PHARMACOKINETICS

• relate the pharmacological effects of a drug and concentration of the drug

in an accessible body compartment as these change in time.

• “dose-concentration part”

WHAT THE BODY DOES TO A DRUG

PHARMACOKINETIC PROPERTIES

1. A bsorption
2. D istribution
3. M etabolism
4. E limination
PHYSIOCHEMICAL FACTORS IN TRANSFER OF DRUGS ACROSS MEMBRANES

• Characteristics of a drug that predict its movement and availability at

sites of action:
 Molecular size and structural features
 Degree of ionization
 Relative lipid solubility of its ionized and non-ionized forms
 Binding to serum and tissue proteins

• In most cases, a drug must transverse the plasma membranes of many

cells to reach its site of action.
 PASSAGE OF DRUGS ACROSS MEMBRANE BARRIERS

• PLASMA MEMBRANE

 Lipid bilayer
- Hydrocarbon tails (inwards) → Lipophilic/Hydrophobic phase
- Hydrophilic head (outwards)
Membrane proteins serves as
- Anchors
- Receptors
- Ion channels
- Transporters
 PERMEATION

• Ability of the drug to move effectively in the body

• Determinants of Drug Permeability:

1. Solubility
- Ability to diffuse through lipid bilayers (lipid solubility) is important for
most drugs

2. Concentration Gradient
- Diffusion down a concentration gradient

3. Surface Area & Vascularity

- The larger the surface area & the greater the vascularity, the better is
 MODES OF PERMEATION AND TRANSFER

1. PASSIVE DIFFUSION
- Directly proportional
- The driving force for passive absorption of a drug is the concentration
gradient across a membrane separating two body compartments
- Reaches the equilibrium when the movement of molecule from one
compartment to another is equal
- Most common way a drug is transported

Net Rate of Penetration = P x SA x (C1 – C2)

 MODES OF PERMEATION AND TRANSFER

1. PASSIVE DIFFUSION

• 2 Types of Passive Diffusion

A. Aqueous Diffusion
- Occurs within the larger aqueous compartments of the body and
across epithelial membrane and endothelial lining of blood vessels
B. Lipid Diffusion
- Determined by the lipid aqueous partition coefficient of a drug
 MODES OF PERMEATION AND TRANSFER

2. CARRIER-MEDIATED MEMBRANE TRANSPORT

• 2 Types of Carrier-mediated membrane transport

A. Facilitated Diffusion
- Other agents can enter the cell through specialized transmembrane
carrier proteins that facilitate the passage of large molecules
- Also driven by a concentration gradient
- The drugs transported through facilitated diffusion are larger & less
lipid soluble
 MODES OF PERMEATION AND TRANSFER

- Characteristics of facilitated diffusion:

 Does not require energy
 Can be saturated
 May be inhibited by compounds that compete for the carrier
MODES OF PERMEATION AND TRANSFER

2. CARRIER-MEDIATED MEMBRANE TRANSPORT

• 2 Types of Carrier-mediated membrane transport
B. Active Diffusion
- This method of drug entry that involves specific carrier proteins that
span the membrane
- Driven by the hydrolysis of ATP
- Capable of moving drugs against a concentration gradient, from a
region of low drug concentration to one of higher drug concentration
- Seen in renal & billary secretion of many acids & bases
- Two limiting factors of Active Transport:
Transport system
 MODES OF PERMEATION AND TRANSFER

- Characteristics of active diffusion:

 Requires energy
 Capable of moving against a concentration gradient
 Saturable
 Selective
 May be competitively inhibited by other co-transported
substance
DRUG ABSORPTION

• Absorption is the movement of a drug from its site of administration into

the central compartment and the extent to which this occurs.
BIOAVAILABILITY

• Bioavailability is defined as the fraction of unchanged drug reaching the

systemic circulation following administration by any route.
BIOAVAILABILITY

• Net absorption may by:

• Characteristic of the dosage form

• Physicochemical properties

• Intestinal metabolism

• Transporter export back into the intestinal lumen

BIOAVAILABILITY

• First-Pass Effect - The first pass effect (also known as first-pass

metabolism or presystemic metabolism) is a phenomenon of
drug metabolism whereby the concentration of a drug is reduced before it
reaches the systemic circulation.
BIOAVAILABILITY
ORAL ADMINISTRATION

 Absorption from the GI tract is governed by factors such as surface

area for absorption, blood flow to the site of absorption, the physical
state of the drug, its water solubility, and the drug’s concentration at
the site of absorption.
 Most convenient
 First pass effect may be signficant
SUBLINGUAL ADMINISTRATION

 Absorption from the oral mucosa has special significance for certain
drugs despite the fact that the surface area available is small. Venous
drainage from the mouth is to the superior vena cava, bypassing the
portal circulation and thereby protecting the drug from rapid intestinal
and hepatic first-pass metabolism.
TRANSDERMAL ABSORPTION

 Not all drugs readily penetrate the intact skin. Absorption of those that
do is dependent on the surface area over which they are applied and
their lipid solubility because the epidermis behaves as a lipid barrier.
RECTAL ADMINISTRATION

 Approximately 50% of the drug that is absorbed from the rectum will
bypass the liver; the potential for hepatic first-pass metabolism thus is
less than that for an oral dose; furthermore, a major drug metabolism
enzyme, CYP3A4, is present in the upper intestine but not in the lower
intestine.

 Less first pass effect than oral

 Bioavailability: 30 - <100
INTRAVENOUS

 Drug delivery is controlled and achieved with an accuracy and

immediacy not possible by any other procedure.
 Most rapid onset
 Bioavailability: 100%
SUBCUTANEOUS

 The rate of absorption following subcutaneous injection of a drug often

is sufficiently constant and slow to provide a sustained effect.

 Smaller volume than IM

 Could be painful

 Bioavailability: 75 - <100%
INTRAMUSCULAR

 Drugs in aqueous solution are absorbed quite rapidly after

intramuscular injection depending on the rate of blood flow to the
injection site.
 Large volume may be feasible
 Bioavailability: 75 – <100%
INTRA-ARTERIAL

• Occasionally, a drug is injected directly into an artery to localize its effect in

a particular tissue or organ, such as in the treatment of liver tumors and

head/neck cancers.
INTRATHECAL

 Intrathecal administration is a route of administration for drugs via an

injection into the spinal canal, or into the subarachnoid space so that
it reaches the cerebrospinal fluid (CSF) and is useful in spinal
anesthesia, chemotherapy, or pain management applications.
PULMONARY ABSORPTION

 Provided that they do not cause irritation, gaseous and volatile drugs
may be inhaled and absorbed through the pulmonary epithelium and
mucous membranes of the respiratory tract. Access to the circulation is
rapid by this route because the lung’s surface area is large.
TOPICAL APPLICATION (MUCOUS MEMBRANE)

• Drugs are applied to the mucous membranes of the conjunctiva,

nasopharynx, oropharynx, vagina, colon, urethra, and urinary bladder
primarily for their local effects.
BIOAVAILABILITY
EXTENT OF ABSORPTION

• Drug may be incompletely absorbed

• Too hydrophilic (eg. Atenolol)
• Too lipophilic (eg. Acyclovir)

• Reverse transporter
• P-glycoprotein – it actively pumps drug out of gut wall cells back
into the gut lumen.
FIRST-PASS ELIMINATION

 Drug can be metabolized in the gut wall (eg. CYP3A4 enzyme

system)
 Metabolism of drug in the liver
Extraction Ratio/Systemic Bioavailability of the Drug

Q= Hepatic Blood Flow F= Systemic Bioavailability of the Drug

Q= 90L/h/70kg f= Extent of absorption
EXTRACTION RATIO/SYSTEMIC BIOAVAILABILITY OF THE DRUG

• Morphine
f=1 F = f (1-ER)
ER = CL/Q
CL = 60L/h/70kg
= 60L/h = 1 ( 1-0.67)
Q = 90L/h/70kg
90L/h
= 0.33
ER = 0.67
F = 33%
RATE OF ABSORPTION

• the rate of absorption is determined by the site of administration and the

drug formulation.

• Both the rate of absorption and extent of input can influence the clinical
effectiveness of a drug.
Extraction ratio and the First- Pass effect:
• Systemic clearance is not affected by bioavailability. However clearance
can markedly affect the extent of availability because it determine the
extraction ratio.
• The effects of the first pass elimination on bioavailability is expressed as
the Extraction Ratio (ER)

• ER = CLliver/ Q

• Drugs with high extraction ratios will show marked variations in

bioavailability between subjects.
• For drugs that are highly extracted by the liver, bypassing hepatic sites of
elimination will result in substantial increases in drug availability

- Morphine
- Isoniazid
- Propanolol
- Several tricyclic antidepressants
• Drugs that are poorly extracted by the liver shunting of blood past the liver
will cause little change in availability

- Warfarin
- Phenytoin
- Theophylline
- Tolbutamide
FIRST-PASS EFFECT:

 It is where bioavailability is reduced

 Accordingly, less than all of the administered dose may reach the
systemic circulation and be distributed to the drug’s site of action.

 If the metabolic or excretory capacity of the liver and the intestine for
the drug is large, bioavailability will be reduced substantially. This
decrease in availability is a function of the anatomical site from which
the absorption takes place.
 THE TIME COURSE OF DRUG EFFECT

 IMMEDIATE EFFECTS:
o Means it has short time course needed to see the action or the effect of the drug.

 DELAYED EFFECTS
o Changes in drug effects often delayed in relation to the changes in plasma
concentration. This delay may reflect the time required for the drug to distribute from
plasma to the site of action.
o A common reason for more delayed drug effects especially those that take many
hours or even days to occur is the slow turn over of a physiologic substance that is
involved in the expression of the drug effect.

 CUMULATIVE EFFECTS
o Means it has a longer time course because the amount of drug needs to be
accumulated first before the effect of the drug will be seen.
D I S T R I B U T I O N
After absorption or injection, drugs may be distributed into interstitial or cellular fluids.

a. Once in the circulatory system, some drugs can bind nonspecifically and
• reversibly to various plasma proteins-albumin or globulins.
1. In this case, the bound and free drugs reach an equilibrium.
2. Only the free drugs exerts a biologic effects; the bound drug stays in
the vascular space and is not metabolized or eliminated.
b. Some areas of the body are not readily accessible to drugs because of anatomic barriers.
c. Some drugs may be sequestered in storage depot- lipid soluble drugs in adipose tissues. The
drugs stored in these depots is in equilibrium with the free circulating drugs. Eventually, the
drugs achieves a free state and is excreted either directly or after it has been metabolized.
Factors/determinants that affects drug distribution

1. Physical and chemical characteristics of drug (lipid to water partition coefficient).

2. Cardiac output

3. Capillary permeability in various tissue

4. Solubility/Lipid content of the tissue

5. Binding to plasma proteins and tissues

6. Size of the organ

7. Blood flow
e. Apparent volume of administration (Vd) and physical volumes

• The apparent volume of distribution (Vd) is an important pharmacokinetic

parameter that reflects the determinants of the distribution of drug in the body

• Vd relates the amount of drug in the body to the concentration in the

plasma

• Physical volumes of different body compartments are less important in

pharmacokinetics.
2. Clinical Distribution

 One compartment model.

1. Simplest and commonly used
pharmacokinetic model system.
2. Distribution of the drug within the
compartment is assumed to be uniform and
is assumed to occur rapidly in comparison
with absorption and elimination.
3. Drugs within the model are assumed to be
distributed just to the organs or tissues with
high blood flow and rapid uniform (brain,
heart, liver, kidneys, lungs, active muscle
 Two compartments model

▪ It is also known as delayed distribution

model

▪ Compartment 1 is central compartment that

represents blood, ECF, and highly perfused
tissues. Equilibrate rapidly with the drug.

▪ Compartment 2 is tissue compartment or

peripheral compartment contains tissues such as
muscles, skin, adipose tissue, that equilibrate
more slowly with the drug

Drugs are not only distributed to the organs or

tissues with rich blood perfusion (central
compartment), but
also to that with low blood flow (peripheral
compartment: fat, skin, bone, resting muscle).
The apparent volume of distribution (Vd) is a quantitative estimate of the tissue
localization of the drug.

The ratio of the amount of drug in the body to the drug concentration in the
plasma or blood.

a. It can be determined by measuring the plasma level of the drug:

b. A high Vd indicates high lipophilicity or many receptors for the drug

METABOLISM
Metabolism

• Process in which our bodies alter xenobiotics enzymatically or non-

enzymatically
• Important mechanism by which the body terminates the action of many
drugs
• In some cases, it serves to activate prodrugs
• Occurs mainly in the liver
• Other organs with significant drug-metabolizing capacity include the GI
tract, kidneys, and lungs
Metabolism

• Most drugs are relatively lipophilic or lipid-soluble

• A characteristic needed for absorption across membranes
• Property that also results in very slow removal from the body because
the unchanged molecule would also be readily reabsorbed from the
urine in the renal tubule
• Our body then converts or metabolizes these drugs and other
xenobiotics into more hydrophilic metabolites which is essential for
their renal elimination from the body, as well as for termination of
their biological and pharmacological activity
Phase I Reactions

• Reactions that convert the parent drug to a more polar (water-soluble) or

more reactive product by unmasking or inserting a polar functional group
such as –OH, –SH, or –NH2
• Involve oxidation, reduction, or hydrolytic reactions and the activities of
Cytochromes P450 or CYPs
• Drug-metabolizing enzymes, especially CYPs, are inducible by some
drugs and inhibited by drugs and competing substrates
• Knowing which CYP metabolizes a given drug and which other drugs may
affect that metabolism is crucial to good drug therapy
Phase II Reactions

• Reactions that increase water solubility by conjugation of the drug

molecule with a polar moiety
• Subgroups that are added include glucuronate, acetate, glutathione,
glycine, sulfate, and methyl groups
• Involve conjugations of the phase I product with a second molecule
Prodrugs

• Pharmacologically inactive compounds that are converted to their

active forms by metabolism
• This approach can maximize the amount of the active species that
reaches its site of action
• Inactive prodrugs are converted rapidly to biologically active
metabolites, often by the hydrolysis of an ester or amide linkage
E.g. ACE inhibitors
Enalapril, for instance, is relatively inactive until converted by esterase
activity to the diacid enalaprilat
Pharmacogenomics

• The study of the impact of genetic variations or genotypes of individuals on

their drug response or drug metabolism
• Several drug-metabolizing systems have long been known to differ among
families or populations in genetically determined ways
• It is expected that pharmacogenomics will become an important part of
patient evaluation in the near future, influencing both drug choice and drug
dosing
Few Principles of Metabolism and Elimination
First-Order Kinetics
• amount of drug metabolized per unit time is proportional to the plasma
concentration of the drug
• fraction of drug removed by metabolism is constant
Zero-Order Kinetics
• a constant amount of drug is metabolized per unit time
• metabolic capacity is saturated at the concentrations usually employed,
and drug metabolism (e.g. ethanol and phenytoin)
• can also occur at high (toxic) concentrations as drug-metabolizing
capacity becomes saturated
Few Principles of Metabolism and Elimination

Inducible Biotransforming Enzymes

• The major drug-metabolizing systems are inducible, broad-spectrum
enzymes with some predictable genetic variations
• Drugs that are substrates in common for a metabolizing enzyme may
interfere with each other’s metabolism, or a drug may induce or enhance
metabolism of itself or other drugs
HALF-LIFE (t 1/2)

 time it takes to remove half of the current concentration of drug from the body

a. Can be eliminated from the body

b. Can be translocated to other body fluids (e.g. intracellular fluid) or it can be destroyed in the
blood
o derived from Vd (volume of distribution) and CL (clearance)
EXCRETION OF DRUGS
 eliminated from the body either unchanged or converted to metabolites

 Excretory organs (except lungs)

o eliminate polar compounds more efficiently
 Substances excreted in the feces

o unabsorbed orally ingested drug

o drug metabolites excreted either in bile or into the GIT (not

reabsorbed)

 Excretion of drugs in breast milk

 Excretion from the lung: for the elimination of anaesthetic gases

RENAL EXCRETION
Has a three processes:

a. Glomerular Filtration: only unbound drug is filtered

b. Active Tubular Secretion: most drugs enter the kidney tubule by tubule secretion
rather than glomerular filtration.
TRANSPORTERS:
o P-gp and multidrug-resistance-associated protein type 2 (MRP2)
o localized in the apical brush-border membrane
o secrete amphipathic anions & conjugated metabolites (such as glucoronides)

SOLUTE CARRIER TRANSPORTER: involved in the secretion of organic bases

MEMBRANE TRANSPORTER: mainly located in the distal renal tubule; for
active reabsorption of drug from tubular lumen back into the systemic
circulation

c. Passive Tubular Reabsorption: some drugs and metabolites are absorbed back
into the bloodstream in the PCT and DCT
BILIARY AND FECAL EXCRETION

 Transporters in the canalicular membrane of the hepatocyte

 Actively secretes drugs and metabolites into bile

 P-gp & BCRP (breast cancer resistance protein, or ABCG2)

o transport a plethora of amphipathic lipid-soluble drugs

 MRP2: secretes conjugated metabolites of drugs

 Drugs & metabolites

o Directly secreted from systemic circulation into the intestinal lumen
o Can be reabsorbed back into the body from the intestine (e.g.
glucoronides)
EXCRETION BY OTHER ROUTES

 Excretion of drugs into sweat, saliva, and tears

o elimination depends on the pH and diffusion of the non-ionized lipid-
soluble form of drugs

 Excretion in the saliva: useful biological fluid to determine drug

concentrations

 Excretion into hair and skin

o sensitive methods of detection of drugs in these tissues have forensic
significance
 CLINICAL PHARMACOKINETICS

 The fundamental tenet of clinical pharmacokinetics is that a relationship exists

between the pharmacological effects of a drug and an accessible
concentration of blood.
 The concentration of drug at its site of action will be related to concentration
of drug in systemic circulation.
 It attempts to provide both a quantitative relationship between dose and
effect.
 The importance of pharmacokinetics in patient care is based on improvement
in therapeutic efficacy and avoidance of unwanted effects that can be attained
by application of its principles when dosage regimens are chosen and
modified
 Four most important parameters governing drug disposition:

Bioavailability
• fraction of drug absorbed as such into systemic circulation

Volume of distribution
• a measure of apparent space in body available to contain drug based on how much is given
versus what is found in systemic circulation

Clearance
• a measure of body’s efficiency in eliminating drug from systemic circulation

Elimination
• t1/2
• a measure of rate of removal of drug from systemic circulation.
CLEARANCE

o Clearance of a drug is the factor that predicts the rate of elimination in relation to
drug concentration ( C ).

o CL = rate of elimination / C

o Clearance, like volume of distribution, may be defined with respect to blood, plasma
or unbound in water, depending on where and how the concentration is measured.

o It is important to note the additive character of clearance.

o Elimination of drug from body may involve process occurring in the kidney, lung,
liver, and other organs.
 CL kidney = rate of elimination / C

CL liver = rate of elimination / C

CL other = rate of elimination / C

 CL systemic = CL kidney + CL liver + CL other

 Other tissues includes lungs and additional sites of metabolism.
Two major sites of drug elimination are KIDNEYS and LIVER

 Renal clearance - Clearance of unchanged drug in urine.

 Within the liver, drug elimination occurs via biotransformation of parent drug to one or
more metabolites, or excretion of unchanged drug into bile or both.

 For some drugs, elimination is not saturable, rate of drug elimination is directly
proportional to concentration.

 Rate of elimination = CL .C

 This is usually referred to as first-order elimination.

 It can be estimated by calculating the area under the curve ( AUC ) of the time
concentration profile after a dose.
CAPACITY-LIMITED ELIMINATION :

 Also known as mixed-order, saturable, dose or concentration dependent,

non linear, Michaelis-Menten elimination.
 Most drug elimination will become saturated if the dose and
concentration are high enough..
 Rate of elimination = Vmax . C / Km + C
 Pseudo- zero order elimination-elimination rate is independent of
concentration.
 It is important for 3 drugs : Ethanol
Phenytoin
Aspirin
FLOW-DEPENDENT ELIMINATION :

 Some drugs are cleared very readily by organ of elimination, so that at any clinically
realistic conc. of drug, most of the drug in blood perfusing the organ is eliminated on
first pass of drug through it.

 Elimination of these drugs will thus depend primarily on rate on rate of drug delivery
to organ of elimination.

 Such drugs called “high-extraction drugs” since they are almost completely extracted
from blood by the organ.

 Blood flow to organ is main determinant of drug delivery.

 But plasma protein binding and blood cell partitioning may also be important for
extensively bound drugs that are highly extracted.
C L I N I C A L P H A R M A C O K I N E T I C S

DISTRIBUTION
VOLUME DISTRIBUTION

• Refers to fluid volume required to contain all of the drug in the body at the
same concentration measured in blood/plasma
VOLUME OF DISTRIBUTION

• Volume of distribution (V)

• Concentration of the drug (C)
• (V) relates the amount of drug in the body to (C) in blood plasma
• (V) reflects the extent of a drug’s presence in extravascular tissue and not
in the plasma
VOLUME OF DISTRIBUTION

• (V) is considered as an imaginary volume

e.g. chloroquine has a (V) of 15,000 L

70 kg man has a plasma volume of 3 L

blood volume of ~5.5 L
ECF outside the plasma is 12 L
Volume of total body water is ~42 L
VOLUME OF DISTRIBUTION

 For drugs that are bound extensively to plasma proteins but not
bound to tissue components
- (V) is low (near plasma levels)

 Some drugs have high (V) even if bound to albumin

- these drugs are sequestered elsewhere
VOLUME OF DISTRIBUTION

 View the body as a single homogenous compartment

 Drug administration occurs directly into the central compartment
 Instant drug distribution throughout the volume
 Clearance occurs in a first-order fashion
VOLUME OF DISTRIBUTION

 First-order kinetics
- drug elimination per unit of time depends on the concentration of
drug in the body
RATE OF DISTRIBUTION

 The multiple exponential decay results from differences in the rates at

which the drug equilibriates to and within the tissues

 Perfusion of the tissue to the partition of drug into the tissue

RATE OF DISTRIBUTION

 Drug administration
 Initial “Central” volume (plasma and tissue reservoirs)
 “Final” volume (decreased plasma concetration)
 Can change depending on the pattern or flow of blood to various
tissues
RATE OF DISTRIBUTION

Perfusion capability affects the rate of distribution

- if slow, drug concentration in plasma increases

- leads to higher systemic concentration
- causes increased concetration in tissues
STEADY STATE

 Rate of drug elimination = drug availability

HALF – LIFE

 The time it takes for the plasma concentration to be reduced by 50%

CLEARANCE

 Measure of the body’s ability to eliminate a drug

 Decreased clearance, increased half-life

EXTENT & RATE OF BIOAVAILABILITY

Bioavailability
• amount of the drug that reaches the systemic circulation
• depends (1) on the administered dose (2) fraction of the dose (F) that is absorbed and
escapes any first-pass elimination.

If a drug is absorbed rapidly (e.g., a dose given as an intravenous bolus) and has a small
“central” volume, the concentration of drug INITIALLY will be HIGH. It will then fall as the
drug is distributed to its “final” (larger).

If the same drug is absorbed more slowly (e.g., by slow infusion), a significant amount of
the drug will be distributed while it is being administered, and peak concentrations will be
lower and will occur later.
NON-LINEAR PHARMACOKINETICS

Nonlinearity in pharmacokinetics (i.e., changes in such parameters as clearance,

volume of distribution, and t1/2 as a function of dose or concentration of drug)
usually is due to
A. saturation of either protein binding,
B. hepatic metabolism, or
C. active renal transport of the drug.
SATURABLE PROTEIN BINDING

As the molar concentration of drug increases, the unbound fraction eventually
also must increase (as all binding sites become saturated).
SATURABLE ELIMINATION

At high drug concentrations, the maximal rate of metabolism is reached and cannot be
exceeded. Under these conditions, a constant amount of drug is eliminated per unit time no
matter how much drug is in the body. Zero order kinetics then apply rather than the usual
first order kinetics.

Some examples of drugs which exhibit non-linear kinetic behaviour are phenytoin, ethanol,
salicylate and, in some individuals, theophylline.
SATURATION OF FIRST PASS METABOLISM

 After oral administration, the drug-metabolising enzymes in the liver are

exposed to relatively high drug concentrations in the portal blood. For drugs
with high hepatic extraction ratios, e.g. alprenolol, an increased dose can
result in saturation of the metabolising enzymes and an increase in
bioavailability (F).
DESIGN OPTIMIZATION OF DOSAGE REGIMENS
Loading Dose
• large initial dose of a substance or series of such doses given to rapidly achieve a
therapeutic concentration in the body

Maintenance Dose
• maintenance rate [mg/h] of drug administration equal to the rate of elimination at
steady state. This is not to be confused with dose regimen, which is a type of drug
therapy in which the dose [mg] of a drug is given at a regular dosing interval on a
repetitive basis.

Where: Dosing Rate = (Clearance x Target Conc.) / Bioavailability

Target Concentration Intervention: Application
of Pharmacokinetics & Pharmacodynamics to
Dose Individualization
 Pharmacokinetic Variables Pharmacodynamic Variables
• Absorption • Maximum effect attainable in the
• Clearance target tissue
• Volume of distribution • Sensitivity of the tissue to the drug
• Half-life

Diseases may modify all of these parameters, and the ability to predict the
effect of disease states on pharmacokinetic parameters is important in
properly adjusting dosage in such cases.
The Target Concentration Strategy

1. Choose the target concentration, TC.

2. Predict volume of distribution (V) and clearance (CL) based on standard
population values with adjustments for factors such as weight and renal
function.
3. Give a loading dose or maintenance dose calculated from TC, V, and
CL.
4. Measure the patient’s response and drug concentration.
5. Revise V and/or CL based on the measured concentration.
6. Repeat steps 3–5, adjusting the predicted dose to achieve TC.
Pharmacokinetic Variables
A. Input
• The amount of drug that enters the body depends on the:
patient’s adherence to the prescribed regimen
rate and extent of transfer from the site of administration to the blood
• Overdosage and underdosage
can frequently be detected by concentration measurements when
gross deviations from expected values are obtained
can be d/t: failure of adherence or absorption abnormalities in the small
bowel
• Variations in the extent of bioavailability
rarely caused by irregularities in the manufacture of the particular drug
formulation
more commonly are due to metabolism during absorption
B. Clearance
• Major impairment of the function of the kidney, liver, or heart – abnormal
clearance may be anticipated
• Creatinine clearance is a useful quantitative indicator of renal function
• Drug clearance may be a useful indicator of the functional consequences
of heart, kidney, or liver failure
Often with greater precision than clinical findings or other laboratory
tests
E.g. when renal function is changing rapidly, estimation of the
clearance of aminoglycoside antibiotics may be a more accurate
indicator of glomerular filtration than serum creatinine
B. Clearance
• Hepatic disease has been shown to reduce the clearance and prolong the
half-life of many drugs
• However, for many other drugs known to be eliminated by hepatic
processes, no changes in clearance or half-life have been noted with
similar hepatic disease. This reflects the fact that hepatic disease does
not always affect the hepatic intrinsic clearance.
• At present, there is no reliable marker of hepatic drug-metabolizing
function that can be used to predict changes in liver clearance in a manner
analogous to the use of creatinine clearance as a marker of renal drug
clearance
C. Volume Distribution

• Reflects a balance between:

Binding to tissues, which decreases plasma concentration and makes
the apparent volume larger
Binding to plasma proteins, which increases plasma concentration and
makes the apparent volume smaller
• Changes in either tissue or plasma binding can change the apparent
volume of distribution determined from plasma concentration
measurements
C. Volume Distribution

• E.g. Digoxin for Older People vs Obese Patients

Older people – smaller apparent volume of distribution of digoxin
(which binds to muscle proteins) d/t relative decrease in skeletal
muscle mass
Obese patients – volume of distribution may be overestimated if based
on body weight and the drug does not enter fatty tissues well, as is the
case with digoxin
C. Volume Distribution

• E.g. Theophylline
Theophylline has a volume of distribution similar to that of total body
water
Adipose tissue has almost as much water in it as other tissues, so that
the apparent total volume of distribution is proportional to body weight
even in obese patients
• Abnormal accumulation of fluid—edema, ascites, pleural effusion—can
markedly increase the volume of distribution of drugs such as gentamicin
that are hydrophilic and have small volumes of distribution
D. Half-Life
• Clearance vs Half-Life
Important in defining the underlying mechanisms for the effect of a
disease state on drug disposition
E.g. half-life of diazepam increases with patient age, but clearance of this
drug does not change with age
Increasing half-life for diazepam results from changes in the volume of
distribution with age
Metabolic processes responsible for eliminating the drug are fairly
constant
 INTERPRETATION OF DRUG

CONCENTRATION MEASUREMENTS
CLEARANCE (CL)

• The clearance of a drug is the theoretical volume of plasma from which the
drug is completely removed in unit time.
CL = Rate of elimination / C

• Clearance is the single most important factor determining drug

concentrations.
• The interpretation of measurements of drug concentrations depends on a clear
understanding of three factors that may influence clearance.
1) dose
2) organ blood flow
3) Intrinsic function of liver and kidneys

Also changes in protein binding may lead to change in clearance when in fact drug
elimination is not altered.
 PLASMA PROTEIN BINDING AND ITS IMPORTANCE

 Plasma protein binding is often mentioned as a factor playing a role in

pharmacokinetics, pharmacodynamics and drug interactions.
 The idea that if a drug is displaced from plasma proteins it would increase
the unbound drug concentration and increase the drug effect but that’s not
how our human body (which is an open system that eliminates unbound
drugs) works.
 First, a dramatic change in the unbound fraction from 1% to 10% releases
less than 5% of the total amount of drug in the body into the unbound pool
because less than one third of the drug in the body is bound to plasma
proteins even in the most extreme cases.
• Second, when the amount of unbound drug in plasma increases, the rate of elimination
will increase.

Factors affecting protein binding include the following :

1) Albumin concentration : Drugs such as phenytoin, salicylates, and

disopyramide are extensively bound to plasma albumin. Albumin levels are low
in many disease states, resulting in lower total drug concentration.

2) Alpha1-acid glycoprotein concentration: It is increased in acute

inflammatory disorders and causes major changes in total plasma concentration
of these drugs even though drug elimination is unchanged.
3) Capacity limited protein binding : The binding of drugs to plasma proteins is
capacity-limited. Therapeutic concentrations of salicylates and prednisolone show
concentration-dependent protein binding.

4) Binding to red blood cells: Drugs such as cyclosporine and tacrolimus bind
extensively inside red blood cells. Typically, whole blood concentrations are
measured, and they are about 50 times higher than plasma concentration. A
decrease in red blood cell concentration (reflected in the hematocrit) will cause
whole blood concentration to fall without a change in pharmacologically active
concentrations.
 TIMING OF SAMPLES FOR CONCENTRATION MEASUREMENT :

 Absorption usually occurs during the first 2 hours after a drug dose and varies
according to food intake, posture, and activity. Therefore, it is important to
avoid drawing blood until absorption is complete (about 2 hours after an oral
dose).
 Some drugs, such as digoxin and lithium, take several hours to distribute to
tissues. Digoxin samples should be taken at least 6 hours after the last dose
and lithium just before the next dose (usually 24 hours after the last dose).
 Aminoglycosides distribute quite rapidly, but it is still prudent to wait 1 hour
after giving the dose before taking a sample.
 VOLUME OF DISTRIBUTION

• Volume of distribution is commonly calculated for a particular patient using body

weight (70 Kg). If a patient is obese, drugs like gentamicin, digoxin, tacrolimus,
gemcitabine that do not readily penetrate fat should have their volumes calculated
from fat-free mass (FFM).

• Patients with edema, ascites, or pleural effusions offer a larger volume of

distribution to the aminoglycoside antibiotics (eg, gentamicin) than is predicted by
body weight.
 CLEARANCE

• Drugs cleared by the renal route often require adjustment of clearance in proportion
to renal function. This can be conveniently estimated from the creatinine clearance,
calculated from a single serum creatinine measurement and the predicted creatinine
production rate.

• The predicted creatinine production rate in women is 85% of the calculated value
and it is the muscle mass that determines creatinine production.

• Muscle mass as a fraction of body weight decreases with age.

REVISING INDIVIDUAL ESTIMATES OF VOLUME OF
DISTRIBUTION & CLEARANCE

• The commonsense approach to the interpretation of drug concentrations

compares predictions of pharmacokinetic parameters and expected concentrations
to measured values.
• If measured concentrations differ by more than 20% from predicted values, revised
estimates of V or CL for that patient should be calculated.
• If the change calculated is more than a 100% increase or 50% decrease in either
V or CL, the assumptions made about the timing of the sample and the dosing
history should be critically examined.