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.
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. 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%).
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.
ReversetDr. 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.
SPD754Another 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.
GW873140A 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.
SCH-DSchering-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.
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.
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.
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.
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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