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TDM (Therapeutic Drug Monitoring)
Reported by Jules Levin
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TDM is testing drug levels in blood to evaluate if a patient has too much or
too little drug in blood or body. Too much drug can cause toxicity and too
lttle can cause viral failure. Whether or not TDM can be useful is
controversial and has not yet been established very well. TDM was the subject
of a plenary oral discussion by David Burger at the 6th Intl Congress on Drug
Therapy in HIV just completed in Glasgow. This is the annual European AIDS
Conference. Several reports of his talk and this subject have been
distributed on the internet. To truly understand TDM and why it has not
caught on very widely, and to read the results from various studies that have
been conducted so far I suggest reading this very comprehensive review of TDM
on the NATAP website:
http://www.natap.org/2002/3pharm/TDM.htm#_Toc522953896
Here is a briefer review of the subject touching on key issues regarding the
utility of TDM including excerpts from the much more detailed and
comprehensive review linked to just above. At the end of this article is a
consensus opinion from experts on TDM.
For several years TDM in HIV has been the subject of much controversy and
several studies. Pharmacology researchers in the USA for the most part feel
TDM use has major flaws. They feel it is not realistic to consider it
reliable for widespread clinical use. One reason is that you are testing
blood levels at a given time point or at multiple time points if used more
appropriately, but what about those other days on which you are not testing.
Patients may not be taking their meds on those days; if the doctor tells the
patient I'll be checking your drug blood levels on a particular day the
patient may take their drugs for the few days before the test and then go
back to poor adherence. Poor adherence could consist of not taking drugs at
all, taking not all drugs at full dose at all times, or not eating properly
according to the diet recommendations for achieving the best blood levels.
So, dietary intake can vary from person to person and fron day to day for a
given individual.
What if patient does not take drugs exactly on time so if therapy should be
taken twice daily and at times they are taken 12 hours apart or at other
times for example at 8am and 5pm? Will TDM drug blood levels give accurate
readings that can be used to accurately evaluate a patient's situation?
One of the major confounders may be incomplete adherence. While patients who
do not take their anti-HIV drugs on schedule or do not comply with dietary
requirements would be expected to have low plasma levels and poor outcomes,
these patients may have Śnormalą plasma levels if they take their doses soon
before a scheduled visit. Thus, patients who fail treatment because of low
drug levels due to poor adherence may actually appear to have normal drug
levels in outcome analyses. Hence, optimal design of trials aimed at the
evaluation of concentration-response relationships should always include a
thorough assessment of patient adherence to treatment. Monitoring of drug
concentrations may be a reliable tool for assessing adherence, particularly
if used in conjunction with other methods.
For drugs whose bioavailability is strongly influenced by the presence or
absence of food, poor adherence to food requirements is likely to have the
same effect on virological response as poor adherence to drug intake. Poor
adherence to food requirements is difficult to monitor in many patients and
may obscure proper interpretation of drug blood levels.
Researchers are not sure when drug blood levels should be tested although it
appears testing at the time of the trough (the lowest point in drug levels
nhear end of dosing period) is best to evaluate if patient has enough drug in
blood is best. But we are not sure about that.
There is too much variability in the accuracy of doing TDM measurements by
different laboratories requires that which might require assays to be
optimized and validated and labs to be evaluated. This problem is one that is
addressed by HIV viral load testing and resistance testinwhere test results
appear more reliable, although interpreting resistance test results is not
reliably performed and not consistent between doctors or experts in
resistance testing.
You probably need to test blood levels at multiple times to truly gauge what
levels a patient is getting. If you are evaluating whether a patient is
getting adequate drug blood levels you will optimally need to draw several
samples for initial evaluation, And after adjusting doses of drug you will
need to again draw several samples of blood to see if adjusting dose was
successful in altering drug blood levels. The exact timimg of when you draw
blood samples is crucial. In France, the Netherlands, and Britain TDM is
commonly used. In clinics in these countries patients commonly have TDM
performed and assessed often by an in-house pharmacologist. In the US system
this becomes much more cumbersome and difficult. The US has much more
patients with HIV and a much larger care system that is already overwhelmed
trying to provide adequate care to all the patients, particularly in large
urban city hospitals. The USA population is much more diverse and in many
instances it may be difficult, regardless of whether the care setting is
private or a public institution, for getting patients to return for several
visits on prescheduled days at specifictimes to perform TDM drug level
testing in the blood. In the US system of care where HMOs and such systems
predominate time and resources are more scarce than in the more public and
government subsidzed systems of Western Europe.
If a patient is of a certain type and the doctor and care provider really
want to use TDM in the proper way in the USA it's possible. You need a doctor
who can and is willing to take the time to properly perform TDM which
includes drawing blood and processing the blood properly. This means blood
needs to be sent to TDM testing center or pharmacologist who knows what to
do. You need a patient is reliably and consistently is properly and
completely adherent; a patient who is honest with the doctor about taking
their meds and a patient who will tell the doctor that over the past two days
exactl their schedule for taking meds and dietary intake. What about patient
weight? Are drug levels which may be good for a patient of 150 lbs the same
for a person of 220 lbs. I don't think we know the ansswer to that. And what
level of drug is appropriate for a 220 lb person? We don't have conclusive
information on that. And of course whether a patient is treatment experienced
or treatment naive and how much experience they have is crucial in
interpreting TDM results and in adjusting proper dosing to achieve the drug
levels you want. You must have a certain expertise in the doctor and
pharmacologist performing the tests, in interpreting the results, and in
selecting proper dose adjustments particularly for the treatment experienced
patient. Then you need a very well qualified pharmacologist and doctor to
evaluate the meaning and significance of the findings. They need to be
familiar with the therapeutic ranges for drug levels targeted for each drug.
One of the reasons TDM has not caught on very widely and has not caught on
the USA is because these optimal circumstances are hard to put into place.
Another confounding factor may be the development of resistance. The
concentrations required to inhibit the replication of a wild type virus may
be lower than those necessary for a strain with decreased susceptibility. For
this reason, measures of drug exposure normalized to measures of viral
susceptibility may correlate better with treatment response
To test drug blood levels you will have to wait for drug levels to reach
steady state after initiating a regimen and this takes about two weeks.
You can use TDM for protease inhibitors and NNRTIs but not yet for NRTIs
because it is uncertain if blood levels reflect where perhaps NRTIs really
work, in the cell. PIs represent the best candidates for TDM with current
assay techniques, although NNRTIs should not be overlooked. Combination
therapy also obscures the relationship between drug level and outcome: most
first-line regimens contain three potent antiretrovirals, so a patient may
still respond favourably to treatment, especially in the short term, even tho
ugh one of the drugs is at suboptimal levels. Other covariables that may
obscure a significant concentration-response relationship include protein
binding and intracellular kinetics (see article linked to above for expansion
on this in chapter 6).
At this point you must realize TDM testing is not very much of a science but
can be of relative utilitity and of how much usefulness depends on the
variations of the factors discussed above. This is why TDM has not caught on
yet and it remains uncertain if it will catch on in a widespread way.
Certainly there will be doctors who use it in their practice for certain
situations but I think it's usefulness can be questionable, and just like
resistance testing in the wrong hands it may not be helpful but might even be
harmful.
What about intrpatient variability and interpatient variability. Plasma
levels of antiretroviral agents vary greatly among patients receiving
standard doses. HIV-1-infected patients constitute a highly heterogeneous
population, in which covariables such as weight, gastrointestinal absorptive
function, hepatic and renal function, adherence to drug intake schedule and
food requirements, drug-drug interactions and many other factors may
contribute to widen the range of plasma concentrations. The stage of HIV
progression may play an important role in the interindividual
variability in pharmacokinetics. Several studies have shown significant
differences in pharmacokinetic values between HIV-negative and HIV-infected
patients, as well as among HIV-infected patients at different stages of
disease progression.
In study settings patient variabilities can be better controlled. In
uncontrolled settings, a number of factors may contribute to increased
intraindividual variability in plasma drug levels: these include patients not
reporting the precise time of last dose intake, variable adherence to food
requirements and lack of full adherence to the last doses (i.e. patient not
at steady-state). Furthermore, drugs such as ritonavir and nelfinavir have
been shown to exhibit a significant circadian effect, so that the
concentrations after a morning dose are different from those after an evening
dose, and indinavir and zidovudine pharmacokinetics may vary throughout the
menstrual cycle This is discussed further in the study linked to above).
What the ability to assess proper drug blood levels when using ritonavir to
boost levels of other protease inhibitors? Although perhaps researchers can
evaluate and assess what are proper drug levels when using ritonavir as
boosters do we have an adequate undertstanding of this now? Because
ritonavir increases the plasma concentrations of other PIs, the future
utility of TDM in HIV management has been questioned; with boosting, PI
levels are less likely to fall below therapeutic ranges except in cases of
poor adherence. This is addressed further in the article linked to.
Consensus
Conceptually, the panel agrees that TDM may represent a practical tool to
improve the outcome of patients receiving HAART. However, at present we
cannot recommend its use in routine clinical practice for three reasons: (1)
existing data are not adequate to confirm the utility of TDM in this setting;
(2) current assays are not sufficiently reliable or standardized; and (3)
interpretation of data is complex, and may require expert advice. To address
these issues, we suggest that the following measures are necessary: (1) large
randomized trials to assess the clinical utility of TDM in the management of
HIV-1 infection; (2) assay standardization; and (3) education programmes for
pharmacists, physicians and patients.
With the caveat that any application of TDM in HIV management should be
validated in clinical trials before being incorporated into routine clinical
practice, the panel has formulated the following list of position statements,
which may help guide TDM trial objectives as well as provide points of
reflection for centres in which TDM is already in use:
1. Levels of systemic exposure to PIs and NNRTIs correlate with their
efficacy as well as some of their adverse effects - i.e. a
concentration-effect relationship exists. Therefore, adjusting PI and NNRTI
concentrations within a therapeutic window may be of benefit, especially in
light of the high interindividual and relatively low intraindividual
variability of plasma levels.
2. TDM has potential utility for patients who are initiating therapy with any
PI or NNRTI or who are changing regimens - regardless of treatment history or
pharmacoenhancement with ritonavir. TDM may help to ensure that appropriate
plasma drug concentrations are achieved
and to identify absorption or metabolic problems as well as unexpected
interactions with over-the-counter or herbal medications that may lead to
suboptimal drug levels.
3. TDM is more likely to be of benefit in specific situations that may occur
at the beginning of a new treatment protocol or during ongoing treatment:
a.If a malabsorption syndrome is suspected
b.If drug interactions likely to cause clinically significant concentration
changes are suspected
c.If more than two drugs with an influence on P450 activity are administered
d.In patients with hepatic impairment
e.In patients with particularly high or low body weight compared to the
population average
f.During pregnancy
g.In children
h.If there is a change in clinical or physiological status that is suspected
of causing abnormal drug levels
i.For evaluation of unsatisfactory virological response
j.For dose intensification of failing regimens
k.In once-daily regimens of PIs using ritonavir pharmacokinetic enhancement
l.In deep salvage therapy in order to expose patients to maximal tolerable
levels while limiting the risk of toxicity (even in cases of ritonavir
boosting)
m.For preventing toxicity in patients with high plasma drug levels
n.In patients who develop adverse reactions while taking PIs, to adjust the
dosage downward while still maintaining therapeutic levels.
4.Pharmacoenhancement with ritonavir does not necessarily mitigate the
utility of TDM. Because of the high interindividual variability in plasma
drug concentrations, and the possibility of higher than normal IC50 values in
pretreated patients, individual patients may have sub-inhibitory trough/IC50
ratios, even though the average trough/wild-type IC50 ratios are high.
5.TDM may have a role in monitoring adherence. Adherence is probably best
monitored with a combination of methods, including patient self-report, pill
count, medication event monitoring systems and possibly TDM. On the other
hand, the evaluation of patient adherence to
treatment is important for a correct interpretation of TDM results
6.Possible interventions resulting from TDM include adjusting dosage or
switching drugs if concentrations are excessive or inadequate - or, if
possible, addressing the factor causing the unsatisfactory drug levels (e.g.
patient education or discontinuation of an interacting drug).
7.The parameters of drug exposure that should be monitored, and their optimal
target values, have not been adequately defined. These may differ depending
on patient treatment history, concomitant antiretroviral drugs in the regimen
and other factors. For example, PI-experienced patients may harbour virus
populations with multi-fold increases in drug IC50 values compared with
wild-type virus; thus, target concentrations may be higher in this clinical
setting. TDM trials and available TDM services should focus on the definition
of such targets by accruing data that integrate pharmacokinetics and
resistance in diverse patient populations.
8.The future of TDM in HIV management may be an integration of
pharmacokinetics and resistance. One of the major objectives of TDM studies
should be to evaluate methods of integrating these data to optimize
treatment. The innovative concept of the virtual inhibitory quotient should
be investigated, since it has potential to be a cost-effective approach, and
as such, adaptable to routine clinical practice.
9.Since the target drug level is usually defined as the ratio of a
pharmacokinetic measure and a resistance measure, the variability of
resistance testing assays, concentration determination and evaluations of the
effect of protein binding on IC50 constitute a major obstacle. An effort
should therefore be made towards assay standardization and quality control
programmes.
10.The use of TDM to adjust dosages on the basis of plasma drug
concentrations assumes that the free drug concentration at the site of action
(the intracellular environment) correlates well with plasma concentrations.
Potential confounding factors that may cause a lack of correlation, such as
concentration-dependent protein binding, tissue penetration and intracellular
accumulation, need to be thoroughly investigated.
11.Procedures for sampling and dose adjustment used to date include protocols
based on peak and trough levels, concentration ratios and Bayesian methods.
Further studies are needed to determine which method will yield the most
useful results or whether alternative methods may be considered.
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