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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5195_Библиотеки_им_академика_М_И_Перельмана.pdf
Figure 7.6 Questionnaire that has been successfully used in an antiepileptic therapeutic drug
management service at Cincinnati Children’s Hospital Medical Center
ADHERENCE AND VARIATIONS IN
PHARMACOKINETICS ARE DIFFICULT TO CONTROL
In an outpatient setting, nonadherence can represent a major problem in
patient management.79 TDM can contribute to detecting nonadherence,
although this will be dependent on the clearance of the drug. For instance,
skipping doses and only taking medication shortly before a visit may not be
obvious for highly cleared drugs but will result in much lower-than-expected
concentrations for more slowly eliminated drugs. Metabolite profiles, when
measured, will almost always change and be indicative for poor or
nonadherence. For inpatients, poor adherence should not be an issue, but can
occur, and inaccurate recording of the timing of the dose in relation to the
blood draw may result in confusion and mistakes. For instance, samples
drawn supposedly as “peaks” but actually taken before the actual dose was
given will give lower-than-expected results and may sometimes have people
question adherence, whereas a PK consult would clearly predict the measured
concentration when assuming a “missed” dose. Over adherence, such as in
drug overdose, can also be identified.
DETERMINATION OF UNBOUND
CONCENTRATIONS OF DRUGS
Typically, in routine TDM, total drug concentrations (protein bound and
unbound or “free”) are measured. Because only the unbound concentration can
diffuse to the extracellular and intracellular space to exert its pharmacologic
action, measurement of unbound concentrations may be of value for highly
protein-bound drugs, for example, phenytoin (~90%), valproic acid (~90%),
and, possibly, carbamazepine (~75%). Changes in unbound concentration may
be the result of hypoalbuminemia, displacement due to endogenous
compounds (such as bilirubin), or a drug–drug interaction (e.g., phenytoin–
valproic acid). Several methods are available to measure unbound
concentrations even in microsamples. Some of the reasons to measure
unbound concentrations as well as some problems with interpretation are
given in a later discussion of phenytoin. A TDM service should be helpful in
deciding which patients would benefit from unbound measurements, but
clinicians should consider such monitoring for drugs with high binding,
especially if there is clinical suspicion of abnormal binding protein
concentrations, including albumin and α acid glycoprotein.
SUGGESTIONS FOR MODEL-INFORMED
THERAPEUTIC DRUG MANAGEMENT: A
TEAM APPROACH
Proper TDM requires cooperation among informed patients or
parents/caregivers and skilled nursing, pharmacy, medical, and laboratory
staff. It is best done by a team approach with everyone involved helping to
provide accurate information; proper sample collection, handling, and
analysis; proper interpretation; as well as correct clinical response and
follow-up.80 The best computed PK/PD modeling and interpretation cannot
overcome inaccurate information or incorrect laboratory analysis. The most
accurate laboratory analysis is not useful without all the necessary
information, proper interpretation, and appropriate clinical response and
follow-up. The most cost-efficient, clinically effective TDM will result when
all members of the health care team (and this should include patients and their
parents/guardians as well) are familiar with, and provide, what is necessary
to properly collect, analyze, interpret, and follow up drug concentration
measurements.
There are a number of components of an effective pediatric PK
consultation or therapeutic drug management service. Table 7.5 presents the
drugs that should be routinely monitored. Most of these drugs have reasonably
well-established concentration–effect and adverse events relationships. The
suggested target concentration ranges are not to be viewed as “fixed,” but
rather as a useful starting point in a new patient. Several drugs and important
drug classes have not been included because their assay is not readily
available or because there is no consensus on the clinical utility of routine
TDM. For instance, we have not included HIV drugs such as the protease
TABLE 7.5
inhibitors, as additional pediatric data are needed to establish child-specific
reference values and to assess the optimal method of TDM.
23,81
Yet, TDM is
considered a useful tool in the treatment of HIV-infected children. TDM has
clearly been useful in individual patients, including those with poor adherence
or who experience unexpected toxic side effects.82 Also not included are
antifungal83 and drugs routinely used in pediatric oncology.84 These drugs are,
however, rapidly becoming part of TDM menus and should be more
commonly monitored/managed in the near future.
Me nu for Pediatric Therapeutic Drug Management
a
Drug Target Range Comments
Antiepileptic
drugs
5,18,19
Carbamazepine 4–9 mg/L More favorable adverse events profile; has
active CBZ-10,11-epoxide metabolite;
autoinduction and in combination with other
AEDs
Ethosuximide 40–100 mg/L Treatment of absence (petit mal) seizures; poorly
established concentration–effect relationship
Phenobarbital 20–40 mg/L Negative effects on cognitive and psychomotor
function; relatively slow clearance; half-life 4–5
d in neonate and ∼2 d in children; inactive
glucuronide metabolite may accumulate in
newborn. Ranges differ for seizure prophylaxis,
for treatment of hyperbilirubinemia
(undetectable), and sedation. Long-term
treatment leads to tolerance causing the
concentration–effect relationship to change over
time.
Phenytoin 5–20 mg/L Concentration-dependent elimination; slower
elimination at high concentrations; highly protein
bound; free level monitoring useful in specific
cases
Primidone 5–12 mg/L Metabolized to phenobarbital
Valproic acid 50–100 mg/L Complex concentration–effect relation; several
drug–drug interactions with other AEDs
Antibiotics
5,92
Gentamicin MDD:
>5–10 mg/L peak
<1–2 mg/L trough
>20 mg/L peak
ODD:
<0.1–0.5 mg/L
Use short courses; preferably maximal duration
of therapy 5–7 d; toxicity may occur despite
therapeutic drug management
Tobramycin MMD:
>5–10 mg/L peak
<1–2 mg/L trough
ODD:
>20 mg/L peak
<0.1–0.5 mg/L
Better intrinsic activity against Pseudomonas
aeruginosa use short courses; preferably
maximal duration of therapy 5–7 d; toxicity may
occur despite therapeutic drug management
Vancomycin <10–15 mg/L trough
20–40 mg/L peak
Rapid infusion may give “red man” syndrome;
increased toxicity when combined with
aminoglycoside
Immunosuppressants Ranges depend on time post-transplant as well
as transplant organ (kidney, liver, heart, or bone
marrow)
Cyclosporine 100–200 μg/L (trough)
Target AUC
174
:<D30: 6.0 ± 2.2; D30–M3: 5.5 ±
1.7; M3–1 y: 4.7 ± 1.2; >1 y: 3.8 ± 1.0 mg/h/LIn
pediatric patients, ranges have been reported as:
<M30: 7.4 ± 2.4; D30–1 y: 5.2 ± 1.4; >1 y: 3.9 ±
1.2 mg/h/L
Sirolimus 4–12 μg/L (with
CsA)10–20 μg/L
(without CsA)
No AUC target consensus range has been
established yet.
123,175
Tacrolimus 5–20 μg/L
Target AUC
125,176
:First week post-
transplantation: 0.15–0.21 mg/h/LLong term:
0.12–0.15 mg/h/L
Mycophenolic acid 1–3.5 mg/L
Target AUC
52,177
: 30–60 mg/h/L
Mycophenolic acid
glucuronide
35–100 mg/L
Miscellaneous
5
Caffeine 5–15 mg/L Prevention of apneas in premature neonates
Digoxin 0.8–2.0 μg/L Concentration–effect relationship with peripheral
compartment; detection of accumulation in renal
compromised patient; endogenous digoxin-like
immunoreactive substances are present in
neonates and may interfere with assay
Methotrexate Depends on
therapeutic regimen
Light sensitive; protect sample from daylight
Theophylline 5–20 mg/L Saturation kinetics; Note 1: methylation to
caffeine in neonate will lead to two active drugs
—theophylline and caffeine. Depending on the
assay method, only one will be detected and
reported
122
Note 2: Target range depends on
condition (asthma requires much lower
concentrations than apnea)
123,124
a
This table is included as an example of what a basic TDM service could provide in terms of routine
assays. For more comprehensive service overview, the reader is referred to the following websites:
http://www.clinchem.med.uni-goettingen.de/downloads/Referenzwerte-2008_06_25.pdf;
http://www.umcg.nl/Professionals/dienstverlening/85932/157322/Pages/Default.aspx
AED, antiepileptic drug; AUC, area under the curve; CBZ, carbamazepine; CsA, cyclosporin A
(cyclosporine); D30, first 30 d post-transplantation; D30–M3, 30 d to 3 mo post-transplant; MDD,
multiple-daily dosing (dosing interval, 8 or 12 h); ODD, once-daily dosing.
GENTAMICIN AND OTHER ANTIBIOTICS
For decades, TDM of the aminoglycosides (gentamicin, tobramycin, amikacin,
and netilmicin) has been primarily focused on avoiding potential
nephrotoxicity and ototoxicity.5 With intermittent dosing (e.g., every 8 hours or
every 12 hours), a trough concentration of 2 mg per L is broadly used as the
cutoff point above which toxicity is likely to occur, although good clinical
evidence-based studies are lacking.85 In addition, it must be realized that
aminoglycoside-related toxicity typically develops slowly and that reducing
the duration of exposure to a maximum of 7 to 10 days will reduce the
incidence of adverse events.
86,87
Few early studies documented clinically
effective concentrations, which resulted in the commonly used 5 to 10 mg per
L postdose target concentrations.
88,89
However, later better understanding of
the PD of aminoglycosides has shifted focus to optimizing efficacy as
well.
90,91
The new paradigm for this class of “concentration-dependent” drugs
is to achieve rapid bacterial killing with as high as possible initial
concentrations. The new target concentrations include high peak
concentrations (i.e., ten times the MIC) and virtually nondetectable trough
concentrations. These targets can be achieved with once-daily dosing
regimens, where the traditional total daily dose is given in one dose instead of
as multiple doses. Other even more extended intervals have also been used.
The transition to higher doses given less frequently is ongoing and has
generated ongoing discussion about whether to keep using the wellestablished peak-and-trough monitoring concept, which is still being used in
many institutions, or to go back to less informative midpoint nomogram
methods or trough-only strategies for the sake of simplicity.92 The traditional
dosing interval in newborns and children is every 8 to 12 hours, but oncedaily dosing is also now being used in the pediatric population.
93,94
Much of
the increased efficacy of once-daily dosing arises because it results in less
underdosing of seriously ill patients. It was not generally appreciated that
such children were underdosed because of the much higher (0.5 to 1.0 L per
kg) volumes of distribution (Vd) aminoglycosides have in septic adults and
children. Giving a single 5 mg per kg dose is the only way to achieve 10 mg
per L concentrations in someone with a Vd = 0.5 L per kg. Renal patients were
also often underdosed when given usual doses. This underdosing was the
result of not understanding the difference between low clearance and high V
d
in renal patients. Clearance determines the interval needed between doses.
Whereas the Vd determines how much should be given to achieve a given
concentration. We have seen renal patients given only 1 mg per kg gentamicin
“because they have slow clearance.” This is not a problem if the patient is not
septic, but a fatal mistake if the patient is really infected, especially with more
resistant bacteria as demonstrated by Moore et al. many years ago.89 Although
a number of studies in adults have reported equivalent efficacy and equal or
less toxicity with once-daily dosing, this approach has not yet become
standard of practice in all hospitals treating pediatric patients. Limited
clinical and efficacy data in children and the difference in PK (e.g., higher
clearance) are among the reasons for lack of general acceptance.95 As a result
of several recent studies, the extended interval-dosing concept has received
much broader acceptance in specific pediatric populations, such as neonates
and patients with cystic fibrosis.
96–101
In our view, aminoglycosides are
particularly suited for PK model–based monitoring using aminoglycoside
concentration-predicted clearance, serum creatinine, or creatinine clearance
PK methods.
102
This will also require (as mentioned previously) that
“therapeutic ranges” be adjusted so that they are specific for the dosing
regimen used. If the goal is to truly individualize therapy, then a TDM strategy
should be adopted that will enable this to occur. This is not the case when
nomograms are implemented. Recently, efficacy of MIPD has been
established for aminoglycosides in very young pediatric populations
103–105
and
obese patients.
106,107
For instance, a model-based dosing regimen was
developed using an amikacin PK model in preterm and term neonates.
105
The
developed dosing regimen has been prospectively evaluated.
104
Similar
strategies have been implemented for vancomycin45 and other antibiotics
108
in
infants and children.
Bacterial MICs have been used for years to individualize drug
concentration targets, such as peaks, troughs, and AUCs. A similar method is
being used for other infectious agents, such as viruses and fungi.
Pharmacogenetics offers the promise of individualizing patient-specific
targets as well. For example, genetic predisposition to aminoglycoside
ototoxicity has been well described.
109
Studies are beginning to demonstrate
that determination of individual susceptibility can be used to predict and
eventually prevent both drug- and patient-specific toxicity. For
aminoglycoside ototoxicity, susceptibility is transmitted by maternal
mitochondrial DNA. It should, therefore, be possible to predict or prevent
such toxicity by maternal testing and altering maternal or newborn dosing or
exposure.
ANTIEPILEPTIC DRUGS
Antiepileptic drugs (AEDs) have been monitored since the 1950s and are
some of the medications for which TDM is most commonly used.
18,19
The
marketing of 18 new AEDs to the epilepsy treatment armamentarium since
1989 has led to increasingly widespread implementation of TDM in AED
therapy.19 Indeed, a recent review article indicated that TDM is now
performed for the 27 AEDs approved for the treatment of epilepsy, which are
also used for a number of other medical conditions such as bipolar disorder
and pain.19 TDM is well established and important in the clinical management
of epilepsy because (a) plasma AED concentrations are correlated better than
dose with efficacy, (b) assessment of therapeutic response is difficult in most
cases as AED treatment is prophylactic and there are no laboratory markers
for clinical efficacy of AEDs, (c) AEDs exhibit substantial PK variability that
results in the highly variable dosages among patients, and (d) the ranges of
therapeutic plasma concentrations have been defined for most AEDs based on
population data, summarizing the exposure–response relationships observed
in clinical studies.19 These AED reference ranges are generally useful for the
majority patients; however, the optimal therapeutic target may be different in
some patients due to variability in disease severity, seizure type, the use of
multiple AEDs, and individual sensitivity to the drug(s). In most cases, the
total concentration (both protein bound and unbound) is being analyzed for
TDM; however, it is suggested that the free concentration is more suitable for
some patients, especially for those who exhibit an irregular protein-binding
profile (e.g., pregnant patients and patients after surgery) and who are taking
highly protein-bound AEDs (e.g., phenytoin carbamazepine and valproic
acid).19 When an AED is displaced from its binding sites, the amount of
unbound and pharmacologic active drug increases, whereas the total
concentration may stay the same or go down as a result of increased
metabolism and elimination. Thus, published therapeutic ranges cannot
necessarily be applied in case of patients with a protein binding different
from that of the population used to generate these ranges. Alternative sample
matrices and assay methodologies including dried blood sport (DBS) and
saliva have been increasingly studied for managing AEDs. Population PK/PD
model–based approaches have been evaluated for many AEDs to control for
the large interindividual variability in drug disposition and response.
110
In a
publication, van Dijkman et al.
111
proposed dosing regimens developed with
model-based simulations for 11 commonly used AEDs in both adults and
children. The authors indicated that the AED target concentrations are unlikely
to be attained without the use of dosing algorithms and individualized dosing
recommendations, given the large PK variability. The model-based dosing
algorithms in conjunction with TDM have the advantage of being able to
personalize and optimize treatments.
111
It has also been shown that the toxicity
of some AEDs is associated with specific, identifiable genetic characteristics.
This provides a way to avoid some concentration-dependent as well as
concentration-independent AED toxicities. Pharmacogenetic differences in
both causes of epilepsy as well as AED targets (e.g., transporters or
receptors) are playing an increasing role in the design of more personalized
AED therapy, but this topic is beyond the scope of this chapter.
IMM UNOSUPPRESSANTS
One of the most rapidly advancing areas in TDM in recent years has been the
measurement of immunosuppressive drugs used to avert rejection of
transplanted organs.
112–115
Cyclosporine has been available and routinely
measured for over 20 years. Despite the fact that its concentration–effect
relationship is not well established, clear associations have been made
between predose or trough cyclosporine concentration (C0) monitoring and
clinical end points. In recent years, there have been major changes in
cyclosporine TDM with the advent of AUC and especially C2 monitoring
strategies.
116–118
Bayesian methods have shown great potential and allow more
flexible sampling.
74,119,120
Trough (C0) monitoring of tacrolimus has also been
well established. However, there appears to be an emerging consensus that
tacrolimus, too, may benefit from alternatives to C0 monitoring. MPA was
originally marketed as “not requiring monitoring.” However, the evidence
supports the benefits of MPA TDM as well,
20,121
as illustrated by a consensus
document on the routine monitoring of MPA published by The Transplantation
Society (TTS) Consensus Group on TDM of MPA in 2010.52 Sirolimus
monitoring has fewer sampling time issues because there is a reasonable
relationship between C0 and AUC. The most optimal way to establish
immunosuppressant dose–exposure relationships is by using Bayesian
estimation with a limited sampling strategy.
122
The limitations for routine
TDM of immunosuppressants are the current lack of a reliable immunoassays,
metabolite activity, and interferences.
123
This is especially relevant in
children, as developmental changes may result in different age-dependent
metabolite patterns. For instance, the metabolism of sirolimus in children is
very different from that reported in adults. This should be considered when
monitoring sirolimus exposure using immunoassays, as metabolite crossreactivity issues may interfere with assay accuracy and influence
interpretation of results.
124
Tacrolimus drug monitoring has been used in solid-
organ transplantation for many years. The latest consensus document on