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Clinical Pharmacology of Antiretroviral Therapy: An Expert Interview With Courtney V. Fletcher, PharmD


Editor's Note:
The success of highly active antiretroviral therapy (HAART) rests upon the use of antiretroviral drugs to achieve maximum virologic suppression with the smallest cost in terms of adverse effects. In HIV care, this balancing act has become increasingly complex over the years. Studies of the clinical pharmacology of antiretroviral drugs (including their use in real-world situations in which patients take these drugs in combination with other medications), have an essential role in the overall care of patients with HIV disease and the development of new agents. Following the 13th Conference on Retroviruses and Opportunistic Infections (CROI) in Denver, Colorado, Mary Anderson, PhD, Clinical Editor of Medscape HIV/AIDS, spoke with Courtney V. Fletcher, PharmD, Professor and Chair, Department of Clinical Pharmacy, University of Colorado Health Sciences Center; Denver, Colorado, to discuss important advances in the clinical pharmacology of HIV disease. Dr. Fletcher's contribution to our understanding of the chemotherapy of HIV disease is attested to by a record that includes about 100 peer-reviewed publications, a similar number of abstracts, and service on the editorial boards of Antimicrobial Agents and Chemotherapy, Pharmacotherapy, and Pharmacotherapy, as well as the Department of Health and Human Services Panel on Clinical Practices for the Treatment of HIV Infection, among many others.

Medscape: Identifying and managing adverse effects of concomitantly administered drugs has long been an important focus of clinical pharmacology. For antiretroviral drugs in particular, drug-drug interactions have had both positive and negative consequences. Especially in salvage settings there has been some interest in using dual-boosted protease inhibitors in an attempt to overcome the limitations posed by drug resistance. What do recent data tell us about the utility of this approach?

Dr. Fletcher: The recent data are mixed. There's some information that suggests that 2 protease inhibitors can be combined together, and there's information that indicates they can't. The challenge, of course, is trying to predict which is going to be the case when you put 2 of these agents together, and I think this is emerging as one of the real issues in clinical pharmacology of antiretroviral agents. These drugs are mixed substrates for cytochrome P450 enzymes and for drug transporters; they may also be inducers or inhibitors of these pathways. As a result, when you put these combinations together, it's getting increasingly difficult to predict which way the interactions are going to go.

In terms of some specific examples, I'll start with some recent data that would suggest that a dual protease inhibitor regimen of atazanavir and lopinavir/ritonavir may have a favorable pharmacokinetic interaction. Investigators from Johns Hopkins University in Baltimore, Maryland, conducted a study[1] in healthy volunteers in which they looked at 3 regimens: (1) atazanavir/ritonavir alone; (2) atazanavir plus lopinavir/ritonavir all at standard doses; and (3) atazanavir and lopinavir/ritonavir together. In the short term, these regimens were well tolerated, and there was no evidence for any adverse pharmacokinetic interaction. The atazanavir concentrations as well as the lopinavir concentrations were really very comparable to historical data. This is a regimen that can now move forward to an evaluation in HIV-infected persons, as this study provides a solid set of data from healthy volunteers that there is no adverse pharmacokinetic interaction.

In contrast, the conclusions were different for data presented on the combination of fosamprenavir and atazanavir.[2] This study also was done in healthy volunteers. These individuals received once-daily oral doses of fosamprenavir alone, at 1400 mg; atazanavir alone at 400 mg; and the combination of both. It's important to stress that ritonavir wasn't included in any of these regimens, so this was done to simply look at these 2 protease inhibitors together.

Amprenavir concentrations were increased with the combination of fosamprenavir and atazanavir. However, the important finding here was that the atazanavir concentrations, both area-under-the-curve and trough levels, were significantly decreased. On average, the atazanavir trough level was 60 ng/mL, and this is a trough concentration that would not be viewed as being virologically effective. So, while the combination was well tolerated in this study, and atazanavir provided a boosting effect on amprenavir concentrations, the large decrease in atazanavir concentrations would be to a level at which you would not recommend a fosamprenavir/atazanavir regimen for further study in HIV-infected individuals. Of course it's not known what would happen in combination with ritonavir and these combinations may be appropriate for evaluation, but the present data provide strong evidence to indicate that the combination of fosamprenavir and atazanavir should not be done.

Medscape: Would it be fair to say that these kinds of studies in healthy individuals can predict or inform us as to which studies should be carried out in HIV-infected people?

Dr. Fletcher: Yes; I think that's exactly the value of these studies. This question also came up during a poster discussion section on complex drug-drug interactions at CROI. There certainly are data to show that there are some differences for certain drugs, with regard to their pharmacokinetics between healthy volunteers and HIV-infected individuals. But while the magnitude of an interaction could be different, there aren't any data that I'm aware of, and no one in the audience would volunteer any information either to state that the existence of an interaction would be different between healthy volunteers and HIV-infected persons. Therefore, I feel fairly confident about taking data that were obtained from studies in healthy volunteers forward into HIV-infected persons with the requirement that you confirm those data in HIV-infected persons.

Medscape: Another antiretroviral combination that would seem quite plausible in this setting of multiclass resistance is tipranavir/ritonavir and enfuvirtide. There was a pharmacokinetic study of that combination at this meeting. What were the key features of that study and what were the most important take-home messages?

Dr. Fletcher: The results of this study[3] were a bit of a surprise. In fact, the title of this abstract itself states that an unexpected drug interaction seems to exist between tipranavir/ritonavir and enfuvirtide (or T-20). The finding was that there were higher tipranavir and ritonavir concentrations when coadministered with T-20. This is really quite surprising because there's not an obvious mechanism, nor did the authors speculate on a mechanism that may explain this. I think that what we're learning a bit about tipranavir/ritonavir is that this combination has one of the more complex metabolic pathways compared with some of the other protease inhibitor combinations. Like other protease inhibitors, tipranavir is a substrate for cytochrome P450 (CYP) 3A, and that's why ritonavir increases the concentrations; but at the same time, tipranavir itself is a potent inducer of p-glycoprotein transporter and that's why it can reduce concentrations of some concomitantly administered protease inhibitors, such as lopinavir/ritonavir. As a result, it's a drug for which it will be very difficult to predict what's going to happen when it's combined with other drugs that are substrates or inducers or inhibitors of transporters or drug-metabolizing enzymes. That said, we do not think of enfuvirtide as being an inhibitor or an inducer of the cytochrome P450 family of enzymes. Whether there may be some ability of enfuvirtide to affect a drug transporter, which might affect tipranavir concentrations, remains to be determined. The pharmacokinetic take-home message from this abstract is a suggestion that there does appear to be an interaction there, but the mechanism of it is really not clear. It really warrants further evaluation in a rigorously designed study vs the observational sparse sampling study presented at this meeting.

In addition to clarifying whether an interaction exists and its mechanism, the clinical significance needs to be established. The combination of tipranavir/ritonavir and T-20 was used extensively during the clinical development of tipranavir/ritonavir. No difference in the safety profile of tipranavir/ritonavir was observed when combined with T20 compared with when it was not. These data, I believe, provide clinicians using this combination with some comfort -- that if tipranavir concentrations are indeed elevated then this does not appear to adversely affect the safety profile.

Medscape: Given the concern about dyslipidemia in patients taking antiretroviral drugs, many physicians use lipid-lowering drugs often with less than optimal results. Were there any new data in this area?

Dr. Fletcher: The new information that was presented on statins involved one of the newest agents of this class, rosuvastatin, and the pharmacokinetics when coadministered with lopinavir/ritonavir.[4] This was a study of 22 HIV-infected individuals and it was really an observational and safety study as opposed to a definitive pharmacokinetic and pharmacodynamic study. What I think we can take away from this study is that rosuvastatin did lower cholesterol, so it did exert a pharmacologic effect that you would expect in a statin. Sparse pharmacokinetic evaluations suggested that the lopinavir/ritonavir levels were not affected by rosuvastatin.

The surprise out of this study was that the rosuvastatin levels appeared to be 1.5- to 2-fold higher than expected. This was not expected because the clearance of rosuvastatin is not thought to be susceptible to drugs that are CYP enzyme inhibitors, such as ritonavir. However, as the study authors note as well, the rosuvastatin pharmacokinetic data were compared with historical controls. Those types of comparisons are always fraught with difficulty, so whether what we're seeing is a true interaction by which rosuvastatin levels are increased or an observation that's confounded because of its comparison with the historical control, is really not known yet. What was brought out during the discussion of this abstract at the "Complex Drug Interaction" poster discussion session is the need for a controlled, intensive, pharmacokinetic study to determine whether there is any interaction between rosuvastatin and lopinavir/ritonavir; it was noted that this study is presently under way.

Medscape: Pharmacogenomics is an area of increasing interest. Were there any new data at this meeting that provide insight into the role of genetics in determining response to therapy or lack thereof, or adverse effects?

Dr. Fletcher: I don't believe that there were any new, clinically significant data presented at this meeting. There were pharmacogenetic data that extended observations previously made. For example, we already know that efavirenz is hepatically metabolized, primarily by the cytochrome 2B6 (CYP2B6) enzyme pathway, and it's been nicely shown at previous CROI meetings that polymorphisms in the cytochrome 2B6 pathway can explain differences in concentrations of efavirenz among various demographic groups of HIV-infected adults. Additional information was presented at this year's meeting on efavirenz and CYP2B6 polymorphisms in pediatric patients[5] and a study on interindividual variation by our European colleagues[6] showing that there may be some individuals who, because of polymorphisms in CYP2B6, have very high efavirenz concentrations These studies didn't really change the bottom line clinically. We know that these polymorphisms exist and that for a drug like efavirenz, they can explain why some people have low concentrations and some people have high concentrations.

Medscape: Were there any new pharmacokinetic data about the use of antiretroviral drugs during pregnancy?

Dr. Fletcher: There were a couple of important abstracts in terms of antiretroviral drugs in pregnancy. The first was one out of the Pediatric AIDS Clinical Trials Group [PACTG] that looked at the pharmacokinetics and safety of tenofovir in pregnant women and their newborns.[7] In this study, data were available from 9 mother-infant pairs, where the mothers received tenofovir at a dose of 600 mg at the onset of labor for vaginal delivery or 4 hours before a planned cesarean section. This study showed that the maternal concentrations were less than those in adults who had received the same 600-mg single dose of tenofovir, and also lower than steady-state levels in HIV-infected persons taking 300 mg once daily. These investigators now plan to study a higher maternal dose of tenofovir in an attempt to try to achieve the same concentrations in a pregnant women that you would achieve in an HIV-infected person taking the standard dose of tenofovir.

Another important piece of information from this study is that cord blood concentrations of tenofovir were measurable, so it does show that the drug is being placentally transferred; but these concentrations were quite variable, so the degree of transfer is really quite broad. Finally, in terms of the concentrations of tenofovir in the infant, all of the concentrations were less than 25 ng/mL when they were measured after 12 hours of age. This is an important finding because it would suggest that if a decision were made to use tenofovir in these infants, then you probably would be able to start therapy relatively early postpartum because these infants aren't born with high amounts of tenofovir in their blood.

There were 2 other studies that were important in terms of pharmacokinetics during pregnancy -- one from Europe and one from the United States that looked at lopinavir. The one from the United States was reported by Mark Mirochnick, [MD, of Boston University School of Public Health, Boston, Massachusetts] and again comes from the Pediatric AIDS Clinical Trials Group.[8] At the International AIDS Conference 2 years ago in Bangkok, this team reported very low concentrations of lopinavir/ritonavir in the third trimester of pregnancy in women who were taking the standard 400/100 mg dose twice daily.[9] At that meeting, they reported that they would be increasing the dose of lopinavir/ritonavir to 533/133 mg twice daily to see whether that could achieve concentrations that you would see in nonpregnant individuals. It was very nice at this meeting to see the outcome of that dose escalation. What they showed was that the 533/133 mg twice-daily dose during the third trimester of pregnancy did achieve the target concentration in the vast majority of those pregnant women -- 20 of 23.

They also looked at the 533/133 mg dose at 2 weeks postpartum and concluded that at that point in time it was acceptable to decrease to the standard 400/100 mg twice-daily dose of lopinavir/ritonavir. Although the concentrations were elevated, it was not to any concerning degree, but they were above the target. These results suggested that the pharmacokinetic changes associated with pregnancy, which resulted in lower concentrations during the third trimester of pregnancy, had resolved by 2 weeks postpartum.

The last aspect of this study was an evaluation of lopinavir concentrations during the second trimester. With the 400/100 mg twice-daily dose, 5 of the 8 women who were studied met the target concentration. These data may then provide evidence that the pharmacokinetic changes associated with pregnancy are beginning to appear during the second trimester. This might imply that a dose increase could be warranted; however, the sample size for this evaluation was quite small and additional information is really necessary.

The findings from this PACTG study[8] differ a bit from those reported by Lyons and colleagues[10] from Europe, who studied a cohort of pregnant women on the standard dose of 400/100 mg of lopinavir/ritonavir. This study was an observational pharmacokinetic study, so there were not the intensive pharmacokinetic profiles that were done in the Mirochnick study. What the investigators from Europe found was a median lopinavir level of approximately 3600 ng/mL and that 94% of the pregnant women had trough concentrations above 1000 ng/mL; 1000 ng/mL has been the suggested threshold concentration for lopinavir in individuals who have a virus with wild-type susceptibility to lopinavir. These authors concluded that the standard dose of 400/100 mg twice daily during pregnancy was adequate, but also recommended the use of therapeutic drug monitoring.

This leaves us with 2 conflicting abstracts: (1) the study by Mirochnick and colleagues suggesting that the higher dose is necessary in the third trimester of pregnancy, and (2) the study by Lyons and coinvestigators concluding that standard dosing is adequate. The intensive pharmacokinetic evaluations employed in the study by Mirochnik with comparisons to postpartum provide compelling evidence for pharmacokinetic changes in lopinavir/ritonavir in the third trimester of pregnancy. The lack of virologic outcome data limits the ability to draw conclusions regarding the adequacy of dosing. The Lyons study used only a sparse sampling strategy, which is not optimal to determine changes in drug disposition. Virologic outcome data were provided to show that 14 (88%) of the 16 women had undetectable viral loads and that all of the infants (n = 9) were HIV PCR-negative. A final issue with the Mirochnick PACTG study is that the dose of 533 mg lopinavir/133 mg ritonavir is no longer available because of the change to the Meltrex 200/50 mg per-tablet formulation of lopinavir/ritonavir. So one either has to use 400/100 mg or would have to go up to 600/150 mg twice daily.

I think most pharmacologists would agree that pregnancy is one area where therapeutic drug monitoring, if available, could be very useful. Therapeutic drug monitoring, however, is much more widely available in Europe than it is in the United States. There are sex differences in pharmacokinetics for certain drugs, and certainly the effect of pregnancy on drug absorption and disposition is going to be different for each woman. Because of all these factors, this is an area in which clinicians, if they have therapeutic drug monitoring available to them, may find this concentration information useful in terms of guiding therapy in their individual patients. Finally, this is an area in which we need much more pharmacokinetic, safety, and virologic information -- not just for lopinavir/ritonavir, but for the other antiretrovirals that are used in pregnant women.

Medscape: What do you think were the most important studies as far as investigational drugs are concerned, and what do you see for the future in terms of PK/PD analyses of investigational antiretrovirals?

Dr. Fletcher: I think the most exciting new drug information was on the 2 integrase inhibitors.[11,12] We're still very early in the development of these drugs, with phase 1/2 trial data being presented. But for both drugs, pharmacokinetic data were presented that helped form a basis for the doses that are presently being studied. Short-term virologic studies showed that both of these drugs in heavily treatment-experienced patients were associated with substantial reductions in viral load and that the short-term safety and tolerability was acceptable.

While these data were very promising for these 2 agents, it is early in drug development and more is going to need to be learned in terms of their pharmacokinetics, susceptibility to drug interactions, and longer-term virologic effect and safety.

In terms of drug interactions, there are some differences between these drugs. The compound being developed by Gilead looks as though it will be developed to be given in combination with ritonavir. We know it is a drug that, like protease inhibitors, is very susceptible to the effects of [CYP] enzyme inhibition and that you can boost concentrations substantially by giving it with ritonavir. The compound being developed by Merck, on the other hand, does not appear to be susceptible to boosting with ritonavir. It's a drug that looks to be cleared more by glucuronidation, and while there are clearly fewer interactions that occur with agents that are glucuronidated as opposed to cleared by the cytochrome P450 family, they're not totally immune from drug interactions. For example, atazanavir inhibits glucuronidation, and ritonavir and rifampin can induce glucuronidation. So there are going to be challenges associated with both of these compounds in terms of fitting them into the polypharmacy that already exists in terms of treating the heavily treatment-experienced patient. Still, this is really very promising news in terms of the integrase inhibitors.

Medscape: It sounds as though the dosing of combination antiretroviral therapy regimens might become increasingly more complex, as you have interactions not just between ritonavir and protease inhibitors but between ritonavir and other members of the HAART regimen.

Dr. Fletcher: I guess I've been in this business long enough to make the pronouncement that this is the most complex drug administration setting that exists in all of medicine at the present time. Among the antiretrovirals, regarding the drugs that I mentioned up front in my comments, there are some that are substrates for drug-metabolizing enzymes and for drug transporters; in addition they may also be inhibitors and inducers of the drug-metabolizing enzymes. Antiretrovirals are used in combination in HAART regimens, and they are increasingly coupled with drugs that are used to treat either complications of therapy or existing concomitant diseases. These combinations of substrates, inducers, and inhibitors creates the potential for complex, 2- or 3-way interactions, and is one of the most difficult areas of modern medicine, and unfortunately seems to be getting more so. Drug interactions pose significant challenges to HIV healthcare providers in terms of trying to understand their mechanisms, apply beneficial interactions, avoid adverse interactions, and manage others.

Medscape: Were there important results in other areas of clinical pharmacology?

Dr. Fletcher: There was new information about drug disposition in sanctuary sites, which I think has some important implications. There were 2 abstracts by investigators from North Carolina[13,14] that looked at antiretroviral concentrations in the female genital tract of 11 different antiretroviral agents. This group of investigators performed very nice detailed pharmacokinetic studies, obtaining blood plasma and directly aspirated genital tract fluids. They were able to look at the area-under-the-curve ratio in the genital tract fluids: blood plasma to assess how well these drugs penetrate into the genital tract. What they found was that nucleoside drugs such as FTC [emtricitabine], 3TC [lamivudine], and zidovudine penetrate very well, actually achieving concentrations higher in the genital tract than in the blood plasma. Then there are some nucleosides such as d4T [stavudine] and abacavir that penetrate much more poorly . Most of the protease inhibitors also appear to penetrate poorly, which is not surprising because of their high degree of protein binding. The potential implications for these data are that they ] may provide information on which drugs are going to be most useful for preexposure and postexposure prophylaxis.

Other work on drug disposition was reported by colleagues from San Diego, who looked at central nervous system penetration of antiretroviral agents.[15] They used data in the literature to assign a penetration score to the antiretrovirals; for multiple drugs, they simply summed this penetration score. What they found was that the higher the penetration score, the lower the viral load in the cerebrospinal fluid. I think this is important because of the renewed interest in the induction/maintenance strategies for antiretroviral therapy. In other words, can you take individuals from a full HAART regimen down to just -- for example -- a boosted protease inhibitor only? I thought this abstract was provocative in terms of ways to think about penetration into sanctuary sites in the setting of full HAART, but also in more simplified regimens.

The last thing I will mention are the new data that emerged on drug safety. CROI has been a good venue for the presentation of long-term safety data. I think this is an important obligation particularly of pharmaceutical companies and regulatory authorities because these drugs can be approved with only 24- to 48-week data, so postmarketing information on long-term safety is essential. Probably the biggest news out of this conference in terms of long-term safety was the risk of nephrotoxicity associated with tenofovir; there were 5 abstracts on this topic.[16-20]

There was information from Gilead on their expanded-access program that now has data from some 10,000 patients in it.[16] This substantial safety dataset shows that over the first 4 years the safety profile of this drug seems to look very similar to what it looked like in clinical trials, and that the rate of serious renal adverse events was quite low -- approximately 0.5%. In contrast, data were presented from the US Centers for Disease Control and Prevention,[17] the Atlanta Veterans Administration Group,[18] the University of Washington in Seattle,[19] and the AIDS Research Consortium of Atlanta.[20], which all showed higher rates of nephrotoxicity. While all these studies were done in slightly different ways, all were retrospective. From the Centers for Disease Control, for example, investigators looked at the medical records of some 11,000 HIV-infected persons (so again a fairly substantial dataset), and found rates of renal impairment higher in persons who received tenofovir than in those who did not, and higher than that reported in the Gilead expanded-access program. [17] The good news is that neither identified a new adverse reaction in these postmarketing surveillance studies of tenofovir; the true rate of tenofovir-associated nephrotoxicity and the factors that may predispose to it, however, warrant additional study and monitoring.

Medscape: Might those differences be due in part to different patient populations?

Dr. Fletcher: Yes. I think this is a real possibility. The Centers for Disease Control series, for example, may be much more of a real-world view of rates of renal dysfunction, whereas the expanded-access program from Gilead is from a much more selected group of patients.

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