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Clinical Pharmacokinetics
Clinical Pharmacokinetics
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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).
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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.
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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
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)
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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
patient’s 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
V2
k12
Dosis V1
C1
k21
C2
ke
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Co
Vd = Dose/Co
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Plasma Drug Concentration g/ml
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4
2
t½
0 2 4 6 8 10 12
Time (Hours)
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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.
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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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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
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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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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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