Drug Update: The Old, the New, the Still to Come
This summary provides a limited and brief overview of abstracts presented at the 11th Conference on Retroviruses and Opportunistic Infections in San Francisco in February. The focus of this review involves drug interactions between antiretrovirals, agents that might be given at the same time as HIV medicines and pharmacokinetic data that may affect how HIV medicines are given or for those newer agents that are likely to be recruiting for patients in clinical trials in the coming months.
Dr. Angela Corbett of the University of North Carolina-Chapel Hill presented data that provides more information on the dual detrimental drug interaction that occurs between Lexiva and Kaletra, initially presented by Dr. Angela Kashuba on behalf of the AIDS Clinical Trials Group (ACTG) at the ICAAC conference in September 2003. Dr. Kashuba had shown that when Kaletra and Lexiva were given together, the drug levels for both drugs were significantly reduced -- meaning these two drugs could not be taken together. Dr. Kashuba's group also showed that giving more Lexiva and/or Kaletra did not overcome this interaction.
However, Dr. Corbett's group tried to determine if the interaction occurred because of the two protease inhibitors (PIs) being taken at the same time, so they separated the doses by 4 and 12 hours in a group of non-HIV infected volunteers. Eleven seronegative persons took Lexiva and Kaletra at full doses (700 mg + 400/100 mg, respectively) together for 10 days at the same time. They then were randomized to either take their PIs at regular doses twice a day at the same time (0H), twice a day four hours apart (4H) or taking 1,400 mg of Lexiva (4 tablets) and 800/200 mg of Kaletra (6 capsules) 12 hours apart (12H). The amount of drug in their blood was then checked after seven days of this new dosing scheme. Dr. Corbett's group found that separating the doses did not improve the Lexiva levels, but did improve the Kaletra levels when the drugs were given twice daily. Even when double doses were administered once daily, the levels were still reduced from historical controls. The authors caution that more research to find out how to dose these two PIs together has to be done and until then, these two medicines should not be used together.
Dr. Heather Wynn Vezina presented clinical results of dosing alterations done on patients receiving Agenerase and Kaletra (lopinavir/ritonavir). Given the recent data showing lowering of both lopinavir and Agenerase when these agents are given together, but still having patients in clinic on this regimen, Dr. Wynn Vezina measured levels of these two agents and made dose adjustments based on those. Levels at the end of the dosing interval for lopinavir were 2-3 times lower than the manufacturer recommends. Agenerase levels were similar to previous reports when given with 100 mg of Norvir. Still, the doses of lopinavir and/or Agenerase were increased in an attempt to improve the levels. Six patients had an extra one or two lopinavir capsules added to their regimen every 12 hours and 3 patients increased their Agenerase intake by one or two capsules every 12 hours as well. Two patients had both done. Diarrhea forced one patient to reduce lopinavir dosing. Lopinavir dose increases in the 6 patients resulted in improvement of plasma levels and improvement in viral loads and CD4 counts at the 12-week time point. This data, again short-term, demonstrates some utility of TDM (therapeutic drug monitoring) in HIV and how select instances may benefit from use of measuring plasma levels of antiretrovirals.
Dr. Scott Penzak of the National Institutes of Health's Warren G. Magnuson Clinical Center presented some important findings revealed when his group decided to test generic anti-HIV medications abroad for how much drug was actually in there. This is vital as many in the world cannot afford the high price for antiretrovirals and seek alternative sources for the drugs -- including black market and counterfeit suppliers.
Dr. Penzak's group tested five PIs and Sustiva (efavirenz) obtained from sources outside the United States. Specifically, they tested products from Zambia, South Africa, Lithuania and Jamaica. The tests they used to determine if the medications contained the amount of drug they were supposed to were the same used by the U.S. Food and Drug Administration (FDA) and applied to manufacturers selling products here in the United States.
They found that most of the drugs were as labeled, despite some being beyond their labeled date of expiration! Most important of the findings was that across the board, ritonavir-containing products (Norvir) failed to meet the standards. Dr. Penzak's group noted these products arrived without having been stored properly -- meaning no refrigeration. Shipping of medicines without proper storage sends an important signal to anyone even thinking about getting their anti-HIV medicines outside of regulated sources -- buyer beware!
Dr. Ramachandran also evaluated the quantity of available generic antiretrovirals, but limited his analysis to those agents available from India-based manufacturers (three of them). This group assessed levels of Sustiva, Viramune (nevirapine), Retrovir (AZT), and Epivir (3TC) -- but not protease inhibitors as was done by the NIH group. They also looked at a combination pill containing Viramune, Epivir, and Zerit (stavudine) -- this is not available in the U.S. and therefore there are no standards to which to compare the concentrations found. These investigators found that the quantity of the single medication in the majority of instances was within the expected range allowed by the FDA (range 0.01-8.3%).
How long does Sustiva hang around after it is stopped? The common thinking was that after about one week plasma levels of Sustiva were not detectable. Data presented by Dr. Stephen Taylor of the University of Birmingham showed that may not be the case. Dr. Taylor measured Sustiva levels in seven HIV-positive patients who had to stop taking the medication for various reasons. These patients had levels measured one, two and three weeks after stopping their Sustiva. This study showed 4, 3 and 2 out of 7 patients still had Sustiva present in therapeutic levels one, two and three weeks after discontinuing therapy. Importantly, this did not result in resistance development in these patients.
Along the same lines was a study conducted in non-HIV infected women in the Netherlands and presented by Dr. Muro of Tumaini, Kilimanjaro Christian Medical College. Single-dose Viramune was administered to 44 women. Blood levels were sampled twice weekly for 21 days. Drug was still detectable in 40 patients at day 11, 28 patients at day 15, 16 patients at day 18, 9 patients at day 21 and still detectable in 7 patients at day 22. There were no predictors for the long duration of drug exposure in this population. This half-life was calculated to be 56.7 hours, or a little more than 2-1/4 days. No resistance data is available as these patients were all HIV-negative.
These two studies provided important data as patients who discontinue Viramune or Sustiva due to side effects may have to wait a little longer before the drug goes away completely. It also questions the amount of time between regimens that may need to take place to avoid drug interactions.
As more information is learned about how the body breaks down anti-HIV agents, correlations to adverse effects are ruled in and out. Sustiva's predominant side effect is neurological toxicity (dizziness, drowsiness, altered dreams, etc.) and a group of researchers from Harvard tried to see if this is related to drug levels. Dr. Heather Ribaudo presented on behalf of this group the pharmacokinetics of Sustiva in various patient populations and how levels related to adverse events, outcomes and drug discontinuation. They found no correlation between levels, outcomes and discontinuation rates, however, they did find that non-Hispanic Caucasians got rid of the drug faster and this may result in higher levels in this population. They found no higher rates of drug discontinuation in other ethnic groups, so it is thought that though this difference may exist, it doesn't warrant concern for patients.
The experimental drugs Reverset and SPD754 showed encouraging results to date.
Dr. Robert Murphy of Northwestern University School of Medicine presented pharmacokinetic information on Reverset (RVT, D-D4FC), a new once-daily nucleoside drug being studied by Pharmasset, Inc. Thirty HIV-positive patients were given this drug as monotherapy in a dose escalating trial. Patients were assigned to receive 50, 100 or 200 mg for 10 days. After 10 days of therapy, viral loads were decreased in all three groups with the 50 and 100 mg groups reporting drops of (on average) 1.67 and 1.8 log10 copies/mL, respectively. Dr. Murphy reported no significant adverse events, but cautioned this is a short-term study and longer studies in combination and in treatment-experienced patients need to be conducted prior to being made more widely available.
Another group of researchers working on the twice-daily nucleoside SPD754 in combination with Epivir had their data presented by Dr. John Bethell. These investigators looked at how SPD754 and Epivir impacted each other in the plasma and inside the cell (remember, it is inside the cells -- CD4 and others -- where these drugs have to work). Twenty-one non-HIV infected individuals took 600 mg SPD754 twice daily with or without 300 mg Epivir once daily for four days. This duration is considered acceptable as neither of these two drugs is expected to accumulate to any great extent in the body of cells over time.
What Dr. Bethell showed was a lack of interaction when the plasma levels of these drugs are examined. However, when the intracellular levels of these agents were looked at, a significant reduction of SPD754 was seen when it was given with Epivir compared to intracellular levels when these agents are given alone. This has significant ramifications in that these two agents will likely not be able to be co-administered (much like Zerit and AZT cannot be given together). It also reinforces that intracellular pharmacokinetic drug interaction studies should be conducted with all new (and existing!) agents to maximize understanding of these agents before they are given to patients.
Of course, this is meaningless if the drug doesn't affect those with HIV. Dr. Collins of Shire Biochem presented clinical findings of SPD754. Sixty-three patients were given SPD754 as monotherapy in dosing regimens once or twice daily and ranging from 200 to 1,600 mg total daily dosing. These HIV-positive volunteers took these doses for 10 days. Viral loads and resistance tests were done after 10 days. In three patients who had baseline mutations that would have limited efficacy of other nucleosides, a strong decrease in viral loads of around one log were seen after this time period. While this data is limited to very small numbers and only for a short period of time, given the need for new agents, it is important for studies to be continued in the population of resistance patients sorely lacking for new agents.
Dr. Adams of Inveresk presented data on the pharmacokinetics -- blood and intracellular of SPD754 -- in the group of 63 HIV-positive patients reported above. What he reported was the preferable accumulation intracellularly when the medication was given twice daily compared to once-daily across all of the dosing arms. Also shown was the possible correlation between blood levels and intracellular levels. This is the first agent to be able to demonstrate this. Other nucleosides and protease inhibitors have had to rely on something in the cells to get across the cell's membrane where these drugs need to be in order to work. This may the first agent that would tell us what is inside the cells by measuring blood levels -- a very beneficial aspect if it holds true in repeated studies.
HIV has to connect or bind to the CD4 cell before it can enter and infect the cell. Blocking binding of HIV to the CD4 cell has long been a site for drug discovery. Approaches to this include going after the CD4 cell's surface membrane receptors, CXCR4, CCR5 and gp120. Though these sites for action have long been known, it has only been recently that orally available drugs have been given to humans. These drugs are being referred to as small molecules, attachment inhibitors or receptor antagonists.
A drug discovered by GlaxoSmithKline, GW873140 is designed to impede viral entry by affecting the receptor CCR5. Dr. Piscetelli of GlaxoSmithKline presented the first human pharmacokinetic data of this compound. Seventy non-HIV infected persons (57 males, 13 females) were administered single doses escalating from 50 mg to 1,200 mg. This was followed by administering the drug twice daily in doses ranging from 200 mg to 800 mg for seven days. Though plasma levels were obtained after the multiple dosing studies, with these drugs what is important is what percent of the CCR5 receptors are occupied -- which were also done. Overall, the drug was well tolerated by the volunteers with some mild gastrointestinal side effects. From the plasma levels, dietary factors are going to be important with this drug as levels went up around two times when given with food. For the percent of receptors bound while taking the medicines, 97% of the CCR5 receptors were occupied 2 and 12 hours after the drug was taken in the multiple dosing studies. This very preliminary information is good news, as these novel approaches to therapy may prove the most effective yet -- but only time and properly conducted studies will tell.
Schering-Plough also has developed two blockers of CCR5 called SCH-C and SCH-D and their data was presented by a group of researchers led by Dr. Shurmann. SCH-D is being pursued for further development due to its higher activity compared to SCH-C. This agent was administered to 48 HIV-positive persons, who had to have been off their antiretrovirals for at least eight weeks and have a CD4 count at or above 200 cells/µL, in doses ranging from 0 to 50 mg twice daily for 14 days. After 14 days of dosing, decreases in viral loads ranged from 1.08 to 1.62 log with a trend reflecting increasing doses of SCH-D. Viral loads rapidly returned to baseline after discontinuing the medication.
Dr. Hanna presented Bristol Myers Squibb's small molecule, BMS 488043, that it has developed to target the gp120 receptor on the CD4 cell's surface. Though this drug has been studied in dose ranging studies before, more focused dosing strategies were shown. Thirty patients were assigned to get, as monotherapy, either 800 mg (12 persons, 3 placebo) or 1,800 mg. Only the 800 mg data was presented. These 12 HIV-infected patients had a mean decrease in viral loads after 14 days of dosing of 1 log10 copies/mL. A significant increase in CD4 counts was seen (106 cells/µL) in the BMS 488043 group compared to placebo. Importantly, no serious adverse effects were seen and no patient had to be discontinued due to side effects.
The pharmacokinetic studies done in non-HIV infected persons over 14 days of this molecule were also presented by Dr. Hanna during a different session. Comparisons of blood levels of this agent when given with or without food showed that improvement was seen when it was given with food -- 3-5 times as much of the drug was in the body. There was no difference seen when the drug was given with a low-fat versus a high-fat meal, thus it seems instructions for this agent would be to take with food.Total drug exposure of the body to this drug was increased by Norvir by 43% -- what that means now is unknown. Also presented by this data was the likelihood of this agent being dosed at 800 mg twice daily, as it would provide sufficient blood levels to suppress viral replication.
These three studies show that progress is being made in exploring new targets for HIV therapies. It is important to realize all of the data presented is short-term, limited numbers and in non-infected populations at times. Despite this, these results are encouraging for continued pursuit of these agents in combination trials for longer durations of time.
Researchers from the University of California presented data on the ability of a micronutrient supplement to improve peripheral neuropathy symptoms related to Videx (didanosine) or Zerit. Forty patients took either a vitamin supplement containing L-carnitine, n-acetyl cysteine and alpha lipoic acid or a placebo twice daily for 12 weeks. Every month the patients returned for assessment of improvement in peripheral neuropathic symptoms and other measures of mitochondrial toxicity. After three months, there was no difference seen between the two arms. What was surprising was the increase in CD4 counts in the micronutrient group versus the placebo. Those taking the vitamin twice daily saw a 26% increase in the absolute CD4 count versus a 2% increase in the placebo group. Dr. Kaiser's group reported failing to meet the primary objective of the study in that no improvement in peripheral neuropathy was seen, but no adverse effects resulted from the additional nutritional supplement and an unexpected increase in CD count was noted.
Filgrastim (Neupogen, rG-CSF), the white blood cell stimulator used after transplants and in persons with neutropenia (low white blood cells -- a not infrequent complication of HIV and its therapy), was shown to increase viral replication in a study presented by Dr. Rapaport of the University of Colorado Health Sciences Center. In a laboratory setting, cells were exposed to levels of filgrastim that would routinely be used in clinical situations. As the amount of filgrastim was increased, HIV replication increased -- similar to the increase seen when IL-2 is given in other viral replication experiments. This research provides an explanation why viral replication may be more likely when patients are given filgrastim to treat incidences of extremely low white blood cells.
The commonly used medications for arthritis and chronic inflammatory conditions, Celebrex and Vioxx, were evaluated for their influence on T-cells by Dr. Kvale and a group from the University of Oslo in Norway. Having only 24 persons who had been on these medications (12 in each group) for six months, they compared the changes in T-cells between these persons and those on similar regimens and responses. Though it was difficult to control for a number of factors, only those persons on the COX-2 inhibitors had increases in two components of the T-cells. Again, the data is no "smoking gun," but they did find that there were small, albeit significant, changes in the CD38 and CD28 sub-fractions of T-cells. Why is this significant? Mainly because it is the CD38 sub-fraction that correlates with HIV progression in patients with detectable viral loads. These investigators plan on evaluating further more patients and for longer durations of time. In the meantime, this would not be cause to consider stopping the COX-2's or not considering initiating them, only a curious fact that warrants further investigation.
Already known is that with protease inhibitors, the only two cholesterol-lowering medicines available for use are pravastatin and atorvastatin. But what about the non-nukes? The AIDS Clinical Trials Group (ACTG) looked at this question in ACTG 5180. Dr. John G. Gerber from the University of Colorado Health Science Center in Denver presented important information on the interaction between either Zocor (simvastatin) or Lipitor (atorvastatin) with Sustiva when given to 27 HIV-negative volunteers. The blood levels of Zocor and Lipitor were measured in patients when given by themselves for three days, then they took Sustiva for two weeks and had Sustiva levels measured. They then restarted Zocor and Lipitor while on Sustiva for another three days and then had the levels measured again.
What they found was a significant reduction in levels of both Zocor (60%) and Lipitor (~45%) when given with Sustiva. Those two drugs did not affect Sustiva levels, thankfully. If these agents are being considered in patients with elevated cholesterol and they are also on Sustiva, then higher doses may be needed in order to get an effect. A word of caution -- this data showed only short-term exposure and close monitoring of side effects should be done when using these agents in combination. There are a number of labs that can run levels on cholesterol-lowering medicines and this may prove beneficial instead of increasing a dose of either of these agents because a drug interaction is expected.
A poster presented by Dr. Ana Rendon of Hospital Carlos III in Madrid demonstrates the complexity and diversity of using therapeutic drug monitoring (TDM) in patients on antiretrovirals. They looked back at all requests for levels in patients to see why levels were being drawn, and importantly, what is being done with the information given to the provider. Most of the requests resulted from toxicity with a particular agent that the provider wanted to either rule out or rule in the role of elevated levels of the drug in that toxicity. Drug toxicity represented 59% of requests, with unexpected virologic failure being the reason for 39% and only 2% for drug interactions.
Higher than expected drug levels were found in 37% of patients with suspected drug toxicity, and lower than expected drug levels were found in 42% of patients unexpectedly failing therapy. The researchers found that 32% of patients had levels changed based on TDM (10 dose reductions, 8 dose increases and 2 regimen changes). Of these 20 who changed therapy based on TDM, 16 or 80% achieved their goal (toxicity resolved or improved viral suppression). In 11 patients in whom follow-up levels have been done, all have achieved expected concentrations. This and Dr. Wynn-Vezina's study are the first data that have shown changes to therapy based on TDM in clinical practice and the results are encouraging. Though retrospective, the positive outcomes support TDM use in select situations and open communication between laboratories running the levels and providers ordering the tests.
Overall, a busy conference with many ideas tossed around for how to better manage this disease. A number of the newer drugs in development are raising curiosity and how they are studied may alter how we approach treatment in persons acutely and chronically infected. Drug interactions and dosing alterations continue to be discovered and with more information comes a better ability of clinicians to manage patients with less side effects. More data is forthwith at Bangkok this summer during the World AIDS Conference -- so look forward to more summaries from that meeting in the coming months.
Patrick G. Clay, Pharm.D., is Assistant Professor at the University of Missouri School of Medicine in Kansas City and HIV Clinical Pharmacist at the Kansas City Free Health Clinic. E-mail firstname.lastname@example.org.
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