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. 1
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.

2
Clinical Pharmacokinetics (3)
Four most important pharmacokinetics
parameters that dictate adjustment of dosage
in individual patients:
• clearance (a measure of the body’s 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).
3
4
 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
5
• 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.

6
 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.
7
 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.

8
 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)
9
 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.

10
 30 



Plasma Drug Concentration g/ml

20


10




    
0 2 4 6 8 10 12 14 16 18
Time (Hours)

AUC yang dihitung dengan menggunakan rumus luas trapesium (…g/ml x jam)
11
 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

12
 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.

13
 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
patient’s age, gender, disease, and the
body composition

14
 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.
15
 Kompartemen Perifer

Kompartemen Sentral
V2
k12
Dosis V1

C1
k21
C2
ke

Model farmakokinetik sistem terbuka dua kompartemen

16
 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

17
 32
Co
Vd = Dose/Co
16


Plasma Drug Concentration g/ml

8 

4 

2 
t½

0 2 4 6 8 10 12

Time (Hours)

The semi-logarithmic plot of plasma concentration vs. time

18
 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)

19
 Half-life (t1/2)
• CL is the measure of body’s 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.
20
 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
21
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) 22
 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

23
 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

24
25
 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)
26