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Therapeutic drug monitoring

Therapeutic drug monitoring (TDM) is defined as the management of a patient's drug
regime based on serum, plasma, or whole blood concentration of a drug.
From: Advances in Clinical Chemistry, 2016

Related terms:
Transplantation, Vancomycin, Aminoglycoside, Pharmacokinetics, Chromatography,
Sirolimus, Specimen, Immunoassay, Mycophenolate Mofetil, Tacrolimus

Therapeutic drug monitoring

Mike Hallworth, in Clinical Biochemistry: Metabolic and Clinical Aspects (Third Edition), 2014

Antimicrobial drugs
Most antimicrobial drugs are well tolerated and do not require therapeutic drug monitoring. The exceptions to this general
principle include the aminoglycoside antibiotics, the glycopeptides vancomycin and teicoplanin, and chloramphenicol.
Aminoglycosides (amikacin, gentamicin, tobramycin)
The aminoglycosides are an important group of antimicrobial drugs used in the treatment of severe systemic infection by
some Gram-positive and many Gram-negative organisms. Amikacin, gentamicin and tobramycin are also active against
Pseudomonas aeruginosa. Streptomycin is active against Mycobacterium tuberculosis and is now generally reserved for
tuberculosis (see below). Neomycin is too toxic for systemic use and can only be used for topical application (skin, mucous
membranes). The parent compounds are produced by moulds of the Streptomyces family (streptomycin, tobramycin,
neomycin) or the Micromonospora family (gentamicin). The different host organisms account for the variation in spelling of
the suffix.
The aminoglycoside antibiotics exhibit relatively simple pharmacokinetics. They are large, highly polar molecules with very
poor oral bioavailability, and must be given parenterally. They are not protein bound and not metabolized, and are excreted
through the kidneys. The plasma half-life is 2–3 h, except when renal function is impaired, but the drug may accumulate in
tissues. If therapy is continued for longer than a week, tissue sites become saturated and plasma concentrations may rise.
These drugs exhibit significant systemic toxicity at plasma concentrations just above those necessary for bactericidal activity.
The main toxic effects are nephrotoxicity and ototoxicity. Nephrotoxicity further reduces the ability to excrete
aminoglycosides, and a vicious cycle may be precipitated. Nephrotoxicity is often reversible, as is mild ototoxicity, but
severely damaged cochlear hair cells cannot be replaced and patients may be left with irreversible hearing loss and
disturbed balance.

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The drug concentration at which bactericidal effects are achieved (the minimum inhibitory concentration, MIC) is relatively
easy to determine in vitro but often has little relevance in vivo, owing to variable penetrance of the drug to the site of
infection and differing conditions at the infection site. Aminoglycosides also show a marked post-antibiotic effect –
suppression of bacterial growth persists for some time after the drug is no longer present in the plasma. This makes
definition of target plasma concentrations difficult, and this difficulty has been compounded in recent years by changes in
the ways in which aminoglycosides are administered.
Until the mid-1990s, aminoglycosides were administered every 8 or 12 h, to give relatively stable plasma concentrations in
view of their short half-life. It has become clearer that less frequent dosing (every 24 h or more) produces higher peak
concentrations, which enhance bacterial kill, and lower trough concentrations, which reduce the systemic toxicity. Such
regimens are more convenient, less toxic, reduce adaptive resistance and are generally more suitable in patients with
normal renal function. The approach was originally devised as once daily dosing, but a more accurate term is probably
‘extended dosing interval’, in which a plasma concentration measurement is used to design an individual dosing interval
which reflects the patient’s needs and renal function. The Hartford nomogram (Nicolau et al. 1995, see Further reading) is
an example of this approach, but local guidelines should be consulted on dosage and serum concentrations. Monitoring is
essential to achieve effective therapy while avoiding toxicity, particularly in infants, the elderly, the obese and patients with
cystic fibrosis, if high doses are being used or if renal function is impaired.

Value of monitoring
high.

Glycopeptides (vancomycin and teicoplanin)

The glycopeptide antibiotic vancomycin is used intravenously in endocarditis and other serious infections caused by Gram-
positive cocci including multi-resistant Staphylococci (MRSA). It is also used orally in the treatment of antibiotic-associated
(pseudomembranous) colitis. Like the aminoglycosides, the glycopeptides are poorly absorbed, not metabolized, excreted
renally and are potentially nephrotoxic and ototoxic. Indications for monitoring have been controversial, but there is
definitely a role for monitoring in patients with poor renal function to achieve maximum effect with minimal toxicity.
Teicoplanin is similar to vancomycin, but has a longer duration of action such that once-daily dosing is sufficient. No
relationship between plasma concentration and toxicity has been established, and teicoplanin is not normally monitored.
Value of monitoring
moderate (vancomycin), low (teicoplanin).

Chloramphenicol
Chloramphenicol is a powerful broad-spectrum antibiotic that carries a risk of serious haematological side-effects when
given systemically. It is used to treat life-threatening infections such as cholera, typhoid fever, resistant Haemophilus
influenzae, septicaemia and meningitis. Chloramphenicol is metabolized in the liver to the active glucuronide, and peak
plasma concentrations (2 h post-dose) in the range 10–25 mg/L (30–77 μmol/L) are desirable. Concentration monitoring is
essential in neonates and recommended in children under four years, the elderly and patients with hepatic impairment.

Value of monitoring
moderate.
Antifungal drugs
The successful management of invasive fungal infections remains challenging to clinicians, and the incidence of invasive
mycosis has risen in parallel with the rise in the population of immunocompromised patients. The morbidity and mortality
caused by these infections remains high, and TDM has a role in ensuring that adequate drug concentrations are attained at
the site of infection without systemic toxicity. Four triazole antifungal drugs (fluconazole, itraconazole, posaconazole and
voriconazole) have been approved for use. They show marked inter- and intraindividual variations in blood drug
concentrations after dosing, owing to variable absorption from the gut (itraconazole, posaconazole) and polymorphism in
the CYP2C19 enzyme (voriconazole). The pyrimidine analogue flucytosine also exhibits wide interpatient variation in blood
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concentration owing to variation in renal elimination. The high pharmacokinetic variability and need for optimal adjustment
of drug exposure to ensure that infections are treated adequately are arguments in favour of TDM, but although
concentration–effect relationships have been demonstrated for the triazoles and flucytosine, optimal target blood
concentrations have not been definitively established and concentration measurements in clinically relevant timescales are
not yet readily available. Itraconazole and flucytosine concentrations should be measured routinely in all patients during the
first week of therapy and in patients with poor responses. Monitoring of posaconazole and voriconazole should be
considered in patients who are not responding to therapy, those with gastrointestinal dysfunction, children and those
taking drugs which interact with triazole antifungal agents.

Value of monitoring
moderate.
Antitubercular drugs
The treatment of active tuberculosis (TB) always requires the use of multiple antibacterial agents. It is usually treated in two
phases – an initial phase using four drugs and a continuation phase using two drugs. The most frequently used regimen is
isoniazid, rifampicin, pyrazinamide and ethambutol (or, rarely, streptomycin), followed by isoniazid and rifampicin. Isoniazid
and rifampicin are the key components of this regimen, and both drugs show significant pharmacokinetic variability. The
majority of patients are completely cured by standard regimens, and TDM has no role in dosage optimization in these
patients. However, patients who are slow to respond to treatment, have drug-resistant TB, are at risk of drug–drug
interactions or have concurrent disease states (e.g. acquired immunodeficiency syndrome) that significantly complicate the
clinical picture may require individualization of drug therapy, and may benefit from TDM. Early intervention guided by
concentration monitoring may prevent the development of further drug resistance. The pharmacokinetic interactions
between antitubercular drugs and other medications can often be of considerable clinical concern. Rifampicin is a potent
inducer of cytochrome P450 CYP3A and decreases plasma concentrations of the HIV-protease inhibitors significantly;
isoniazid is a P450 enzyme inhibitor. Patients with HIV are at particular risk for drug–drug interactions.
When TDM is justified, the 2 h post-dose concentrations of isoniazid, rifampicin, pyrazinamide and ethambutol are usually
most informative. Unfortunately, low 2 h values do not distinguish between delayed absorption or malabsorption and non-
adherence. In such cases, a second sample, often collected at 6 h post-dose, provides additional information. Trough
concentrations of many anti-TB drugs are below the limit of detection of current assays and have limited relevance. Plasma
concentrations required for effective therapy, especially on multi-drug regimens, are only partially known, as detailed
pharmacokinetic and pharmacodynamic information in humans is lacking. There is a clear dose–response relationship for
rifampicin and pyrazinamide and low isoniazid concentrations are also associated with poorer outcomes. Second-line TB
drugs such as p-aminosalicylic acid, cycloserine and ethionamide are not usually monitored. Streptomycin is used against
resistant organisms. It is nephrotoxic and should be used with great care in patients with renal impairment; concentration
monitoring is essential in such patients.

Value of monitoring
moderate.

Antiretroviral drugs
Several classes of antiretroviral drugs are used in the management of infection by HIV:
• nucleoside reverse transcriptase inhibitors, e.g. zidovudine, abacavir, didanosine, emtricitabine, lamivudine, stavudine
and tenofovir
• non-nucleoside reverse transcriptase inhibitors, e.g. efavirenz, etravirine and nevirapine
• protease inhibitors, e.g. atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and
tipranavir
• fusion inhibitors, e.g. enfuvirtide

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• entry inhibitors, e.g. maraviroc
• integrase inhibitors, e.g. raltegravir.

The nucleoside reverse transcriptase inhibitors (NRTIs) are pro-drugs that require activation by intracellular
phosphorylation. Plasma NRTI concentrations therefore do not correlate with clinical effect and NRTIs are not suitable for
TDM.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) display highly variable pharmacokinetics; the cytochrome P450
isoenzyme involved in their metabolism (CYP2B6) has a polymorphic variant resulting in slower metabolism and higher
plasma concentrations. The protease inhibitors (PIs) also have highly variable pharmacokinetics, but their plasma
concentrations have been shown to correlate with virological response. Therapeutic drug monitoring for NNRTIs and PIs
may have an important adjunctive role in individualizing therapy in high-risk patients or those with PI resistance. Adherence
remains a major problem, especially in developing countries where patient understanding is often poor. Concentrations are
normally monitored 1h post-dose. Protease inhibitors and NNRTIs can be quantitated by liquid chromatography tandem
mass spectrometry (LC-MS) in a single run.

Value of monitoring
low to moderate.

Introduction to Therapeutic Drug Monitoring

Amitava Dasgupta, in Therapeutic Drug Monitoring, 2012

Conclusions
Therapeutic drug monitoring is required for a small fraction of drugs used in pharmacotherapy, but for these drugs such
monitoring is essential in order to achieve maximum efficacy of the drug as well as to avoid drug toxicity.
Therapeutic drug monitoring is also useful in avoiding adverse drug events. Currently, the old approach of
therapeutic drug monitoring for avoiding drug toxicity needs to be revised due to new developments in information
technology, new analytical procedures for less frequently monitored drugs, and new clinical pharmacological expert
opinions in the presentation of laboratory medicine results. Today, therapeutic drug monitoring can be used to prevent an
adverse drug reaction rather than confirming the cause of an existing adverse drug reaction. Therefore, blood should be
drawn for therapeutic drug monitoring after the pharmacokinetic steady state has been reached (five times the elimination
half-life of the drug) after administration of low to moderate dosage under the intended poly-medication if the patient is
considered not to belong to the normal patient population. The benefits of therapeutic drug monitoring include significant
cost saving because hospitalization will be shortened for the patient, and avoidance of expensive diagnosis and treatment of
an adverse drug event [82].

Advances in antibiotic measurement

Amitava Dasgupta, in Advances in Clinical Chemistry, 2012

14 Conclusions
Therapeutic drug monitoring of aminoglycosides and vancomycin is essential in order to avoid drug toxicity especially
nephrotoxicity and irreversible ototoxicity. Chloramphenicol therapy requires therapeutic drug monitoring but this drugs is
used infrequently due to its toxicity. Other antibiotics are less frequently monitored due to wide therapeutic index.
Therefore, other than aminoglycoside, vancomycin and few antibiotics immunoassays are not commercially available, and
only chromatographic methods can be applied for their monitoring in human serum or plasma. Because of complex nature
of chromatographic techniques, small- to medium-size laboratories do not have the capability of using such methods, and

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only reference laboratories and larger medical centers as well as academic medical centers offer such testing. This is a
limitation because a patient experiences an unexpected toxicity from an antibiotic may be benefitted if serum drug level
result is available to the clinician within hours of ordering, and only patients in large medical centers and academic centers
can get the benefit of in-house offering of therapeutic drug monitoring of uncommon antibiotics. For a patient in a small-
or medium-size hospital, the clinician must wait for few days up to a week for the result to come back from a reference
laboratory.

Monitoring free mycophenolic acid concentration

Amitava Dasgupta, in Personalized Immunosuppression in Transplantation, 2016

4.7 Conclusion
Therapeutic drug monitoring of mycophenolic acid using serum or plasma is useful for avoiding rejection as well as toxicity
such as neutropenia. In general, pre-dose concentration is measured, but better correlation exists between mycophenolic
acid AUC0–12 h and clinical efficacy as well as toxicity. Interindividual pharmacokinetics of mycophenolic acid, however, is
highly variable, and there are overlapping concentrations between therapeutic range and toxicity. Mycophenolic acid is
strongly protein bound (97–99%), mostly to serum albumin. Whereas for solid organ transplant recipients with normal
renal and liver function, therapeutic drug monitoring of total mycophenolic acid is sufficient, for transplant recipients with
renal insufficiency, hypoalbuminemia, and liver disease, the free fraction of mycophenolic acid may be significantly elevated,
so monitoring free mycophenolic acid along with traditionally monitored total mycophenolic acid is strongly
recommended.

Challenges in Therapeutic Drug Monitoring of Digoxin and

Other Anti-Arrhythmic Drugs
Amitava Dasgupta, in Therapeutic Drug Monitoring, 2012

Challenges in Monitoring Class IB Anti-Arrhythmic Drugs

Therapeutic drug monitoring of the Class IB anti-arrhythmic drugs lidocaine and mexiletine is recommended. Lidocaine
cannot be given orally due to first-pass metabolism, and must be given by the intravenous route. If lidocaine therapy is
continued for a short time, therapeutic drug monitoring may not be needed; however, if treatment is continued beyond 24
hours then therapeutic drug monitoring is recommended in order to avoid adverse drug effects. Immunoassays are
available for therapeutic drug monitoring of lidocaine, which are robust and mostly free from interferences.
Lidocaine is metabolized to monoethylglycinexylidide and glycinexylidide, both pharmacologically active but less active than
the parent drug. The major initial metabolite of lidocaine, monoethylglycinexylidide, can be used for assessment of hepatic
function in transplantation, and in critical care medicine. Because of the relatively high excretion ratio, this liver function
test depends not only on hepatic metabolic capacity but also on hepatic blood flow. For determination of the
monoethylglycinexylidide concentration in serum, both chromatographic methods (gas chromatography and high-
performance liquid chromatography) and the fluorescence polarization immunoassay are available. Although
chromatographic methods are free from interference, immunoassay showed cross-reactivity with 3-hydroxy
monoethylglycinexylidide [58].
Lidocaine is strongly bound to serum alpha-1-acid glycoprotein, and concentration of this acute-phase reactant increases in
renal disease, hepatic dysfunction and myocardial infarction, and in patients taking classical anticonvulsants. Therefore, the
pharmacologically free fraction of lidocaine may be reduced in these patients, requiring higher total lidocaine serum levels
than the recommended lidocaine therapeutic range of 1.5–5.0 μg/mL. Because the usual therapeutic range of lidocaine

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does not apply in these patients, especially patients after myocardial infarction, free lidocaine monitoring is recommended
[59].
Mexiletine has similar electrophysiological properties to lidocaine, but can be administered orally because it does not
undergo significant first-pass metabolism like lidocaine. The bioavailability of mexiletine is over 90% and plasma protein
binding is approximately 70%. The elimination half-life is 10 hours, but this drug is extensively metabolized by the liver,
with more than 11 metabolites identified. Various pathophysiological parameters affect the disposition of mexiletine, and,
due to overlapping concentrations between the therapeutic and toxic ranges, therapeutic drug monitoring is
recommended. Myocardial infarction, therapy with opioid analgesics, and antacids all reduce the rate of absorption of
mexiletine after oral administration, while metoclopramide enhances its absorption. Rifampin, phenytoin and cigarette-
smoking enhance the elimination of mexiletine, whereas ciprofloxacin, propafenone and liver cirrhosis decrease its
elimination. Factors affecting the elimination of mexiletine may be clinically important, and dosage adjustments are often
necessary [60]. Again therapeutic drug monitoring can be useful for dosage adjustment. Mexiletine is administered as a
racemic mixture, but the R-isomer demonstrates higher anti-arrhythmic potency than the S-isomer. The S-isomer
concentration in the serum, based on area under the curve, is greater than that of the R-isomer due to enhanced clearance
of the R-isomer in the urine [61]. Usually, chromatographic methods are employed for monitoring mexiletine without
resolving optical isomers. However, a chiral column can be used for determination of mexiletine enantiomers in plasma
[62].

Therapeutic drug monitoring using mass spectrometry

P.J. Jannetto, in Mass Spectrometry for the Clinical Laboratory, 2017

Abstract
Therapeutic drug monitoring (TDM), the measurement of medications in whole blood, serum, or plasma, plays a vital part
in the management of patient’s prescribed drugs with narrow therapeutic ranges. Drug concentrations are used to assess
and adjust the dosage of a medication to optimize the therapeutic effectiveness while minimizing adverse side effects. The
use of mass spectrometry (MS) to perform TDM has been used due its superior sensitivity and specificity over
immunoassays which have traditionally been used to measure these compounds. While MS has several advantages for
TDM, laboratories need to fully comprehend the unique challenges and limitations of implementing this technology. This
chapter will review the clinical, technical, and strategic considerations involved in the implementation of MS to perform
TDM with illustrated examples (tacrolimus, levetiracetam, busulfan, and methotrexate) from the author’s laboratory.

Causes and Manifestation of Nephrotoxicity

Vassilios Fanos, Laura Cuzzolin, in Comprehensive Pediatric Nephrology, 2008

High Trough and Peak Levels

Therapeutic drug monitoring (TDM) has two major objectives: to ensure therapeutic concentrations and to avoid toxicity. In
adult patients, therapeutic efficacy and toxicity correlated well with serum concentrations.40 Most investigators relate the
nephrotoxicity to high trough levels (measured immediately before the next administration of AMG). They should be kept
below 10 mg/ml for amikacin and below 2 mg/ml for the other AMGs.
Peak levels (obtained 30 minutes after an IV administration or 60 minutes after an IM administration) of GNT, TBR, and
NTM should be maintained at 5 to 8 mg/ml. Peak levels of AMK should be maintained at 15 to 25 mg/ml. Even if the
necessity of routine TDM in the first week of life has been questioned,41,42 neonates (especially in preterm infants) often
require TDM and an individually adjusted therapeutic regimen.43,44 However, AMG nephrotoxicity can occur even with
proper TDM.12

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Clinical Pharmacokinetics and Drug Interactions

Nilanjan Saha, in Pharmaceutical Medicine and Translational Clinical Research, 2018

6.3.4 Therapeutic Drug Monitoring [14]

Therapeutic drug monitoring is the determination of drug concentrations in the biological matrix of patients, the
interpretation of which is utilized to evolve drug therapy that is safe and efficacious. Thus, therapeutic drug monitoring
(TDM) can result in rapid optimization of therapy which otherwise would require several dose changes using only clinical
leads. In conjunction with monitoring of clinical effects produced by the drug, utilization of TDM leads to rapid
optimization of drug therapy.
TDM is useful when the following criteria are met:
1. A good correlation exists between the pharmacologic response and plasma concentration. An increase in drug
concentration in the biological matrix, for example plasma, is related to an increase in efficacy and/or toxicity related to
the drug.
2. Drug concentrations cannot be predicted from a given dose, as result of inter-individual variability.
3. The drug has a narrow therapeutic index (i.e., the therapeutic concentration is close to the toxic concentration).
4. The pharmacological effects of the drug cannot be monitored easily (e.g., monitoring blood pressure for
antihypertensives) or the adverse effects cannot be easily differentiated from lack of efficacy of a drug.
TDM is useful for antiepileptics like valproate sodium, carbamazepine, phenytoin, mood stabilizer lithium, antibacterial
gentamicin, and antiasthma drug theophylline. However, TDM is a resource intensive procedure and must be used
optimally in the following scenarios:
1. Assessment of patient compliance during chronic therapy.
2. To identify drug interaction when new concomitant medication(s) is/are added to a narrow therapeutic index drug.
3. Rapid optimization of therapy.
4. Sometimes for change of brands or to identify batch-to-batch variation in drugs with a very narrow therapeutic window.

TDM is planned with assessment of a minimum number of samples for estimation of drug concentration. The method of
analysis must be robust, standardized, and validated, and less time consuming, to allow quick reporting of results. Samples
are frequently collected before administration of the next dose of drug for analysis of trough concentration.

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