Mixing and Matching Meds:
ICAAC Update
by Patrick G. Clay, PharmD
At the 41st Interscience Conference
of Antimicrobial Agents and Chemotherapy (ICAAC) held in Chicago
in December 2001, there were presentations discussing Therapeutic
Drug Monitoring (TDM) in HIV. What researchers and some clinicians
are doing now is conducting studies, or in some cases select
sampling of plasma (the part of the blood that is without
cells), of their patient populations. They are doing this
to determine if the amount of drug getting into a person’s
blood is not what is expected nor desired. This may allow
the clinician to adjust the dose of the antiretroviral, as
in some cases when another drug the patient is taking may
be causing the drug level to be an undesirable one.
Many of the ICAAC presentations
focused on: 1) how drug-to-drug and drug-to-food interactions
may alter plasma levels of various drugs and 2) how plasma
levels may relate to viral load suppression or resistance.
Only a few focused on the actual monitoring of drug levels,
primarily protease inhibitors, and how the process can significantly
affect the results. Outcome data are not being discussed in
this article and more details on how these persons faired
while on these medicines are available at the conference web
site: www.icaac.org.
Flaherty, et al.,
Abstract # 1791, presented much anticipated data on the interaction
between Videx (didanosine, ddI) and Viread (tenofovir). Viread
is the new kid on the block, and is only taken once a day.
So a big question was: how does it function when taken with
Videx, the only other nucleoside analog that can also be taken
once a day. Together, they might make a good nucleoside base
for HIV therapy. It’s a tricky question, because Viread can
be taken with food, but both Videx and Videx-EC (the newer,
non-buffered capsule) must be taken on an empty stomach.
The jury is still out on
what is the best way to construct a pill regimen with these
two medicines in the same patient, but there are studies being
done that may give us this answer. However, this research
has yet to be completed. In this pharmacokinetic analysis
using non-HIV infected persons, didanosine and tenofovir were
given to 15 (8 male/ 7 female) for 7 days. The plasma levels
obtained were compared to when the same subjects took each
drug individually. The Gilead Science study (makers of Viread)
demonstrated an increase in both the total drug exposure (AUC)
and the maximal drug level in the plasma (Cmax) of didanosine
of about 44% and 20%, respectively, when ddI was taken one
hour before tenofovir. All medications were administered in
the fasting state. This should not affect the results when
applied to the clinical setting, as when tenofovir is administered
with food it would not likely cause much greater changes in
didanosine pharmacokinetics. (1)
This should also not be any different in HIV infected persons
as Kearney, et al., presented the effect of demographic
variables on the pharmacokinetics of tenofovir in 56 HIV positive
persons getting nearly identical tenofovir levels (Abst. 504).
In a related research study,
Bristol-Myers Squibb presented data showing that when Videx-EC
(didanosine EC) was administered with food (high and low fat)
compared to fasting in a total of 99 HIV negative persons
(Abst. 499). The authors reported that the extent of absorption
was lower when given at the same time with either a low or
high fat meal by 27% and 19%, respectively. Additionally,
it was reinforced that Videx-EC needs to be taken at least
1 hour prior to any food as a 24% decrease in total drug exposure
was seen when it was given only 1 hour before a light meal.
Several combination protease
inhibitor pharmacokinetic profiles were presented. Can the
popular Fortovase/Norvir combination be taken only once a
day? Research presented here suggests that it can—but more
research needs to be done to prove that the once-daily dose
is actually effective. Montaner, et al., showed data on 20
HIV positive African Americans (11 men/ 9 women) receiving
Fortovase (saquinavir soft-gel) 1600 mg with 100 mg of Norvir
(ritonavir) once daily (Abst. 1920). After four weeks of therapy,
the trough level was drawn (the amount of drug in plasma at
the end of a dosing period—in this case it was done at 24
hours after the previous dose). Good news: the average drug
plasma level was about 9.4 times greater than what an acceptable
trough level would be. Shelton, et al., presented data
on 12 (5 male/ 7 female) methadone patients taking 1600 mg
saquinavir/100 mg ritonavir once daily (Abst. 492). In this
patient population, somewhat lower troughs were seen compared
to Montaner’s data, yet 83% of these persons still had levels
that would be expected to suppress viral replication (lower
the viral load).
The optimal Agenerase (amprenavir)
dose to be used with ritonavir was being researched by Garraffo,
et al. (Abst. 489). Here, researchers provided scientific
evidence for combination doses that were already widely prescribed
by HIV specialists.
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Using 10 (9 male/ 1 female)
HIV-infected persons, plasma levels of amprenavir were obtained
and compared to various dosage regimens. Each patient took
amprenavir at full FDA-approved dosage (8 100 mg capsules
twice daily), then 600 mg amprenavir with 100 mg of ritonavir
twice daily and then finally, 1200 mg amprenavir with 200
mg ritonavir once daily. Each dose was taken for 10 days prior
to 8-10 plasma levels being taken. The elimination of amprenavir
(APV) from the body was decreased by 50% when given with either
dose of ritonavir (RTV). The trough levels of amprenavir were
higher when subjects received the 600 mg APV/100 mg RTV compared
to 1200 mg APV/200 mg RTV, but both of these were much higher
than that seen with 1200 mg APV twice daily. Since this conference,
the FDA has approved the 600 mg APV/100 mg RTV dosing regimen.
Correlating the levels of
Viracept (nelfinavir) to future regimen failure was the intent
of Le Moing, et al. (Abst. 1733). These researchers
examined single time point plasma levels of 407 patients taking
successful regimens (viral load <500 copies/mL) containing
indinavir (240 subjects) or nelfinavir (167 subjects) for
at least 4 months. As you would expect, the researchers found
a correlation between lower than expected plasma concentrations
of nelfinavir levels as well as lower levels of its active
metabolite (M8) and failure of therapy (at least one viral
load >500 copies/mL after the fourth month). (In the past
few years research has found that a drug’s metabolite—the
form it takes inside the body—is often more important than
the drug itself, for all diseases. This is one of the earliest
studies looking at an HIV drug metabolite.) The authors did
point out weaknesses of the study and stress the need for
further studies to be done in a controlled, research environment
prior to any recommendations being made about monitoring plasma
levels of any antiretroviral.
This point was reinforced
by DiCenzo et al. (Abst. 751 and 487). This collaboration
of notable researchers presented two posters that examined
what information could be learned from different sampling
methods. Basically, they took single time samples (at any
point during the day when the patient came into the clinic
and was taking the medicine) and compared how accurate and
reproducible the results were when compared to a full day’s
worth of blood draws. The results are important in helping
clinicians understand how to best utilize and interpret TDM
data. These researchers found that taking less than two blood
samples during one dosing period was not informative. The
recommendation was that for the most precise and unbiased
estimates to be obtained, at least 2 to 3, but seeking 4 to
6 samples would give the best data. The likelihood of a clinic
being able to fiscally, physically or emotionally have every
patient on antiretrovirals get this intensive sampling procedure
done is small.
To summarize, the data presented
at ICAAC that displayed research on the use of measuring antiretroviral
blood levels do not support this being done as a part of routine
clinical practice. This is not meant to dissuade clinicians
from measuring plasma levels when legitimate concerns arise
regarding absorption, interactions or other clinical scenarios.
Obtaining plasma levels of antiretrovirals at this time point
should continue to be pursued in prospective, randomized,
controlled research environments in order to provide infected
and affected persons, clinicians and third-party payors (insurance)
with consistent, clear and indisputable results. With upcoming
conferences in 2002 (4th International Workshop on Antiretroviral
Clinical Pharmacology, World AIDS, 42nd ICAAC, etc.) where
more TDM studies are surely to be presented, it is hoped these
answers are forthcoming.
1Kakuda
TN PL, et al. Pharmacological basis for concentration-controlled
therapy with zidovudine, lamivudine and indinavir. Anti Microb
Agent Chemo. 2001;45(1):236-42.
2Barditch-Crovo
P DS, et al. Phase I/II trial of the pharmacokinetics,
safety, and antiretroviral activity of tenofovir disoproxil
fumarate in human immunodeficiency virus-infected adults.
Anti Microb Agent Chemo. 2001;45:2733-9.
Patrick G. Clay, PharmD
is an Assistant Professor of Pharmacy Practice at the University
of Missouri-Kansas City School of Pharmacy. He is also the
HIV Clinical Specialist at the KC Free Health Clinic, 3515
Broadway, Kansas City, MO 64111. Clay can be reached by phone:
(816) 777-2721; fax: (816) 753-0804; or email: claypg@umkc.edu.
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