CHAPTER–1

INTRODUCTION TO CLINICAL PHARMACOKINETICS

INTRODUCTION:

This book is about using drug serum concentrations, pharmacokinetics and pharmacodynamics to
individualize the optimize patient responses to drug therapy. Some call this therapeutic drug
monitoring, as we will, but others also call it applied pharmacokinetics or clinical
pharmacokinetics. But any of these names, it blends knowledge of therapeutics, pharmacology,
pharmacokinetics, laboratory technology and clinical medicine and applies it to certain drugs that
requires determination of patient-specific dosage regimens to maximize therapeutic effectiveness
while minimizing toxicity.

Pharmacokinetics, sometimes described as what the body does to a drug, refers to the movement
of drug into, through and out of the body-the time course of its absorption, bioavailability,
distribution, metabolism and excretion. Pharmacokinetics of a drug depends on patient-related
factors as well as on the drug’s chemical properties. Some patient-related factors (e.g. renal
function, genetic makeup, sex, age) can be used to predict the pharmacokinetic parameters in
populations. Other factors are related to individual physiology.

The effects of some individual actors (e.g. renal failure, obesity, hepatic failure, dehydration) can
be reasonably predicted, but other factors are idiosyncratic and thus have unpredictable effects.
Because of individual differences, drug administration must be based on each patient’s needs—
traditionally, by empirically adjusting dosage until the therapeutic objective is met. This approach
is frequently inadequate because it can delay optimal response or result in adverse effects.
Knowledge of pharmacokinetic principles helps prescribers adjust dosage more accurately and
rapidly. Application of pharmacokinetic principles to individualize pharmacotherapy is termed
therapeutic drug monitoring. Drug pharmacokinetics determines the onset, duration, and intensity
of a drug’s effect.
Therapeutic drug monitoring requires a working knowledge of pharmacokinetics principles, back
ground that is assumed for readers of this book. There is schematic relation between the
[1]
pharmacokinetic and pharmacodynamic phases of drug transit through the body . Three
pharmacokinetic variables—bioavailability, volume of distribution, clearance---influence the
temporal changes in serum or plasma concentrations. The serum concentration is assumed to have
a direct relationship to the pharmacologic effect. As TDM anchors on maintaining selected drugs
with narrow range of serum concentrations, understanding the influence of pharmacokinetic
variables on concentration is essential.

Figure 1-1. Relation between the pharmacokinetic and pharmacodynamic phases of drug
transit through the body.

PHARMACOKINETIC VARIABLES:
The pharmacokinetic variables shown in figure 1-1 are bioavailability, volume of distribution and
clearance. Although these variables are patient specific, individual values for a large cohort of
patients are averaged to yield a mean value for each parameter. This mean value is often called the
population value, as the mean represents all of the individual values, a specific patient a standard
deviation of the mean; he or she is usually termed a normal. Pathologic and physiologic changes,
however, may further alter these normal values in this patient [2]
Bioavailability (ƒ )
Bioavailability is the fraction of unchanged drug that reaches the systemic circulation after
administration. Implicit in this definition is the concept that a comparison is being made. If the
comparison is made between an oral and an intravenous formulation of a drug, which by definition
has 100% bioavailability, the absolute bioavailability of the drug is measured. If the comparison
is made between two different oral formulations, then the relative bioavailability of these
formulations is determined. As shown in Figure 1-2, three indices of drug bioavailability usually
are estimated: the maximum drug concentration in plasma (Cmax), the time needed to reach this
maximum (tmax), and the area under the plasma- or serum-concentration vs time curve (AUC).
Generally there is also an initial lag period (tlag) that occurs before drug concentrations are
measurable in plasma.

FIGURE 1-2: Hypothetical plasma-concentration vs time curve after a single oral drug dose.
Calculation of the area under the plasma-level vs time curve (AUC) requires extrapolation of
the elimination phase curve beyond the last measurable plasma concentration, as shown by
the dotted line.

As a fraction, it is a dimensionless term that is the product of two factors, absorption and
presystemic extraction in itself comprises two types of mechanisms; first pass metabolism of
absorbed drug via the liver before reaching the systemic circulation, and metabolism or
biotransformation of absorbed drug in the gastrointestinal tract by mucosal cells or flora prior to
 systemic availability. As such, the following discussion focuses on first-pass extraction by the
liver alone.
F= AUCpo
AUCiv
Where, F = bioavailability
AUCpo = Dose corrected area under curve of non- intravenous oral drug
AUCiv = area under the curve intravenous
OR
ƒ = (fraction absorbed) (fraction not metabolized by first-pass extraction)
For intravenous administration ƒ is 1. For other routes of administration ƒ may be less than 1. For
oral administration, ƒ may be less than 1, not only because of incomplete absorption through gut
but also because of metabolism that occurs in the liver during first-pass through the portal
circulation prior to reaching the systemic circulation.
E.g.: oral Theophylline ƒ is nearly 1 because of little first pass metabolism & for lidocaine ƒ is less
than 0.2 because of extensive first-pass metabolism [3].
Drug examples which are having poor and good bioavailability:
 When a medication is administered intravenously, its bioavailability is 100%.
 When a medication is administered via routes other than intravenous, its bioavailability is lower
due to intestinal epithelium absorption and first-pass metabolism.
 Weakly acidic drugs i.e. Glipizide Ibuprofen, Aceclofenac, Barbiturates will be best absorbed in
acidic environment (because it gains proton and become un-ionized)
 Weak bases i.e. Amphetamines, opiates, Diazepam in an acidic environment, H+, the drug gains a
proton and become ionized.

Factors affecting bioavailability of drugs:

Factors influencing the bioavailability of drugs can be divided into four main categories:

 Physicochemical agents - The physicochemical properties of a drug are important for its
bioavailability. Examples of physicochemical factors include drug solubility in the digestive
environment, chemical stability, lipophilicity, ionizability, and pharmaceutical form.

 Biological agents – Age, sex, physical activity, genetic phenotype, stress ,disorders(e.g.
achlorhydria, malabsorption syndromes) or previous GI surgeries (e.g. bariatric surgery)

 Pharmaceutical agents – Excipients such as binders, solvents and stabilizers

 Patient factors – Gender, genotype, health status and diet.

 0thers - Gastric acidity, Organ blood flow, Digestive enzyme activity, Intestinal micro flora,
Biological barriers.[4]

Calculating oral bioavailability:

[Example-1]

A drug dose [20 mg] is given to three groups of patients. Each group received different
formulation of this drug. The following average area under the serum concentration / time
curve (AUC) was found each group.
1) Oral liquid AUC = 1340 mg*hr/l
2) Oral capsule AUC = 1190 mg*hr/l

3) Intravenous bolus AUC = 1620 mg*hr/l

What is the bioavailability of the liquid and oral capsule form? What is their relative
bioavailability to each other?
Sol n: FLi = AUCpo 1340mg hr/l 0.827 (or) 82.7%

AUCiv 1620 mg hr/l

Fcap = AUCpo 1190mg hr/l 0.735 (or) 73.5%

AUCiv 1620 mg hr/l

Distribution of drugs:

The one-compartment open model is the simplest way to describe the process of drug distribution
and elimination in the body. This model assumes that the drug can enter or leave the body (ie, the
model is “open”), and the entire body acts like a single, uniform compartment. The simplest route
of drug administration from a modeling perspective is a rapid intravenous injection (IV bolus).
The simplest pharmacokinetic model that describes drug disposition in the body is the IV bolus
model where the drug is injected all at once into a box (the human body) or compartment, and the
drug distributes/equilibrates instantaneously and rapidly throughout the compartment. Drug
elimination from the compartment also begins to occur immediately after the IV bolus injection.

Figure 1-3 showing one –compartment model in distribution of drugs

The volume in which the drug seems to be distributed is termed the apparent volume of
distribution, VD. The apparent volume of distribution assumes that the drug is theoretically rapidly
and uniformly distributed in the body throughout the apparent volume. The VD is determined from
the injected amount or the dose and the plasma drug concentration Cp0 immediately after injection.
For simplicity, it is assumed that the injected dose disperses and distributes instantly. This model
is also termed a well-stirred one-compartment model. [5]

The two-compartment model divides the body into central and peripheral compartments to
account for varying blood perfusion rates among organs and tissues, affecting drug distribution.
The central compartment includes blood and highly perfused tissues with rapid drug distribution,
while the peripheral compartment contains tissues with slower drug distribution. After a single IV
bolus dose, the drug concentration is high in plasma and low in tissues. The drug distribution
between compartments follows a first-order process with rate constants known as transfer
constants or micro constants. This leads to a rapid decline in plasma drug concentration and an
increase in tissue concentration until equilibrium is reached. Following this, both compartments
experience a slow decline in drug concentration due to elimination. The plasma drug concentration
decline occurs in two phases: the rapid distribution or ɑ phase and the slower elimination or β
phase.

Figure 1-4: Showing two-compartment model with first-order absorption and elimination.
AGI, A1, and A2 are the amounts of drug in gastrointestinal tract (GI), central compartment
(including plasma), and peripheral compartment, respectively. ka, k12, k21, and k10 represent
the first-order fractional rate constants for absorption, distribution, redistribution, and
elimination.

Drug concentrations in the compartments equal to the amounts divided by

volumes: C1=A1/V1 and C2=A2/V2. Drug concentration in the central compartment is equal to the
concentration in the plasma: CP=C1. Clearance (in units L/h) is often used instead of the fractional
rate constants (in units h-1); in pharmacokinetics the distribution volume is given in volume units
(L), and rate constants can be represented as the ratio of clearance and distribution
volume, k=CL/V.
In the case of oral administration of the drug, at time t=0 the amount of drug in the central and
peripheral compartments is zero (A1 (0) = A2 (0) = 0), and the initial amount in gastrointestinal
tract (effective dose) is:
AGI (0) = D×S×F (1)(1)AGI(0) = D× S ×F
Where, D is the administered dose of the drug,

S is the salt factor (fraction of administered dose that is made up of pure drug), and

F is the bioavailability factor (fraction of dose that reaches the systemic circulation). [6]

Volume of Distribution (νᴅ):

Volume of distribution is a pharmacokinetic concept which is used to describe the distribution of
drugs in the body as relative to the measured concentration [7].
In other words "(νᴅ) a pharmacokinetic parameter that relates the total amount of drug in the body
to the concentration in the bloodstream”

The volume of distribution is given by the following equation:

Amount of drug ∈the body

νᴅ = Drugblood plasma concentration (C)

νᴅ is defined as the total amount of drug in the body divided by its concentration in plasma. Thus,
νᴅ reflects the degree to which the drug is present in extravascular tissues rather than in the
plasma. A drug with a high νᴅ tends to leave the plasma and enter other compartments in the body,
leading to low plasma concentrations. A drug with a low νᴅ tends to remain in the plasma,
meaning a lower dose of a drug is required to achieve a given plasma concentration.

νᴅ is dependent on both the chemical properties of a drug (e.g. highly lipid-soluble drugs have
good cell penetration, resulting in high νᴅ, while drugs which bind to plasma proteins such as
albumin have a reduced νᴅ) and patient physiology. Clinically, νᴅ is of most significance for
determining an initial loading dose of an antibiotic, assuming that successful therapy is directly
linked to its plasma concentration. [8]
The volume of distribution plugs into loading dose calculations. It can also help you decide
instantly whether your drug is going to be cleared by dialysis and it can be used to retrospectively
estimate the magnitude of a drug overdose. The concept is relatively easy to explain. Say, having
given 1 gram of something, one is presented with a sample of blood in which there is only 1mg
per liter of this drug. If the drug were dispersed in the blood alone, one would be forced to
conclude that it has been dispersed in a truly ridiculous 1000 liter blood stream, in some sort of
enormous fluid-filled patient.

Figure 1-5: Showing volume of distribution concept

Different volumes of distribution:

Initial volume of distribution (Vinitial):

It represents the behavior of the drug during the first rapid phase of distribution through the central
compartment.

Extrapolated volume of distribution (Vextrap)

It establishes a delayed concentration of medication disperse using peripheral compartments

(tissues of the skin, fat and muscle) to see how it is distributed in the tissues.
Non-compartmental volume of distribution (Varea)

Varea is an attempt to get around the errors of focusing on just one compartment at a time. It uses a
non-compartmental pragmatic model, easily calculated from serial concentration measurements.

Clearance ᵡ
Varea¿ β
=
(AUC × β )

Where β = Terminal elimination time constant

ᵡ = Dose of the drug

Steady-state volume of distribution (VSS)

VSS describes the volume of distribution during steady state conditions, i.e. when there is a stable
drug concentration [7].

Amount of drug∈the body ∈equilibrium conditions

VSS¿ Steady−state plasma concentration(Css)

Calculating volume of distribution

[Example-1]

A 42- year old male patient with body weight 70kg was diagnosed with severe infection
involving pseudomonas aeruginosa and MRSA (Methicillin-resistant S. aureus). He received
2000mg of appropriate antibacterial agent as a continuous IV infusion (loading dose). The peak
plasma concentration of administered antibiotic was measured as 28.5 mg/L. calculate apparent
volume of distribution of anti microbial agent.

Given, Age= 70 kg

Dose= 2000mg

Plasma concentration =28.5 mg/L

 Amount of drug ∈the body
νᴅ = Drugblood plasma concentration (C)

2000 mg
νᴅ¿ 28 .5 mg/ L 70 .175 L

If you want to convert into L/kg then,

70. 175 L
νᴅ ¿ 70 Kg
=1 L /Kg

Protein Binding:
The phenomenon of complex formation of drug with protein is called as protein binding of drug
As a protein bound drug is neither metabolized nor excreted hence it is pharmacologically inactive
due to its pharmacokinetic and Pharmacodynamic inertness.

Figure 1-6: showing Protein binding and Drug distribution

 Protein + drug ⇌ Protein-drug complex
Binding of drugs to proteins is generally of reversible &irreversible.
 Reversible generally involves weak chemical bond such as:
1. Hydrogen bonds
2. Hydrophobic bonds
3. Ionic bonds
4. Vander Waal’s forces
 Irreversible drug binding, though rare, arises as a result of covalent binding and is often a reason
for the carcinogenicity or tissue toxicity of the drug.

Protein-binding may affect drug activity in one of two ways: either by changing the effective
concentration of the drug at its site of action or by changing the rate at which the drug is
eliminated, thus affecting the length of time for which effective concentrations are maintained [9].

Half-Life (t1/2):
Half-life is defined as the time required for the concentration of a drug in blood or plasma to
reduce to half (50%) of its initial value [E.g. given below]. It is a hybrid parameter, determined by
clearance and volume of distribution, as demonstrated in Eq. For an orally administered drug, a
single daily dose is often considered optimal for patient compliance, though this can vary
depending on the target and indication [10].

0.693
Half−life= K

Illustrative example:

In the event that a 100 milligram (mg) dose of an intravenous drug with a half-life of 15 minutes is
administered, the following would be true:

 15 minutes after the drug administration, 50 mg of the drug remains in the body
 30 minutes after the drug administration, 25 mg of the drug remains in the body
  45 minutes after the drug administration, 12.5 mg of the drug remains in the body
 1 hour after the drug administration, 6.25 mg of the drug remains in the body
 2 hours after the drug administration, 0.39 mg of the drug remains in the body

For drugs with linear pharmacokinetic behavior, half-life is one of the most useful
pharmacokinetic variables for clinicians:

 t1/2 determines the time it takes for dosage regimen to reach steady-state serum levels;
50%, 75%, 88% and 94% of steady-state is achieved in one, two, three, and four half-life
periods respectively.
 t1/2 contributes to know how much greater serum levels will be at steady state compared to
first dose.
 t1/2 determines how long it takes for the serum concentration to be reduced after a dose.
 t1/2 influences the choice of dosage interval. The longer the half-life, the less often the drug
needs to be administered [11].

Zero- order kinetics:

Zero-order kinetics describes reactions where the rate is not affected by the concentration of the
drug used. In pharmacokinetics, this is usually a result of a saturation of the active site with excess
medication, so the rate of binding is negligible, and the rate of transforming the drug dictates the
reaction's rate.
[A] = - k t + [A] 0
Where,
A is concentration at time=t or the amount of active drug left at a specific time
A 0 is concentration at t=0, or the dose size of the drug
K is the rate of elimination.

There are two reasons a reaction would appear to have zero-order kinetics. One reason is if there
are multiple reactants and one has a much larger concentration, and the other is that there is a very
small surface area/active site for the reaction. This usually occurs with medicine because of a
small, active site that gets saturated.
E.g. Cisplatin, a chemotherapy drug; aspirin, a pain medication; and fluoxetine, a selective
serotonin reuptake inhibitor (SSRI), are drugs that follow zero-order elimination kinetics.

Importance of zero- order elimination:

It is crucial to know if a drug is zero-order or not because it affects how and when a drug is
administered. Administering a toxic zero-order drug is much more dangerous than if it were first-
order because the drug will accumulate in the body for much longer than if it were first-order. The
initial rate of elimination from a first-order drug would be faster.

However, zero-order drugs are crucial in maintaining a drug's concentration in the therapeutic
window for longer than a first-order drug would. This could limit the side effects of the drugs, as
well as reduce the number of times a drug needs to be taken.

If zero-order drugs are well understood and monitored, they can be used for long-term treatments
more effectively than first-order drugs [12].

HALF-LIFE DERIVATION OF ZERO-ORDER REACTION

R 0−R
K= Kt = R0 – R
t

R0
t = t1/2 ; R=
2

R0
K t1/2 = R0 -
2
2 R 0−R 0
K t1/2 = 2
R0
K t1/2 =
2
R0
t1/2 =
2K

First- order kinetics:

First-order kinetics refers to a reaction wherein the overall rate behavior of a reaction follows
a first-order rate equation, which is rate = K[A], where [A] represents the concentration of
reactant A, and k is the rate constant. As it follows the first-order rate equation, the rate of
reaction is, thus, directly proportional to the concentration of only one reactant [13].

Figure 1-7: Showing zero order and first order kinetics

HALF-LIFE DERIVATION OF FIRST ORDER REACTION:

R0
[K = 2.303
t
log
R ]
R0
t = t1/2 ; R=
2

2.303 R0
log
K = t 1/2 R0
2

2.303
t1/2 = log 2= (0.3010)
t

2.303× 0.3010
t1/2 = K
 0.693
Half−life= K

Clearance (CL):
Clearance (Cl) is a pharmacokinetic parameter representing the efficiency of drug elimination.
This is the rate of elimination of a substance divided by its concentration. The parameter also
indicates the theoretical volume of plasma from which a substance would be completely removed
[14]
per unit time. Usually, clearance is measured in L/h or mL/min . In pharmacokinetic terms, it is
the parameter that mathematically links the bioavailable dose rate with the average steady-state
serum concentrations during the dosage interval (Cavg.ss):

(CL) (Cavg.ss) = (ƒ) (dose/τ)

The quantity reflects the rate of drug elimination divided by plasma concentration. Excretion, on
the other hand, is a measurement of the amount of a substance removed from the body per unit
time (e.g., mg/min, μg/min, etc.). While clearance and excretion of a substance are related, they
are not the same thing.

Substances in the body can be cleared by various organs, including the kidneys, liver, lungs, etc.
So, the term clearance refers to various organs is called total systemic clearance. Thus, total body
clearance is equal to the sum clearance of the substance by each organ

CL= CLsystemic =CLkidney + CLliver + CLother

Each of these pathways has the potential to become saturated if the dose is high enough and this is
shown mathematically by an expression like the Michaelis-Menten equation in enzyme kinetics:

CL= Vmax

Kmax + Cavg.ss
Here Vmax is the maximum amount of drug that may be eliminated per unit of time and Km is the

serum concentration at which the rate of elimination is 50% of Vmax

For many drugs, however, clearance is solely a function of renal excretion. In these cases,
clearance is almost synonymous with renal clearance or renal plasma clearance. Each substance
has a specific clearance that depends on how the substance is handled by the nephron.

Clearance is a function of:

1) Glomerular filtration

2) Secretion from the peritubular capillaries to the nephron

3) Reabsorption from the nephron back to the peritubular capillaries.

Clearance is variable in zero-order kinetics because a constant amount of the drug is eliminated
per unit time, but it is constant in first-order kinetics, because the amount of drug eliminated per
unit time changes with the concentration of drug in the blood.

Clearance can refer to the volume of plasma from which the substance is removed (i.e., cleared)
per unit time or, in some cases, inter-compartmental clearances can be discussed when referring to
redistribution between body compartments such as plasma, muscle, and fat [14].