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TABLE 7.1
PK/PD modeling and simulation (M&S). This has facilitated the establishment
of population-specific starting dosing regimens based on specific factors that
are predictive of exposure and response. PK/PD models serve as a priori
knowledge that link the drug dose to exposure and subsequent effects.
Especially in pediatrics, where growth and maturation are correlated, agerelated variation in PK/PD can be taken into account quantitatively with the
M&S approach
3,14
(see “Model-Informed Precision Dosing” section). A
posteriori TDM as defined by IATDMCT includes dose adjustment after the
start of therapy based on treatment-related feedback data collected from a
particular patient, such as blood concentration measurements and/or clinical
biomarkers indicating drug response. Proper a posteriori TDM requires
interpretation of drug concentration measurements and/or biomarker data with
consideration of preanalytical conditions, clinical information, and the
clinical efficiency of the current dosage regimen. Although frequently dose
adjustments are made based on a simple comparison of the observed
concentration versus therapeutic target range, using a population PK/PD
model in combination with individualized forecasting techniques such as
Bayesian estimation can facilitate more precise and rapid target attainment
(see later examples).
The rationale for using TDM to optimize dosing of a given drug is
contingent on three important requirements: (a) there is a better association
between the concentration and the therapeutic effect than between the dose
and the effect, (b) TDM and dose individualization will reduce variability
and will better predict the patient’s concentration–time profile, and (c)
maintenance of drug concentrations within desired target ranges (see later
discussion) improves clinical outcome by either increasing efficacy or
reducing toxicity or both.15 Proper TDM requires that dosing regimens are
then further individualized based on individual measured concentrations and
responses. The criteria for monitoring (managing) drugs in children are
similar to those in adults. Generally accepted indications for concentration
measurements are summarized in Table 7.1.
Indications for Therapeutic Drug Monitoring
Drugs with a narrow therapeutic index (NTI)
Inadequate response
Higher than standard dose required
Serious, unexpected, or persistent side effects
Suspected toxicity
Suspected nonadherence
Suspected drug–drug or drug–diet interactions
New preparation, changing brands
Other illnesses, for example, hepatic/renal problems, inflammatory diseases
The cost-effectiveness of TDM has also been demonstrated as a result of
dose reduction and the reduced duration of hospitalization for many
treatments.16 In addition, it is suggested that the use of TDM potentially
reduces relapse rates as it is helpful to detect nonadherence to medication
before rehospitalization.
In pediatrics, the use of TDM has been common in (a) the treatment of
epilepsy,
17–19
(b) transplantation,20 and (c) drug therapy in neonates.21 In recent
years, TDM has also been increasingly implemented in other important
therapeutic areas in pediatrics, such as psychiatry,22 HIV,23 and inflammatory
diseases,
24,25
including therapies involving monoclonal antibodies. Oncology
is another emerging therapeutic area where TDM is increasingly being used
for dose optimization. However, TDM implementation in children is still not
as common as in adult populations.
26
THE THERAPEUTIC RANGE CONCEPT
Despite decades of TDM, recommended target concentrations (therapeutic
ranges) are largely empirical, population rather than individually based,
independent of assay method used, seldom consider time after dosing, and
seldom are the result of evidence-based studies. The therapeutic range is also
commonly misunderstood even for commonly monitored drugs such as
digoxin, aminoglycosides, phenobarbital, phenytoin, and theophylline.
Interpretation of TDM results is still almost exclusively focused on altering
dosing to get measured concentrations within a published “therapeutic
range”.27 The “therapeutic range” is defined as the range of drug
concentrations associated with a high degree of efficacy and a low risk of
dose-related toxicity in the majority of patients. This is not the same as the
optimal concentration for each individual patient. Furthermore, the emphasis
in measuring drug concentrations has been mostly toxicity oriented and for
drugs with a narrow therapeutic index (NTI). NTI drugs are defined as those
drugs where small differences in dose or blood concentration may lead to
dose and blood concentration dependent, serious therapeutic failures, or
adverse drug reactions.
The “therapeutic range” concept is hampered by some important
problems.28 First, defining a single, time-independent concentration range
leaves the physician with the uncertainty of how to choose the optimal dose
when in fact a range of dosing regimens would produce a “therapeutic
concentration” at some time in the regimen. Second, the definition of a
therapeutic range does not differentiate among concentrations but assumes that
all concentrations within the range may be equally desirable. Third, the ranges
depend on a number of other things, including time after a dose, time on a
particular regimen, the condition being treated, the assay used, and the
possibility of active metabolites. Problems created by assays with different
specificity for active and inactive metabolites or interfering substances are
more commonly a problem in pediatric than in adult patients. Poor
understanding of the therapeutic range has led to a rather naive and even
potentially dangerous “numbers-only,” three-step, all-or-nothing interpretation
of the concentration–effect relationship. This simplistic approach assumes that
any concentration below the lower end of the range will be of no benefit to the
patient, that anywhere within the range the patient will be okay, and that above
the upper end of the range the patient will experience unacceptable adverse
reactions. None of these may be true in any given patient.
DISTRIBUTION PHASE
Immediately after administration, drugs must distribute into the blood and then
to tissues in the body. This results in initial concentrations that are much
higher than, and which do not show a log-linear correlation with,
postdistributional concentrations. This is true for most, if not all, drugs given
intravenously, and for several drugs (e.g., digoxin and clonazepam), this
phenomenon also occurs after oral administration. There are large differences
between trough and distribution concentrations even for drugs with a very
long half-life. Digoxin, for example, can have postdose peak concentrations of
3 to 5 ng per mL in patients with trough concentrations of less than 1 ng per
mL. There are also greatly different concentration–effect relationships
between distribution and postdistributional concentrations at the site of
action.29 If not appreciated, this can lead to inappropriate decreases in digoxin
doses or even use of Digibind, digoxin antigen-binding fragments (personal
experience). Unfortunately, many physicians believe, and teach, that sampling
time is not important for drugs with long half-lives because concentrations are
not expected to change much when dosing intervals are much shorter than the
drug’s half-life. Although true well after completion of the distribution phase,
this is not true when comparing trough values with concentrations obtained
during distribution. Randomly collected clonazepam concentrations have been
used to claim that there is a poor relationship between concentrations and
effect. However, it is highly likely that this conclusion is based on the fact that
clonazepam, despite having relatively slow clearance, also has very high
distribution concentrations relative to predose (trough) concentrations even
after oral administration.30 Concentrations drawn during the distribution phase
(4 to 6 hours after dosing) will not correlate with effects because they do not
reflect the effect site concentration. PK modeling of digoxin or clonazepam
with respect to concentrations at their sites of action (heart muscle and brain,
respectively) is needed to attempt to correlate concentrations and effect.
Bayesian modeling, but not linear correlation methods, can deal with
sampling during the distribution phase, but sampling and accurate information
on administration time become even more critical.
29,31
Unfortunately, in
pediatrics, the time of drug administration is not as easy to determine as it is
in adults. Decades ago, Leff and Roberts showed that it can take hours for
drugs put into an intravenous setup to actually reach the patient.32 This is still
true to date, as the delivery of drugs administered by intravenous infusion in
extremely low-birth-weight neonates can be substantially extended due to the
small volumes and low infusion rates used in these patients.12 Appreciation of
both distribution phase sampling as well as the practical problems of
ascertaining actual drug administration time for different intravenous setups,
fluids and administration rates, and sites is required to properly interpret
some drug concentrations.
THE STEADY-STATE CONCEPT
Steady state is another commonly misunderstood PK principle. Drug
concentrations fluctuate over a defined range once a patient reaches steady
state. If the clearance of a drug which follows first-order PK stays the same,
then the patient receiving the drug will reach one half (50%) of eventual
concentrations after one half-life, 3/4 (75%) after two half-lives, 7/8 (87.5%)
after three half-lives, 15/16 (94%) after four half-lives, and so on. This is
commonly misinterpreted to mean that drug concentrations should be
measured after three to four doses have been given. However, drugs are
seldom given every half-life. Drugs with much shorter half-lives than the
dosing interval reach steady state long before three to four doses, and drugs
with very long half-lives may not reach steady state until after many dozens of
doses unless a loading dose is given. A patient with a gentamicin half-life of 1
to 2 hours who is given a dose every 8 hours is very close to steady state after
a single dose, whereas a patient receiving a drug with a half-life of 36 hours
every 8 hours without a loading dose does not reach steady state for almost a
week. Routine orders to measure a drug concentration after three or four
doses demonstrate a lack of understanding of basic PK principles let alone
any appreciation for the effects of individual differences in drug clearance. In
addition, attainment of steady state described above assumes that the patient’s
clearance is not changing over time; something which is almost never true in a
critically ill patient or even in a healthy newborn or young child.
DEVELOPMENTAL ASPECTS OF DRUG DISPOSITION
AND RESPONS
Proper PK/PD guidance is especially important in patients with rapidly
changing PK (clearance) and responses (PD). Although this applies to most
critically ill, hospitalized patients, it applies especially to neonates and
children because of large, often rapid developmental changes in both PK and
PD.
33,34
It has been well documented that development of physiology and
organ function (e.g., liver and kidney) mostly occurs in the early phases of life
up to approximately 2 years of age.33 In children aged 2 years and older,
maturation is mostly completed, and the changes in PK parameters such as
clearance and volume of distribution can be well described using an
appropriate body size scaling factor, such as allometric scaling.
35–37
The
developmental changes in PK of medications that occur between birth and
infancy create challenges for physicians who desire to prescribe medications
on a rational, age-appropriate, individual basis. Routine TDM of prescribed
drugs and their active metabolites can be of great help to individualize dose
requirements during long-term treatment.15 In addition, the ratio of
metabolite(s) to parent drug can also give important information on
(non)adherence and can reveal unusual metabolic patterns.
Increasingly, proper interpretation of measured drug concentrations is
being used to provide important insights into the different PK behavior in
neonates, children, and adolescents.38 Of all routinely monitored drugs, the
aminoglycosides have been studied most extensively. PK data for gentamicin,
tobramycin, netilmicin, and amikacin are available across (arbitrary)
pediatric age categories: preterm newborns, term newborn infants (0 to 27
days), infants and toddlers (28 days to 23 months), children (2 to 11 years),
and adolescents (12 to 16 or 18 years).
39,40
These studies have demonstrated
that in the premature neonate, drug clearance is reduced and volume of
distribution increased as compared with older children and adults, and
glomerular filtration (the predominant route of elimination) by the immature
kidney is reduced.
41,42
Volumes of distribution are larger than those in older
pediatric patients because of larger body water fat content and higher body
surface-to-weight ratios. Such increased volume of distribution in newborns
has also been observed for other drugs.43 An overview of age-related PK
changes and PK parameter estimates for gentamicin and vancomycin
44,45
as
index drugs is summarized in Table 7.2. Drug clearance rapidly increases
with age as the kidney develops and the total body water decreases. Although
the limitations of serum creatinine or creatinine clearance as a diagnostic
biomarker of kidney function has been recognized,46 the creatinine
concentration in plasma or calculated creatinine clearance remains a good a
priori indicator of individual renal drug elimination.
47,48
Individual
differences in renal drug clearance can, therefore, be predicted before or
during dosing and used to individualize dosing (both dose and dosing
frequency). In addition, however, clearance of renally cleared drugs such as
TABLE 7.2
gentamicin can be used to predict renal function more accurately than
creatinine clearance calculations used in adults.49 This is especially useful in
the newborn, where maternal creatinine contributes to neonatal creatinine
concentration in the first days after birth (see case presentation in later
discussion). Besides renally cleared drugs, recent studies have provided
evidence on the developmental changes in clearance of drugs that are
predominantly metabolized. Anderson and Holford in a series of articles
quantitatively describe the relationship between young age and the
developmental trajectory of clearance as a percentage of adult clearance.
35–
37,50
Age -Related Difference s in Pharmacokinetic Parameters for
Aminoglycosides and Vancomycin
Drugs that are metabolized often show large, unpredictable interindividual
and sometimes intraindividual differences in PK behavior. This interpatient as
well as intrapatient variability may be further increased if the drug is taken
orally, because of differences in absorption, transport, as well as intestinal
metabolism. TDM can detect such interindividual as well as intraindividual
variations. However, a single measurement will only describe the net results
of all the different underlying processes (e.g., bioavailability, absorption,
distribution, metabolism, excretion) involved. For instance, a concentration
that is lower-than-expected based on data for that patient population can be
the result of poor adherence, absorption problems, increased metabolism and
excretion, or any combination of these.
DOSE ADJUSTMENTS BASED ON
THERAPEUTIC DRUG MONITORING DATA
The decision to alter a generally accepted dosing regimen either before or
during ongoing therapy is frequently based on an empirical trial-and-error
decision-making process where different pieces of clinical information are
considered. Patients in whom a rapid onset of effect is required or patients
who exhibit lower or higher effects than expected after initiation or alteration
of therapy can clearly benefit from proper TDM. In the nonresponding patient,
concentration measurements will help the clinician decide whether
nonadherence is present, whether a medication error is possible, whether a
drug–drug or drug–diet interaction has occurred, or whether individual
differences in PK or PD require a different dose or frequency of dosing or
whether alternate therapy is indicated. This is true even for drugs for which a
well-described “therapeutic range” is unknown.
Appropriate timing of sample collection is crucial for the appropriate
interpretation of drug concentrations. Within a dosing interval, the predose or
trough concentration is usually the sampling time after steady state is
achieved, but efficacy is questioned. In the case of adverse events or
(suspected) toxicity, sampling is preferably done at the time maximal side
effects are experienced. Other sampling strategies may be required for drugs
that exhibit a complex PK profile and poor correlation between the trough
concentration and the area under the concentration–time curve (AUC). An
example of this is mycophenolic acid (MPA), a drug with complex absorption
characteristics and which exhibits enterohepatic recycling.
51,52
Lack of all
necessary information, such as the actual time of drug intake, how long after
dosing was started, whether a loading dose was used, timing of concomitant
medications, and time of sampling, makes it more difficult, or sometimes
impossible, to interpret results. TDM laboratories and services can play an
important role in improving patient outcomes and the efficient use of TDM by
providing up-to-date guidelines and educating physicians and other health
care providers about what information is necessary to properly interpret any
result. This information must either be accurately provided with laboratory
requests or obtained by TDM service personnel. Unless the ordering
professional is thoroughly familiar with PK and analytical principles, all drug
concentrations should include an individualized PK interpretation.
53–57
For
several drug classes, the use of population models and the application of
Bayesian optimization algorithms have been shown to be a clinically useful
and cost-effective way to provide such interpretations.
29,58
These algorithms
are quite different from dosing nomograms, which are used to predict
“average” or initial doses in various populations.
REACTIONARY THERAPEUTIC DRUG
MONITORING
Many clinical laboratories offer some form of TDM menu. However, test
results are commonly reported as “numbers only” (i.e., without PKappropriate interpretation), in a similar manner as general chemistry test
results are reported (result with a reference range). This type of reporting is
misleading and does not optimally use what is known about the drug’s PK
characteristics. As opposed to most endogenous compounds, drug
concentrations are not stable over time and are governed by known and
predictable PK principles. In addition, more in-depth interpretations (i.e., PK
consultation), with the possible exception of aminoglycosides and
vancomycin, are seldom offered. As a result, dose adjustments frequently are
made on an ad hoc basis relying on one or more “numbers” (i.e.,
concentration measurements) that are within or outside a “therapeutic range.”
This can best be described as “reactionary TDM,” where a standard dose is
administered, and a concentration is checked to verify whether it is
“therapeutic.” The process is often toxicity driven; if the concentration is
“toxic” (i.e., above the “therapeutic range”), the dose will be empirically
lowered, and the concentration will be checked again. If “subtherapeutic,” the
dose may be empirically increased, with measurements being repeated until
“therapeutic.” If the first measurement is within the therapeutic range, things
are considered “okay,” and no further action is taken. It is obvious that such
reactionary TDM does not take into consideration PK principles or the full
concentration–time profile, individual PK/PD differences, time to attain
steady state, or patient-specific PD targets. It does not lead to efficient use of
resources and has not been shown to produce optimal outcomes. However,
many studies have documented that proper PK/PD guidance, but not
“reactionary TDM,” is effective.58 Such guidance can improve overall use of
resources and produce better and more cost-efficient outcomes, fewer
inappropriately drawn samples, more concentrations within the desired range,
fewer dose adjustments, and reduction in the incidence of adverse events.
58–60
MODEL-INFORMED PRECISION DOSING
To overcome the shortcomings of reactionary TDM, the implementation of
population PK/PD model–based prediction and the application of Bayesian
adaptive control have been advocated as clinically useful strategies and costeffective ways to improve precision dosing and rapid target attainment. It is of
interest to note that the model-based approaches using Bayesian estimation
were pioneered in the late seventies but never found the broad clinical
acceptance they deserved.
61,62
In recent years, with the advent of more
powerful and easier-to-use software tools, renewed interest has been sparked
for the implementation of model-based therapeutic optimization and clinical
pharmacometrics.4 Such strategy and approach to therapeutic optimization is
now being coined as “model-informed precision dosing” (MIPD) and is part
of a wider context of precision medicine.63 MIPD is designed to identify
optimal dosage regimens in a particular patient(s) using statistical and/or
mathematical models representing drug responses, including individual
PK/PD. MIPD provides a quantitative framework to use prior experience
accumulated from previous patients and/or subjects who participated in
clinical trials for dose optimization in a current and future patient. As part of
the TDM process, MIPD is particularly useful for both a priori TDM (initial
dosage regimen optimization based on identifiable patient characteristics) and
a posteriori TDM (real-time dose individualization based on measurements,
such as drug concentrations and response biomarkers) (see later discussion
and examples). MIPD can provide an important extension of TDM.