College of Pharmacy/Clinical Pharmacy Department ‫ بسمة زهير‬.

‫د‬
Therapeutic Drug Monitoring
Introduction
Clinical Pharmacokinetic and Pharmacodynamic Concepts(1-4)

Pharmacokinetics: is the study of the absorption, distribution, metabolism, and excretion

(ADME) of drugs.
Pharmacodynamics: is the relationship between drug concentration and pharmacological
response.
Clinical pharmacokinetics: is the application of pharmacokinetic concepts and principles in
humans in order to design individualized dosage regimens which optimize the therapeutic
response and minimize the adverse drug reaction.

Therapeutic drug monitoring (TDM):

TDM is the process of measuring serum drug concentrations and using the results to optimize
dose regimens so that drug concentrations can be maintained within a target therapeutic
range.
• Laboratories measure patient serum or plasma samples for many drugs, including
antibiotics (eg, aminoglycosides and vancomycin), theophylline, antiepileptics (eg,
phenytoin, carbamazepine, valproic acid, phenobarbital, and ethosuximide), methotrexate,
lithium, antiarrhythmics (eg, lidocaine and digoxin), and immunosuppressants (eg,
cyclosporine and tacrolimus).

Characteristics of drugs suitable for TDM:

1- The drug has a narrow therapeutic range.
2- A good relationship exists between plasma concentrations and clinical effects. This
relationship allows to predict pharmacologic effects with changing plasma drug
concentrations.
3- There is significant pharmacokinetic variability (inter- or intra-individual).
4- The desired therapeutic effect is difficult to monitor by the observation of the clinical
parameters i.e. a precise clinical end point is not available (e.g. anticonvulsants, anti-
arrythmics, antidepressants etc.).
5- An appropriate cost-effective analytical test must be available for the analysis of drug
and/or its active metabolites.

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Indications for TDM include:
1- Monitoring adherence to drug therapy.
2- Individualising therapy (during early treatment and during dosage changes).
3- Diagnosing undertreatment.
4- Diagnosing and avoiding toxicity.
5- Monitoring and detecting drug interactions.
6- Guiding withdrawal of drug therapy.

Steady state condition:

• When drugs are given on a constant basis (e.g. a continuous intravenous infusion or an
oral medication given every 12 hours), serum drug concentrations increase until the rate
of drug administration equals the rate of drug metabolism and excretion.
• At that point, serum drug concentration reaches a constant value and this equilibrium
condition is known as steady state.
• Steady state condition is extremely important because usually steady-state serum or blood
concentrations are used to assess patient response and compute new dosage regimens
(Figure 1).

Figure 1. Steady state condition. The solid line shows serum concentrations in a patient
receiving a drug intravenously (solid line) and orally (dashed line).

Linear versus non-linear pharmacokinetics:

• If a plot of steady state concentration versus dose yields a straight line, the drug is said to
follow linear pharmacokinetics (Figure 2). In this situation, steady-state serum
concentrations increase or decrease proportionally with dose (e.g., a 50% increase in
dose yields a 50% increase in steady-state concentration).

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• Most drugs follow linear pharmacokinetics.
• When steady-state concentrations change in a disproportionate fashion after the dose is
altered, a plot of steady-state concentration versus dose is not a straight line and the drug
is said to follow non-linear pharmacokinetics (Figure 2).
• When steady-state concentrations increase more than expected after a dosage increase,
the most likely explanation is that the metabolism of the drug has become saturated. This
phenomenon is known as saturable or Michaelis-Menten pharmacokinetics (Figure 2).
Both phenytoin and salicylic acid follow Michaelis-Menten pharmacokinetics.

Figure 2. Linear pharmacokinetics (solid line). Michaelis-Menten pharmacokinetics

(upper dashed line). Saturable plasma protein binding or autoinduction (lower dashed
line).

• When steady-state concentrations increase less than expected after a dosage increase,
there are two typical explanations (Figure 2):
1- Some drugs, such as valproic acid and disopyramide, saturate plasma protein binding
sites so that as the dosage is increased steady-state serum concentrations increase less
than expected.
2- Other drugs, such as carbamazepine, increase their own rate of metabolism from the
body as dose is increased so steady-state serum concentrations increase less than
expected. This process is known as autoinduction of drug metabolism.
• Drugs that exhibit non-linear pharmacokinetics are often very difficult to dose correctly.

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Clearance:
• Definition: clearance (Cl) is the volume of serum or blood completely cleared of the
drug per unit time. Thus, the dimension of clearance is volume per unit time, such as
L/h or mL/min.
• The liver is most often the organ responsible for drug metabolism while in most cases the
kidney is responsible for drug elimination.
• The gastrointestinal wall, lung, and kidney can also metabolize some drugs, and some
medications are eliminated unchanged in the bile.
• Clearance is the most important pharmacokinetic parameter because it determines the
maintenance dose (MD) that is required to obtain a given steady-state serum
concentration (Css):

MD = Css ⋅ Cl
• Target steady-state concentrations are usually chosen from previous studies in patients
that have determined minimum and maximum effective concentrations that produce the
desired pharmacological effect but avoid toxic side effects. This range of steady-state
concentrations is known as the therapeutic range for the drug.
• The therapeutic range should be considered as an initial guideline for drug concentrations
in a specific patient; drug dose and steady-state concentrations should then be titrated and
individualized based on therapeutic response.
• For example, the therapeutic range for theophylline is generally accepted as 10–20 µg/mL
for the treatment of asthma with concentrations of 8–12 µg/mL considered as a
reasonable starting point.
• The clearance for an organ, such as the liver or kidney, is determined by the blood flow
to the organ and the ability of the organ to metabolize or eliminate the drug.
• Liver blood flow (LBF) and renal blood flow (RBF) are each about 1–1.5 L/min in
adults with normal cardiovascular function.

• The ability of an organ to remove or extract the drug from the blood or serum is
usually measured by determining the extraction ratio (ER), which is the fraction of drug
removed by the organ,
• The drug clearance for an organ is equal to the product of the blood flow to the organ and
the extraction ratio of the drug. Therefore, hepatic clearance (ClH) for a drug would be:

ClH = LBF ⋅ ERH

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 , and renal clearance (ClR) for a medication would be:

ClR = RBF ⋅ ERR

• The total clearance for a drug is the sum of the individual clearances for each organ that
extracts the medication. For example, the total clearance (Cl) for a drug that is
metabolized by the liver and eliminated by the kidney is the sum of hepatic and renal
clearance for the agent:

Cl = ClH + ClR

Hepatic clearance:
• Hepatic clearance depends on the intrinsic ability of the enzyme to metabolize a drug
(intrinsic clearance; Cl′int); the unbound fraction of drug present in the blood (free
fraction); and liver blood flow.
• The relationship between the three physiological factors and hepatic drug clearance is:

Where LBF is liver blood flow, fB is the fraction of unbound drug in the blood, and

Cl′int is intrinsic clearance.

• For drugs with a low hepatic extraction ratio (ERH ≤ 0.3), hepatic clearance is mainly a
product of the free fraction of the drug in the blood or serum and intrinsic clearance:

ClH = fB ⋅ Cl′int
• In this case, drug interactions that displace drug molecules bound to proteins will
increase the fraction of unbound drug in the blood (↑fB); more unbound drug molecules
will be able to leave the vascular system and enter hepatocytes where the additional
unbound drug will be metabolized, and hepatic drug clearance will increase.
• Additionally, drug interactions that inhibit or induce the cytochrome P-450 enzyme
system (decreasing or increasing Cl′int, respectively) will change the hepatic clearance of
the medication accordingly.
• The hepatic clearance of drugs with low extraction ratios does not change much when
liver blood flow decreases secondary to liver or cardiac disease.

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• Examples of drugs with low hepatic extraction ratios are valproic acid, phenytoin, and
warfarin.
• For drugs with high hepatic extraction ratios (ERH ≥ 0.7), hepatic clearance is mainly a
function of liver blood flow:

ClH = LBF
• The rate limiting step for drug metabolism in this case is how much drug can be delivered
to the liver because the capacity to metabolize drug is very large.
• In this case, hepatic clearance is very sensitive to changes in liver blood flow due to
congestive heart failure or liver disease.
• However, the hepatic clearance of drugs with high extraction ratios does not change
much when protein binding displacement or enzyme induction or inhibition occurs
due to drug interactions.
• Examples of drugs with high hepatic extraction ratios are lidocaine, morphine, and most
tricyclic antidepressants.

Renal clearance:
The physiological determinants of renal clearance are glomerular filtration rate (GFR), the
free fraction of drug in the blood or serum (fB), the clearance of drug via renal tubular
secretion (Clsec), and the fraction of drug reabsorbed in the kidney (FR) and renal blood
flow (RBF):

Volume of distribution:
• Volume of distribution (V) is an important pharmacokinetic parameter because it
determines the loading dose (LD) that is required to achieve a particular steady state
drug concentration immediately after the dose is administered:

LD = Css • V

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• The volume of distribution is a hypothetical volume that relates drug serum
concentrations (C) to the amount of drug in the body (AB):

C = AB/V
• Thus, the dimension of volume of distribution is in volume units, such as L or mL.
• The physiologic determinates of volume of distribution are the actual volume of blood
(VB) and size (measured as a volume) of the various tissues and organs of the body
(VT). How the drug binds in the blood or serum compared to the binding in tissues is
also an important determinate of the volume of distribution for a drug.
• The equation that relates all of these physiologic determinates to the volume of
distribution is:

• This equation can help clinicians understand why a drug has a large or small volume of
distribution, or why the volume of distribution might change under various
circumstances.
• The volume of distribution can be very small if the drug is primarily contained in the
blood (warfarin V = 5–7 L), or very large if the drug distributes widely in the body and
is mostly bound to body tissues (digoxin V = 500 L).
• For example, the reason warfarin has such a small volume of distribution is that it is
highly bound to serum albumin so that the free fraction of drug in the blood (fB) is very
small.
• Digoxin has a very large volume of distribution because it is very highly bound to
tissues (primarily muscle) so that the free fraction of drug in the tissues is very small.
• An example is how the volume of distribution changes when plasma protein binding
drug interactions occur. If a drug that is highly bound to plasma proteins is given to a
patient, and then a second drug that is also highly bound to the same plasma protein is
given concurrently, the second drug will compete for plasma protein binding sites and
displace the first drug from the protein. In this case, the free fraction in the serum of the
first drug will increase (↑fB), resulting in an increased volume of distribution:

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 Half-life and elimination rate constant:
• When drugs that follow linear pharmacokinetics are given to humans, serum
concentrations decline in a curvilinear fashion (Figure 3). When the same data is plotted
on a semilogarithmic axis, serum concentrations decrease in a linear fashion after drug
absorption and distribution phases are complete (Figure 4). This part of the curve is
known as the elimination phase.
• The time that it takes for serum concentrations to decrease by 1/2 (one-half) in the
elimination phase is a constant and is called the half-life (t1/2).
• The half-life describes how quickly drug serum concentrations decrease in a patient after
a medication is administered, and the dimension of half-life is time (hour, minute, day,
etc.).

Figure 3. Serum concentration/time profile for a patient receiving a drug orally (solid
line) and by intravenous bolus (dashed line). When the drug is given orally, serum
concentrations initially increase while the drug is being absorbed and decline after drug
absorption is complete.

Figure 4. Data from Figure 3 plotted on semilogarithmic axes. Serum concentrations

decline in a straight line in both cases.

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• Another common measurement used to express how quickly drug serum concentrations
decline in a patient is the elimination rate constant (ke). The dimension for the
elimination rate constant is reciprocal time (hour−1, minute−1, day−1, etc.).
• The half-life and elimination rate constant are related to each other by the following
equation, so it is easy to compute one once the other is known:

t1/2 = 0.693/ke
• The elimination rate constant can also be measured graphically by computing the slope of
the log concentration versus time graph during the elimination phase:

ke = −(ln C1 − ln C2)/(t1 − t2)

• Half-life is important because it determines the time required to reach steady state and
the dosage interval. It takes approximately 3 to 5 half-lives to reach steady-state
concentrations during continuous dosing.
• Half-life is also used to determine the dosage interval for a drug. For example, it may be
desirable to maintain maximum steady-state concentrations at 20 mg/L and minimum
steady-state concentrations at 10 mg/L. In this case, it would be necessary to administer
the drug every half-life because the minimum desirable concentration is one-half the
maximum desirable concentration.
• The half-life and elimination rate constant are known as dependent parameters
because their values depend on the clearance (Cl) and volume of distribution (V) of the
agent:

t1/2 = (0.693 ⋅ V)/Cl

ke = Cl/V
• The half-life and elimination rate constant for a drug can change either because of a
change in clearance or a change in the volume of distribution.
• Because the values for clearance and volume of distribution depend only on
physiological parameters and can vary independently of each other, they are known as
independent parameters.

Michaelis-Menten or saturable pharmacokinetics:

• Drugs that are metabolized by the cytochrome P-450 enzymes and other enzyme systems
may undergo Michaelis-Menten or saturable pharmacokinetics. This is the type of

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 nonlinear pharmacokinetics that occurs when the number of drug molecules overwhelms
or saturates the enzyme’s ability to metabolize the drug.
• When this occurs, steady-state drug serum concentrations increase in a disproportionate
way after a dosage increase (Figure 2).
• In this case the rate of drug removal is described by the classic Michaelis-Menten
relationship that is used for all enzyme systems:

rate of metabolism = (Vmax ⋅ C)/(Km + C)

where Vmax is the maximum rate of metabolism, C is the substrate concentration, and
Km is the substrate concentration where the rate of metabolism = Vmax/2.
• The clinical implication of Michaelis-Menten pharmacokinetics is that the clearance of a
drug is not a constant but is concentration- or dose-dependent. As the dose or
concentration increases, the clearance rate (Cl) decreases as the enzyme approaches
saturable conditions:

Cl = Vmax/(Km + C)
• This is the reason concentrations increase disproportionately after a dosage increase.
• There is so much interpatient variability in Michaelis-Menten pharmacokinetic
parameters for a drug (typically Vmax = 100–1000 mg/d and Km = 1–10 mg/L for
phenytoin) that dosing drugs which follow saturable metabolism is extremely difficult.
• The volume of distribution (V) is unaffected by saturable metabolism and is still
determined by the physiological volume of blood (VB) and tissues (VT) and the unbound
concentration of drug in the blood (fB) and tissues (fT):

V = VB + (fB/fT)VT
• Also, half-life (t1/2) is still related to clearance and volume of distribution using the same

equation as for linear pharmacokinetics: t1/2 = (0.693 ⋅ V)/Cl. However, since

clearance is dose- or concentration-dependent, half-life also changes with dosage or

concentration changes. As doses or concentrations increase for a drug that follows
Michaelis-Menten pharmacokinetics, clearance decreases, and half-life becomes longer

for the drug: ↑t1/2 = (0.693 ⋅ V)/↓Cl.

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• The clinical implication of this finding is that the time to steady state (3–5 t1/2) is longer
as the dose or concentration is increased for a drug that follows saturable
pharmacokinetics.
• Under steady-state conditions the rate of drug administration equals the rate of drug
removal. Therefore, for a drug that is only removed by metabolism by one enzyme
system, the Michaelis-Menten equation can be used to compute the maintenance dose
(MD) required to achieve a target steady-state serum concentration (Css):

• When the therapeutic range for a drug is far below the Km value for the enzymes that
metabolize the drug, this equation simplifies to:

MD = (Vmax/Km) . Css
or, since Vmax/Km is a constant,

MD = Cl ⋅ Css
• Therefore, in this case, drugs that are metabolized follow linear pharmacokinetics. First
order pharmacokinetics is another name for linear pharmacokinetics.
• When the therapeutic range for a drug is far above the Km value for the enzyme
system that metabolizes the drug, the rate of metabolism becomes a constant equal to
Vmax.
• Under these conditions only a fixed amount of drug is metabolized because the enzyme
system is completely saturated and cannot increase its metabolic capacity. This situation
is also known as zero-order pharmacokinetics.
• For example, the average Km for phenytoin is about 4 mg/L and the therapeutic range
for phenytoin is 10 to 20 mg/L. Therefore, most patients experience Michaelis-Menten
kinetics while taking phenytoin.
• Based on these facts, it can be seen that any drug that is metabolized by enzymes
undergoes Michaelis-Menten pharmacokinetics. But, the therapeutic ranges of most drugs
are far below the Km for the enzymes that metabolize the agent. Because of this, most
medications that are metabolized follow linear pharmacokinetics. However, even in these
cases saturable drug metabolism can occur in drug overdose cases where the drug
concentration far exceeds the therapeutic range for the medication.

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Bioavailability:
• When a drug is administered extravascularly, the entire dose may not enter the systemic
circulation. The fraction of the administered dose that is delivered to the systemic
circulation is known as the bioavailability for the drug and dosage form.
• For drugs that follow linear pharmacokinetics, bioavailability is measured by comparing
the total area under the serum concentration time curve (AUC) for the extravascular and
intravenous doses (Figure 5).
• If the extravascular and intravenous doses are the same, the bioavailability for a drug
can be calculated by dividing the AUC after oral administration (AUCPO) by the AUC
after intravenous administration (AUCIV):

F = AUCPO/AUCIV

• If it is not possible to administer the same dose intravenously and extravascularly, the
bioavailability calculation can be corrected to allow for different size doses for the
different routes of administration:

F = (AUCPO/AUCIV)(DIV/DPO)
where DIV is the intravenous dose and DPO is the oral dose.

Figure 5. Area under the serum concentration/time curve (AUC).

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Bioequivalence:
• Bioequivalence is achieved when the serum concentration/time curve for the generic
and brand name drug dosage forms (or two different dosage forms of the same drug) are
considered superimposable and identical using statistical tests.
• Concentration/time curves are superimposable when the area under the total serum
concentration/time curve (AUC), maximum concentration (Cmax), and time that the
maximum concentration occurs (Tmax) are identical within statistical limits (Figure
6).
• The ratio of the area under the serum concentration/time curves for the generic
(AUCgeneric) and brand name (AUCbrand) drug dosage forms is known as the relative
bioavailability (Frelative) since the reference AUC is derived from the brand name drug

dosage form: Frelative = AUCgeneric/AUCbrand

Figure 6. Area under the serum concentration/time curve (AUC), the maximum
concentration (Cmax), and the time that the maximum concentration occurs (Tmax).

References:
(1) BAUER LA. Applied Clinical Pharmacokinetics. Second Edition ed. USA: McGraw-Hill;
2008.
(2) BAUER LA. Applied Clinical Pharmacokinetics. Third Eedition ed. USA: McGraw-Hill;
2014.
(3) BAUER LA. Clinical Pharmacokinetics and Pharmacodynamics. In: DiPrio JT, Talbert
RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: A
Pathophysiologic Approach. 12th Edition ed.: McGraw Hill Education; 2022.
(4) Kang JS, Lee MH. Overview of Therapeutic Drug Monitoring. The Korean Journal of
Internal Medicine 2009;24(1):1-10.

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