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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.

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Clinical Pharmacokinetics (3)

Four most important pharmacokineticsparameters 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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0 2 4 6 8 10 12 14 16 18

10

20

30

Time (Hours)

Pla

sma

Dru

g C

on

cen

tra

tion

g

/ml

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

V2

C2

Dosis V1

C1

ke

k21

k12

Model farmakokinetik sistem terbuka dua kompartemen

Kompartemen Sentral

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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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0 2 4 6 8 10 12

Time (Hours)

2

4

8

16

32

Pla

sma

Dru

g C

on

cen

tra

tion

g

/ml

t ½

Co

Vd = Dose/Co

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 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)

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Examples of pharmacokinetic

calculationThe 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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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

Examples of pharmacokinetic

calculation

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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)