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Drug Update:
The Old, The New, The Still to Come
by Patrick G. Clay, PharmD |
 This
summary provides a limited and brief overview of abstracts presented
at the 11th Conference on Retroviruses andOpportunistic 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. |
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Lexiva + Kaletra—still a bad
idea
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
1400 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.
Dosing Agenerase + Kaletra—trying
to juggle, walk and chew gum all at the same time
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.
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 Caveat
emptor—Buyer Beware!
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%).
It keeps going, and going, and going…
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 ¼ days. No
resistance data is available as these patients were all HIV-negative.
These two studies provided important
data as patients whodiscontinue 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.
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Sustiva neurologic side effects not
related to levels
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.
Drug levels of the newer agents for
HIV: so far, so good
The experimental drugs Reverset and
SPD754 showed encouraging results to date.
Reverset
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.
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SPD754
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 1600 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.
Receptor blockers: GW873140, SCH
C, SCH D
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.
GW873140
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 1200 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 D
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.
BMS 488043
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 1800 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 BMS488043 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 realizeall 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. |
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Momma always said to take your vitamins!
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.
Neupogen stimulates more than just
white blood cells
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.
COX-2 inhibitors and CD4—drug-disease
interaction?
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.
Sustiva, Lipitor and Zocor
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.
To measure or not to measure drug
levels—that is the question
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.
Summary
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, PharmD, 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 claypg@umkc.edu.
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