight. The data showed that the efavirenz level was almost similar in the 600-mg group compared with the 800-mg group. There were very few people in the 600-mg group who had subacute efavirenz levels. On the other hand, in the 800-mg group there were more toxic efavirenz levels. So we have to find a balance between the toxicity of the 800-mg level and also the added cost, compared with possibly more virologic failures with the 600-mg dose. But I think that the data clearly show that the 600-mg dose is adequate for the majority of patients.Dr. Wainberg: So that's good news on one hand, but it also shows how difficult it is sometimes for clinicians in developing countries to use efavirenz without encountering problems. What do you think is going to represent some of the most important research that we need to get done in the next 2 years before we regroup at the International AIDS Conference in Toronto?Dr. Burger: You can see at this conference that, on one hand, we have pharmacokinetic studies on double-boosted PIs, which is very relevant in the developed world for multidrug-resistant patients. On the other hand, we have seen some basic studies looking at drug interactions that we have never taken seriously, but now they are becoming important, because people in developing countries are using these drugs. I think you have 2 different ways of doing research and must look at the needs in both parts of the world.There's clearly more data needed on the HAART regimens in developing countries -- what is the efficacy and toxicity of the fixed-dose combinations? What are the drug interactions that are relevant in the developing world? This is clearly what must be done.You must also be aware that the quality of the medication being used must be ensured. There was a presentation today on pharmaceutical equivalence for fixed-dose combinations. We haven't seen any bioequivalence data yet, and the same is true for other regimens. These fixed-dose combinations and other generic drugs can only be marketed on the basis of pharmaceutical equivalence, not only bioequivalence, which I think we need in this part of the world and in Africa to ensure that we are going to treat patients correctly.Dr. Wainberg: Thank you very much, David. I think without question your research and that of your colleagues has advanced our field a great deal and has provided practical benefit to clinicians and the patients who they're treating. Good luck with your continued research. <ol><li>Walmsley S, Leith J, Katlama C, et al. Pharmacokinetics and safety of tipranavir/ritonavir (TPV/r) alone or in combination with saquinavir (SQV), amprenavir (APV), or lopinavir (LPV): interim analysis of BI1182.51. Program and abstracts of the 15th International Conference on AIDS; July 11-16, 2004; Bangkok, Thailand. Abstract WeOrB1236.</li><li>Myrick F, Miller MD, Borroto-Esoda K. In vitro anti-HIV-1 combination studies of tenofovir with abacavir and lamivudine in primary cells. Program and abstracts of the 15th International Conference on AIDS; July 11-16, 2004; Bangkok, Thailand. Abstract WeOrB1237.</li><li>Geel J, Pitt J, Orrell CJ, Van Dyk M, Wood R. The effect of fluconazole on nevirapine pharmacokinetics. Program and abstracts of the 15th International Conference on AIDS; July 11-16, 2004; Bangkok, Thailand. Abstract WeOrB1238.</li><li>Manosuthi W, Sungkanuparph S, Vibhagood A, et al. A randomized controlled trial of efavirenz 600 mg/day versus 800 mg/day in HIV-infected patients with tuberculosis to study plasma efavirenz level, virological and immunological outcomes: a preliminary result. Program and abstracts of the 15th International Conference on AIDS; July 11-16, 2004; Bangkok, Thailand. Abstract MoOrB1013.</li></ol>