CHAPTER 1

Overview of Therapeutic
Drug Monitoring
William Clarke
Department of Pathology, Johns Hopkins University School of Medicine,
Baltimore, MD, United States

CONTENTS
1.1 INTRODUCTION 1.1 Introduction .... 1
1.2 Principles of
The vast majority of drugs are managed in a very standard way: The drugs are TDM........................ 1
dosed on a unit per body mass (eg, mg/kg) basis, and then the dosage is
adjusted based on the clinical response as empirically assessed by a physi- 1.3 Clinical Areas
in Which TDM is
cian. This is often described as “titration to clinical effect.” For a small subset Routine Practice ... 2
of drugs, the clinical effects (pharmacodynamics) can be assessed objectively 1.3.1 Epilepsy ...............3
through laboratory measurements—for instance, Coumadin and assessment 1.3.2 Organ
of coagulation via international normalized ratio measurement, or statin Transplantation .............5
drugs and blood lipid levels. For an even smaller subset of drugs, the phar- 1.3.3 Cardiology
(Antiarrhythmic Drugs)...7
macokinetic pharmacodynamic relationship is not predictable from the
1.3.4 Psychiatry............8
dose, and the pharmacokinetics are highly variable between individuals; for 1.3.5 Infectious
these drugs, management can be particularly challenging. It is for these drugs Disease ..........................9
that therapeutic drug monitoring (TDM) is most effective. 1.3.6 Oncology............ 11
1.4 Conclusions .. 12
References .......... 13
1.2 PRINCIPLES OF TDM
TDM in practice is performed by collection of a blood sample at a known
time relative to administration of the last (or next) dose. The concentration
of drug and/or metabolite is measured in the sample and compared to a tar-
get range or predicted pharmacokinetics for the drug. In order for TDM to be
effective and necessary, several criteria must be met: (1) The drugs must have
a narrow therapeutic index (the difference between the minimum effective
concentration and the toxic concentration, relative to the pharmacokinetic
variability), (2) the relationship between the drug dose and concentration in
blood must be highly variable and/or not predictable, (3) the relationship
between blood concentration and clinical or toxic effect must be well-
defined, (4) there should be serious consequences for under- or overdosing, 1
W. Clarke & A. Dasgupta (Eds): Clinical Challenges in Therapeutic Drug Monitoring. DOI: http://dx.doi.org/10.1016/B978-0-12-802025-8.00001-5
© 2016 Elsevier Inc. All rights reserved.
2 CHAPTER 1: O v e r v i e w o f T h e r a p e ut i c D r u g Mo n i t o r i n g

and (5) the result of TDM testing must be interpretable and actionable—there
should be an effect on clinical outcomes. It should answer a clinical question.
There are some drugs that meet most of the criteria for TDM but for which
measurement of drug concentrations is not particularly useful. For instance,
when the drug is administered as a prodrug, the biologically active form of
the drug is a metabolite of the administered substance. Therefore, measure-
ment of the administered drug does not help with guidance of therapy, and
the active metabolite must be measured (eg, irinotecan and SN-38). In other
cases, the drug is converted to its active form intracellularly, so blood mea-
surements are not reflective of the therapeutic activity (eg, antiretroviral drugs
and peripheral blood mononuclear cells). In addition, drugs for which toler-
ance can be developed (eg, narcotics and pain management) prevent the util-
ity of TDM because the effective blood concentration range is a moving target
and not stable within an individual patient.
Although the primary function of TDM is to allow for adjustment of the drug
dose, there are other applications of TDM results (eg, questions to be
answered). For example, TDM in antiretroviral management in patients with
HIV is not necessary for optimization of dose; however, it is vitally important
to confirm adherence to the prescribed drug regimen in the context of increas-
ing viral loads and apparent therapeutic failure. The TDM results can be used
to assist in the determination of whether the patient has developed viral resis-
tance to the prescribed drugs or whether the patient has simply stopped tak-
ing the drugs. Another question that can be answered is whether drug is being
absorbed at all. For instance, gastrointestinal (GI) inflammation could pre-
vent drugs administered orally from entering the circulation. It is important
to remember that TDM is a tool for assessing the clinical presentation of the
patient. Most therapeutic target intervals were not derived from large clinical
studies but, rather, are based on the observations and data from a single site.
The absence of a therapeutic interval does not mean that TDM lacks utility,
provided that there are specific criteria for interpretation of the result and it
will aid in clinical decision-making.

1.3 CLINICAL AREAS IN WHICH TDM IS ROUTINE

PRACTICE
Certain pharmacotherapies in patients with specific clinical conditions
require routine TDM. Most of these drugs are used for treating chronic condi-
tions such as epilepsy, but certain toxic antibiotics, such as aminoglycosides
and vancomycin, require TDM if used for more than 2 days. These clinical
situations and drugs that are subjected to TDM are discussed in this section.
 1.3 Clinical Areas in Which TDM is Routine Practice 5

monohydroxycarbamazepine (MHC). MHC is responsible for the antiseizure

activity of the drug, and it is the component that is measured in the blood for
TDM. The half-life for MHC is longer than that of oxcarbazepine (8 10 h vs
1 2.5 h). The therapeutic interval for MHC is reported generally as
3 35 μg/mL [9]. Toxicity associated with MHC includes dizziness, drowsiness,
GI toxicity, tremor, ataxia, and abnormal gait. These toxicities can sometimes
occur even when the drug concentration is within the therapeutic interval.

1.3.2 Organ Transplantation

Organ transplantation is an extremely complex medical procedure, and
immunosuppression is central to controlling the body’s response to the
transplanted organ to ensure a successful xenograft. Management of these
powerful drugs requires a balance of ensuring enough drug exposure to pre-
vent rejection while keeping the concentration of the drug low enough to
avoid toxic effects. TDM is an essential tool in the process, allowing rapid
titration of blood concentrations of the drug to maximize immunosuppres-
sion and avoid acute rejection while minimizing adverse events from expo-
sure to the drug.
Tacrolimus is a calcineurin inhibitor, and it is the most widely used immu-
nosuppressive drug used in transplantation. It can be administered either
intravenously or orally, and it exhibits significant interindividual variability.
Tacrolimus is monitored in whole blood rather than serum or plasma, and a
general therapeutic interval is reported as 5 15 ng/mL for C0 concentrations
[10], although in practice target concentration ranges are more narrow and
dependent on the type of organ transplanted, as well as the time from trans-
plantation. Adverse effects of elevated concentrations of tacrolimus in blood
include nephrotoxicity, neurotoxicity, hypertension, and nausea.
Cyclosporine A (CsA) is a calcineurin inhibitor that has been available for
longer than tacrolimus but is not as widely used. CsA is available in both
intravenous and oral forms, with variable absorption and distribution; it is
also highly protein bound. CsA is found in both plasma and red blood cells,
but measurement of the drug primarily occurs in whole blood samples
because the drug distributes into red cells in vitro after collection as the
temperature decreases. The general target interval for C0 concentrations is
100 400 ng/mL [11], although the target in clinical practice is dependent on
multiple factors, including the type of transplant, time from transplantation,
method of analysis, and coadministered drugs. There is evidence that C2
(peak concentration 2 h after administration) is more closely correlated with
clinical outcomes [12]. CsA is metabolized in the liver by CYP3A4, so it
demonstrates significant interindividual pharmacokinetic variability and is
6 CHAPTER 1: O v e r v i e w o f T h e r a p e ut i c D r u g Mo n i t o r i n g

susceptible to drug drug interactions. Adverse effects of high CsA concentra-

tions include renal toxicity, as well as liver or CNS effects.
Sirolimus is an interleukin-2 (IL-2)-inhibiting drug that targets the mTOR
(mammalian target of rapamycin) receptor, which interrupts the cell cycle.
Sirolimus is primarily metabolized by CYP3A4/5, so it exhibits significant phar-
macokinetic variability and is susceptible to drug drug interactions. The half-
life of sirolimus is relatively long (48 72 h) compared to those of the other
immunosuppressants, so it takes longer to achieve steady-state concentrations
after initiation of therapy or with a dosage change. Generally, the therapeutic
interval for sirolimus is 4 12 ng/mL, but as with the other drugs, it is depen-
dent on transplant type and comedication, in addition to other variables [13].
Sirolimus is measured in whole blood samples rather than serum or plasma
due to its significant distribution into red blood cells. The benefit of this drug
is that it does not have renal toxicity, making it appealing for use in kidney
transplantation. However, significant toxic effects are still possible, including
leukopenia, thrombocytopenia, and hypercholesterolemia.
Everolimus is a structural analog of sirolimus, and as such they share the
same target and mechanism of action (mTOR inhibition). The primary differ-
ence between everolimus and sirolimus is that everolimus has a shorter half-
life (18 36 h) and its toxic effects are less significant. However, it is still
important to manage this drug using TDM for optimal therapeutic effect
while minimizing toxicities. Everolimus is also measured in whole blood
samples for TDM. The target therapeutic interval is 3 15 ng/mL, with modi-
fications based on coadministered medications, transplant type, and time
from transplantation [14].
Mycophenolic acid (MPA) is an inhibitor of inosine monophosphate dehy-
drogenase, which inhibits cell group by inhibition of purine synthesis. MPA
is the active compound; however, the drug is actually administered as a pro-
drug such as mycophenolate mofetil (CellCept) or mycophenolate sodium
(Myfortic), which is an extended-release formulation. The drug is used in
conjunction with either calcineurin or mTOR inhibitors as adjuvant therapy
for immunosuppression. The drug has a relatively short half-life (9 18 h)
and is not distributed into red blood cells like the other commonly used
immunosuppressant drugs. Important differences for MPA include the fol-
lowing: (1) The measurement of the drug is in plasma rather than whole
blood; and (2) a peak or C0 measurement is not sufficiently correlated with
the area under the curve (AUC), so a single measurement is not sufficient. It
is recommended that AUC with limited sampling be used for TDM of this
compound [15]. The primary toxicity for MPA is GI toxicity; there is some
debate about whether TDM is really needed for MPA or whether the dose
can just be reduced if GI toxicity is observed.