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Clinical Pharmacokinetics (1)

A fundamental hypothesis of clinical pharmacokinetics
is that a relationship exists between effects of a drug
and concentration of the drug in biological fluids.
Clinical pharmacokinetics attempt to provide both a
quantitative relationship between the dose and effect
and a framework with which to interpret
measurements of drug concentrations in biological
fluids.
The importance of pharmacokinetics in patient care
rests on improvement in therapeutic efficacy that can
be attained by attention to its principles when
dosage regimens are chosen and modified.
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Clinical Pharmacokinetics (2)

It is a discipline that use mathematical
models to describe and predict drug
amounts and concentrations in various
body fluids and the change in these
quantities overtime.

Clinical Pharmacokinetics (3)

Four most important pharmacokinetics
parameters that dictate adjustment of dosage
in individual patients:
clearance (a measure of the bodys ability to
eliminate drugs);
volume distribution (a measure of the apparent
space in the body available to contain the drug);
elimination half-life ( a measure of rate of
removal of drug from the body);
and bioavailability (the fraction of drug
absorbed as such into the systemic circulation).
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Clearance (1)
Is defined as that fraction of the apparent
volume of distribution is removed in unit
of time ml/min/kg
Indicates the volume of biological fluid
that would have to be completely freed of
drug to account for elimination
The total body clearance is usually
subdivided into renal and non-renal
(hepatic) clearances
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 The plasma clearance of cephalexin is 4.3

ml/min per kg with 90% of the drug excreted
unchanged in the urine. For 60-kg man, the
clearance from plasma would be 258/min, with
renal clearance accounting for 90% of this
elimination. Thus the kidney is able to excrete
cephalexin at a rate such that the drug is
completely removed (cleared) from
approximately 232.2 ml of plasma per minute.
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Clearance (2)
Is the most important concept to be considered when
a rational regimen for long-term drug administration
is to be designed. We want to maintain steady-state
concentrations of a drug within a known therapeutic
range.
The steady-state will be achieved when the rate of
drug elimination equals the rate of drug
administration:
Dosing rate = CL . Css (1-1)
If the steady-state concentration of drug in blood is
known, the rate of drug clearance by the patient will
dictate the rate at which the drug should be
administered.
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Clearance (3)
The clearance of a given drug is constant over
the range of concentration encountered
clinically, because the absolute rate of drug
elimination is essentially a linear function of its
plasma concentration.
It means that the elimination of most drugs
follows first order kinetics a constant fraction
of drug is eliminated per unit of time.

First Order Kinetics (1)

It is a type of kinetic behavior that apply to a
large number of drugs.
Drug distribution or elimination obeys this
model.
It means that the rate of change of drug
concentrations overtime varies continuously in
relation to the concentration itself.
This concept can be presented in mathematical
language: C/t = -kC
k is a rate constant = a proportionality factor
per unit of time.
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First Order Kinetics (2)

The equation indicates that when drug
concentrations are high, the rate of decline of
drug concentration is also high. At low
concentration, the rate of decline is also low.
When plotted on a graph, the concentration
starts at an initial value at zero time, then
declines in a curvilinear fashion.
At high concentration, the rate of decline is
rapid, at low levels the decline is slow.
The graph shows that first-order kinetic governs
an exponential fall in drug concentrations
overtime: Ct = C0 e-kt
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First-Order Kinetics (3)

When plotted on semilogarithmic graphs, the
first order process becomes straight line, from
which it is easy to determine half-life and rate
constant (k).
Ct = C0 e-kt (e=2.7828) ln Ct = ln C0 kt log
Ct = log C0 kt/2.303. (C0 is the intercept;
k/2.303 is the slope of the straight-line; ).
When Ct = 1/2 Co t1/2 (half-life) = 0.693/k
k = 0.693/t1/2
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Clearance (4)
Drug clearance is similar to creatinine
clearance, where the rate of creatinine
elimination in the urine is relative to its
concentration in plasma.
Clearance of a drug is its elimination by all
routes normalized to the concentration of
the drug in biological fluid where
measurement can be made:
CL = Rate of elimination/C (1-2)
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Clearance (5)
For a single dose of a drug with complete
bioavailability (F=100%) and first order kinetic
elimination, total systemic clearance may be
determined from a mass balance and the
integration of equation (1-2) over time:
CL = F.Dose/AUC
(1-3)
AUC is the total area under the curve that
describes the drug concentration in the systemic
circulation as a function of time, from zero to
infinity.
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Plasma Drug Concentration g/ml

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10

10

12

14

16

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Time (Hours)

AUC yang dihitung dengan menggunakan rumus luas trapesium (g/ml x jam)
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Volume of distribution
Is defined as the fluid volume that would be
required to contain all the drug in the body at
the same concentration as in the blood or
plasma:
Vd = amount of drug in the body/C
(1-4)
The plasma volume is about 3 L, blood volume is
5.5 L, the extra cellular fluid is 12 L, and the
volume of TBW is 42 L for a typical 70 kg man

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Volume of distribution
Many drugs exhibit Vd for an excess of those
values. For example, if 500 ug of digoxin were in
in the body of a 70 kg subject, a plasma conc.
Of 0.75 ng would be observed.
Vd = 500 ug/0.75 ng/ml = 700 L, a value 10 x
greater than TBW of 70 kg
Digoxin distributes preferentially to muscle,
adipose tissue and its specific receptor, leaving a
very small amount in the plasma.
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Volume of distribution
Vd may vary widely depending on pKa,
degree of binding to plasma protein, the
partition coefficient of the drug in fat, the
degree of binding to other tissues, and so
forth
Vd for a given drug can vary according to
patients age, gender, disease, and the
body composition
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Volume of Distribution
The Vd in equation (1-4) considers the body as
single compartment. In this one-compartment
model, all drug administration occurs directly
into the central compartment and distribution of
drug is instantaneous throughout volume (V).
Clearance of drug from this compartment occurs
in a first order kinetic; that is, the amount of drug
eliminated per unit time depends on the amount
(concentration) of drug in the body
compartment.
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Kompartemen Perifer

Kompartemen Sentral
V1

Dosis

C1

k12

k21

V2

C2

ke

Model farmakokinetik sistem terbuka dua kompartemen

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Volume of distribution
The decline of plasma concentration with time for a
drug introduced into one-compartment model :
Ct = (Dose/Vd) . exp(-kt) (1-5)
Ct = C0 . exp(-kt)
k = 0.693/t1/2
(1-6)
k = the rate constant for elimination that reflects
the fraction of drug removed from the
compartment per unit of time.
The one-compartment model is sufficient to apply
to most clinical situation for most drugs
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32

Co
Vd = Dose/Co

Plasma Drug Concentration g/ml

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t
0

10

12

Time (Hours)

The semi-logarithmic plot of plasma concentration vs. time

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Half-Life (t1/2)
It is the time it takes for the plasma
concentration as the amount of drug in the
body to be reduced by 50%.
It is a derived parameter that changes as a
function of both clearance and Vd.
Relationship between t1/2, clearance, and
Vd at steady state is given by:
t1/2 = 0.693. Vss/CL (1-7)
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Half-life (t1/2)
CL is the measure of bodys ability to
eliminate a drug; as CL decreases due to
a disease process, t1/2 would be expected
to increase. This reciprocal relation is valid
only when the disease does not change
Vd.
T1/2 of diazepam increases with aging; it is
not CL that change as a function of age,
but the volume of distribution.
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Half-Life (t1/2)
Changes in drug protein binding may affect its CL as well
as its Vd, leading to an unpredictable changes in t1/2.
Although it can be a poor index of drug elimination, t1/2
provides a good indication of time required to reach
steady state after a dosage regimen is initiated. It is
required four half-lives to reach approximately 94% of a
steady-state drug concentration in the body.
It is also and indication of the time for a drug to be
removed from the body, and a means to estimate the
appropriate dosing interval.

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Steady-State Drug Concentration

A steady-state concentration will be achieved
when a drug is administered at a constant rate.
At this state, drug elimination (the product of
clearance and concentration; see equation 1-2)
will equal the rate of drug availability.
This concept also extend to intermittent dosage.
During each interdose interval, the concentration
of drug rises and falls. Equation 1-1 still applies,
but it describes the average drug concentration.
Average concentration when the steady-state is
attained:
Css = F. Dose / (CL . T) (1-8)
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Bioavailability
Is defined as the amount of administered
drugs which reaches the systemic intact
It is determined from the relationship
between AUC after equivalent IV and PO
doses
F (absolute) = AUC after oral dose/AUC after IV dose
F (relative) = AUC after an oral dose of me-too product
AUC after an oral dose of original product
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Nonlinear Pharmacokinetics Due to

Saturable Protein Binding
As protein binding become saturated, the unbound
fraction eventually has to increase.
For a drug of low hepatic extraction ratio, saturation of
protein binding will cause both Vd and CL to increase as
drug conc. increase; t1/2 may remain constant. For such
a drug, Css will not increase linearly as the rate of drug
administration is increased ( see equation 1-8).
For a drug of high hepatic extraction ratio, saturation
of protein binding will not change hepatic CL, but the
increase in Vd would increase the t1/2; Css can remain
linearly proportional to the rate of drug administration.
Most drugs fall between two extremes.

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Nonlinear Kinetics Due to Saturable

Metabolism
The Michaelis-Menten equation describes the
nonlinearity of saturable metabolism:
CLp = Vm.Cp / (Km+Cp) (1-9)
CLp = total plasma clearance; Vm = the maximal rate of
elimination; Km = the plasma concentration at which half
of the maximal rate of elimination is reached; Cp =
plasma drug concentration.
All active processes will become saturable, but they
appear to be linear if values of drug concentrations are
much less than Km. When they exceed Km, nonlinear
kinetics are observed.

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Nonlinear Kinetics Due to Saturable

Metabolism
The major consequences of saturation of metabolism are
the opposite of those saturation of protein binding.
Saturation of protein binding will lead to increased CL
because CL increases as drug conc. Increases, whereas
saturation of metabolism may decrease CL.
When both conditions are present simultaneously, they
may cancel each others effects, and surprisingly linear
kinetics may result.
Saturable metabolism causes first-pass metabolism to
be less, Css increases greater than increase in the rate
of drug administration.
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Nonlinear Kinetics Due to Saturable

First-Pass Metabolism
It causes oral first-pass metabolism to be
less than expected ( higher bioavailability,
F ), there is a greater fractional increase in
Css:
dosing rate. Km
Css = --------------------Vm dosing rate
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Optimization of Dosage Regimens

In drug therapy usually it is asked: What degree
of effect is desired and achievable?
Some effect of the drug is easily measured (e.g.,
blood pressure), so it can be used to guide
dosage, and a trial-and-error approach to
optimal dosage is both practical and sensible.
For some drugs, the effects are difficult to
measure, toxicity and lack of efficacy are both
potential danger, or the therapeutic window is
narrow. In these circumstances doses must be
titrated to achieve a target level.
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Target-Level Strategy of Dosage

Regimens
A desired (target) steady-state concentration of the drug
in plasma is chosen, and a dosage is computed that is
expected to achieve this value. Drug concentrations are
subsequently measured, and the dosage is adjusted if
necessary to approximate the target more closely.
To apply the target-level strategy, the therapeutic
objectives must be defined in a range called therapeutic
range. For many drugs, the lower limit of therapeutic
range appears to be equal to the concentration that
produces half of the greatest possible effect. The upper
limit of the range is fixed by toxicity (5% to 10% of
patients will have a toxic effect).
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Maintenance Dose of Dosage

Regimens
Drugs are administered in a series of repetitive
dose as a continuous infusion in order to
maintain a steady-state concentration in plasma
within a given therapeutic range. Thus,
calculation of the appropriate maintenance
dosage is a primary goal.
To maintain the target concentration, the rate of
drug administration is adjusted such that the rate
of input equals the rate of loss:
Dosing rate = target Cp . CL/F (1-10)
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An Example of Maintenance Dose

Calculation
A steady-state plasma concentration of
theophylline of 15 mg/l is desired to relieve
acute bronchiale asthma in a 68-kg patient. If the
patient does not smoke and is otherwise normal
except for asthmatic condition, one can use a
mean theophylline clearance of 0.65 ml/min/kg.
F = 1 because the drug is to be given
intravenously.
Dosing rate = Target . CL/F = 15 ug/ml x 0.65
ml/min/kg = 9.75 ug/min/kg = 40 mg/h for a 68kg patient.
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Dosing Interval for Intermittent Dosage

(1)
Marked fluctuations in drug concentrations between
doses are not beneficial.
If absorption and distribution were instantaneous,
fluctuation of drug concentrations between doses would
be governed entirely by the drugs elimination half-life.
If the dosing interval (T) was chosen to be equal to the
half-life, then the total fluctuation would be twofold.
For some drugs with a narrow therapeutic range, it may
be important to estimate the maximal and minimal
concentrations that will occur for a particular dosing
interval.

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Dosing Interval for Intermittent Dosage

Css,min can be determined by the use of equation:
f.Dose/Vss
Css,min = --------------------- . Exp(-kT) (1-11)
1-exp(-kT)
One may easily predict Css,max by omitting the
exp(-kT) in the numerator of equation (1-11).
f.Dose/Vss
Css,max = -------------------(1-12)
1-exp(-kT)

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Examples of Css,max and Css,min

Calculation
The clinician wants to maintain plasma concentration of
theophyllin at 15mg/l with oral dose of 960 mg/day. What
is the appropriate dosage regimen for this patient?
For a 12-hour dosing interval (T) the maximal and
minimal concentration would be:
480mg/34 liters
Css,max= -------------------------- = 21.7 mg/l
0.65 ml/min/kg
Css,min= (21.7mg/liter . (0.35) = 7.6 mg/l

For T=6, Css,max=17mg/l; Css,min=10mg/l

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Loading Dose
A loading dose is one of a series of doses
that may be given at the onset of therapy
with the aim of achieving the target
concentration rapidly:
Loading dose=Target concentration.Vss/F

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Therapeutic Drug Concentration

Monitoring (1)
The major use of measured drug concentrations at
steady-state is to refine the estimate of CL/F for the
patient being treated:
CL/F (patient) = dosing rate/Css (measured)

The calculated CL/f can be used to adjust the new

maintenance dose to achieve the desired target
concentration:
Adjusted dosing rate=target concentration.CL/F

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Therapeutic Drug Concentration

Monitoring
If a drug follows first-order kinetics, the average,
minimum, and maximum concentrations at
steady-state are linearly related to dose and
dosing rate. Therefore, the ratio between the
measured and the desired concentration can be
used to adjust the dose:
Css(measured) Dose(previous)
----------------- =
-----------------Css(desired)
Dose(new)

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 If the measured steady-state concentration (Css)

is found to be 1.65 ng/ml rather than a desired
level of 1.3 ng/ml, what is the appropriate dose
for a patient receiving digoxin 0.375 mg/day?
Css (measured)
New dose = -------------------- X previous dose
Css (desired)
= 1.3 / 1.5 X 0.375 = 0.25 mg/day.

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Pharmacokinetic data available for

designing and optimizing dosage
regimens
Availability (%)
Urinary excretion (%)
Bound in plasma (%)
Clearance (ml/min/kg/BW)
Volume of distribution (L/kg BW)
Half-life (hours)
Effective concentration (g/ml)
Toxic concentration (g/ml)

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Examples of pharmacokinetic
calculation
The Vd and clearance of theophylline is 35
L and 3 L/h respectively in a 70 kg person.
If the target concentration is 10 ugr/ml,
then the loading dose is :
Loading dose = Target Cp . Vss/F

= 10 g/ml . 35 L = 350 mg
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Examples of pharmacokinetic
calculation
Maintenance dose rate = clearance . concentration
= 3 l/h . 10 mg/l = 30 mg/h
= 720 mg/day
Half-life = 0.693 . Vd/CL = 0.693 . 35 L/ 31/h
= 8 hours
The expected time to achieve 90 % Css is about 4
half-lives or 32 hours
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