Expt. 13 Calculation of pharmacokinetic parameters from a given data

ExperimentNo. 13
Calculationof pharmacokineticparameters
from a given data
Mr. Vishal Balakrushna Jadhav
Assistant Professor (Pharmacology)
GES’s Sir Dr. M. S. Gosavi COPER, Nashik-5
1

Overview of Discussion
• Objective
• Pharmacokinetics (PKs) and Clinical Pharmacokinetics
• Plasma Drug Concentration-TimeProfile
• Peak Plasma Concentration (Cmax)
• Time of Peak Concentration (tmax)
• Area Under the Curve (AUC)
• Bioavailability(BA)
• Volume of Distribution (Vd)
• Half-Life(t1/2)
• Clearance (CL)
• Loadingand Maintenance Dose
• Result and interpretation
2

Objective
To study different types of pharmacokinetic parameters.
3

Pharmacokinetics (PKs) and Clinical Pharmacokinetics
The word pharmacokinetics derived from Greek words- pharmakon-
drug and kinesis- movement/ motion→ movement of the drug
throughout the body.
Division of pharmacology deals with fate of drug→ ADME profile of
drug into the human body.
Pharmacokinetics speaks with what body does with the administered
drugs?
Absorption (A) Process of movement of unchanged drug from the site
of administration to systemic circulation.
Distribution (D) Process of reversible transfer of a drug between blood
and the extravascular fluids and tissues.
Metabolism (M) Process of conversion of one chemical form to
another under the influence of various enzymes.
Excretion (E) Process of irreversible transfer of drugs and/or their
metabolites from internal environment to external environment.
4

Pharmacokinetics
It is the kinetics of drug absorption, distribution, metabolism and
excretion (KADME) and their relationship with the pharmacologic,
therapeutic or toxicologic response in man and animals.
Clinical Pharmacokinetics
It is an application of pharmacokinetic principles in the safe and
effective management of individual patient.
5

Plasma Drug Concentration-TimeProfile
A direct relationship exists between the concentration of drug at the
biophase (site of action) and the concentration of drug in plasma. A
typical plasma drug concentration-time curve obtained after a single
oral dose of a drug and showing various pharmacokinetic and
pharmacodynamic parameters as shown in figure. Such a profile can
be obtained by measuring the concentration of drug in plasma
samples taken at various intervals of time after administration of a
dosage form and plotting the concentration of drug in plasma (Y-
axis) versus the corresponding time at which plasma sample was
collected (X-axis).
6

Fig. A typical plasma concentration-time profile showing pharmacokinetic
and pharmacodynamic parameters, obtained after oral administration of
single dose of a drug. 7

Peak Plasma Concentration (Cmax)
 The point of maximum concentration of drug in plasma is called as
the peak and the concentration of drug at peak is known as peak
plasma concentration. It is also called as peak height
concentration and maximum drug concentration.
 Cmax is expressed in mcg/ml.
 The peak plasma level depends upon the administered dose, rate of
absorption, and rate of elimination.
 The peak represents the point of time when absorption rate equals
elimination rate of drug. The portion of curve to the left of peak
represents absorption phase i.e. when the rate of absorption is
greater than the rate of elimination. The section of curve to the
right of peak generally represents elimination phase i.e. when the
rate of elimination exceeds rate of absorption. Peak concentration
is often related to the intensity of pharmacological response and
should ideally be above minimum effective concentration (MEC) but
less than the maximum safe concentration (MSC).
8

Time of Peak Concentration (tmax)
 The time for drug to reach peak concentration in plasma (after
extravascular administration) is called as the time of peak
concentration.
 It is expressed in hours and is useful in estimating the rate of
absorption.
 Onset time and onset of action are dependent upon tmax.
 This parameter is of particular importance in assessing the efficacy
of drugs used to treat acute conditions like pain and insomnia which
can be treated by a single dose.
9

Area Under the Curve (AUC)
 It represents the total integrated area under the plasma level-time
profile and expresses the total amount of drug that comes into the
systemic circulation after its administration.
 AUC is expressed in mcg/ml X hours.
 It is the most important parameter in evaluating the bioavailability
of a drug from its dosage form as it represents the extent of
absorption.
 AUC is also important for drugs that are administered repetitively
for the treatment of chronic conditions like asthma or epilepsy.
10

Bioavailability(BA)
 Bioavailability refers to the rate and extent at which the active
moiety (drug or metabolite) enters systemic circulation, thereby
accessing the site of action.
 It is denoted as f.
 Bioavailability is the amount of the administered drug that is
available to have an effect.
 Bioavailability of a drug is largely determined by the properties of
the dosage form (which depend partly on its design and
manufacture), rather than by the drug's physicochemical
properties.
 Drugs given intravenously may be considered to be 100%
bioavailable as they are administered directly into the circulation.
 Administration of highly lipid soluble drugs by oral route means that
some of the drug molecules will be lost due to first pass metabolism
and thus bioavailability is reduced. For calculating bioavailability (f)
drug is give by IV route and by intended route of administration.
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 Plasma concentration curves are plotted and area under plasma
concentration curve (AUC) is measured for each mode of
administration.
 For new preparations of the same drug, bioavailability can be
compared to see their bioequivalence. Bioequivalence is whether
both preparations give same bioavailability in the body or not.
Clinical significance
 Oral dose is more as compared to IV Dose.
 Marked interindividual variation in first pass metabolism, hence
dose required.
 Hepatic diseases affect first pass metabolism, hence concentration
achieved will be high.
 Drug interactions can occur when two drugs compete for same
pathway of first pass metabolism.
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Volume of Distribution (Vd)
 It is defined as apparent or hypothetical volume of body fluids that
can accommodate the total mount of drug administered so that the
concentration achieved is equal to concentration in the plasma.
 If total amount of administered drug = 1000 mg and plasma conc.
achieved = 50 mg/l, then Vd will be calculated as given in figure.
 The Vd is calculated as the ratio of the dose present in the body and
its plasma concentration.
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Fig. Vd calculation

 Vd gives an idea about distribution of drug as given in tables.
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Tab. Vd as related to drug present in body
Tab. Vd of commondrugs

 Vd depends on the following factors:
 Blood flow rate in different tissue
 Lipid solubility of drug
 Partition coefficient of drug and different
types of tissues
 pH
 Binding to biological material.
 Vd is often proportional to body weight. In
obesity Vd is lower than expected from the
body weight.
 In edema, Vd is larger than expected for the
body weight.
15
Other formulae for Vd
Clinicalsignificance
 Hemodialysis in drug poisoning: Drugs
with low Vd can be easily removed by
hemodialysis, e.g. Salicylates
 Calculation of loading dose (LD)

Half-Life(t1/2)
 The half-life (t1/2) is the time taken for the circulating plasma
concentration of a drug to fall to 50% of original/peak
concentration, for example: Aspirin 15 minutes , and Phenobarbital
2-6 days.
 Half-life is a derived parameter that changes as a function of both
clearance and volume of distribution. Half-life is constant in first
order kinetics. Half-life increase with increase in concentration in
zero order kinetics.
 Plasma protein binding increase half-life
 Drug widely distributed and sequestrated in tissues got longer half-
life, e.g. amiodarone
16

 Approximately 4-5 half-lives are required for complete elimination
of drug from the body:
 one t½ = 50% drug is eliminated,
 two t½ = 75% (50 + 25) drug is eliminated,
 three t½ = 87.5% (75 + 12.5) drug is eliminated, and
 four t½ = 93.75% (87.5 + 6.25) drug is eliminated.
Clinical significance
 Half-life determines frequency of administration or dosing interval
of drug, e.g. If t½ is 12 hours, then drug is given twice a day.
 When rate of absorption equals rate of elimination steady state is
said to be achieved.
 The clinician usually wants to maintain steady-state concentrations
of a drug within a known therapeutic range, assuming complete
bioavailability.
 Approximately 4-5 half-lives are required to reach steady state.
17

 In most clinical situations, drugs are administered in a series of
repetitive doses or as a continuous infusion in order to maintain a
steady-state concentration of drug in plasma within a given
therapeutic range. At steady state the rate of drug administration is
equal to drug elimination and the mean concentration remains
constant.
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Clearance (CL)
 Clearance is the most important concept to be considered when a
rational regimen for long term drug administration is to be
designed.
 Clearance is defined as the volume of the plasma cleared of the
drug in a unit time.
 It is expresses as ml/minute. If given clearance is 5 ml/minute, it
means that 5 ml of plasma is cleared of the drug.
 Most of the drugs follow first order kinetics for clearance.
 Total body clearance is: CL = CLrenal + CLhepatic + CLother
19
Otherformulae for CL

 If a drug is only excreted by glomerular filtration, CLrenal can not
exceed GFR (120 ml/min), e.g. Aminoglycoside antimicrobials.
 If a drug is completely removed by tubular secretion, CLrenal can
not exceed renal plasma flow (700 ml/min), e.g. Penicillin.
 Reabsorption can decrease CLrenal to as low as 1ml/min.
 Clearances is constant in zero order kinetics. Zero order kinetics are
saturable kinetics, e.g. Phenytoin. It is also known as non-saturable
kinetics. Most of the drugs follow first order kinetics.
 Clearance increase with increase in concentration in first order
kinetics.
20

Loadingand Maintenance Dose
 The loading dose is one or a series of quickly repeated doses that
may be given at the onset of therapy with the aim of achieving the
target concentration rapidly. The appropriate magnitude for the
loading dose is:
 Loading dose depends on extent of distribution. If a drug is widely
distributed in the body a large loading dose is required to fill the
distribution sites.
 A loading dose may be desirable if the time required to attain
steady state by the administration of drug at a constant rate (four
elimination half-lives) is long relative to the temporal demands of
the condition being treated.
21
 Maintenance dose To maintain steady state a
maintenance dose is required. Maintenance dose
depends on clearance. Whatever dose is lost in
clearance is replaced by maintenance dose.

Result and interpretation
Different types of pharmacokinetic parameters were studied.
22

Expt. 13 Calculation of pharmacokinetic parameters from a given data

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