This document provides information on pharmacokinetics, including key terms and concepts. It discusses volume of distribution, clearance, half-life, steady state, and loading/maintenance doses. Volume of distribution relates the amount of drug in the body to its concentration in blood or plasma. Clearance is the rate of drug elimination. Half-life is the time for a drug amount to reduce by half. Steady state is reached when the dosing rate equals the elimination rate. Loading doses are used to quickly reach the target concentration for drugs with long half-lives, while maintenance doses are repeated to maintain steady state. Therapeutic drug monitoring measures drug levels to adjust doses for each patient.

1. PHARMACOKINETICS
Presenter
Dr. Nipa Mendapara
Junior Resident
Department of Pharmacology
AIIMS New Delhi

2. Basic terminologies (PK):
1. Volume of distribution (V)
2. Clearance (Cl)
3. Half-life
4. Steady-state
5. Loading/maintenance dose
6. Therapeutic drug monitoring (TDM)
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4. Pharmacokinetics
• It is the quantitative study of drug movement in, through and out of
the body.
• The intensity of drug response is related to concentration of the drug
at the site of action, which in turn is dependent on its
pharmacokinetic properties.
• Pharmacokinetics determine the route(s) of administration, dose,
latency of onset, time of peak action, duration of action and
frequency of administration of a drug.
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5. Importance of PK
• The importance of pharmacokinetics in patient care is based on the
Improvement in therapeutic efficacy and the avoidance of unwanted
effects that can be attained by application of its principles when
dosage regimens are chosen and modified
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6. Processes of Pharmacokinetics (PK)
• ADME, the Absorption, Distribution, Metabolism, and Elimination of
drugs.
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7. VOLUME OF DISTRIBUTION (V)
• An apparent volume of distribution is “the volume that would
accommodate all the drug in the body, if the concentration
throughout was the same as in plasma”.
• Volume of distribution (V) relates the amount of drug in the body to
the concentration of drug (C) in blood or plasma.
V = Amount of drug in the body/C
• The volume of distribution may be defined with respect to blood,
plasma, or water (unbound drug), depending on the concentration
used in equation (C = Cb, Cp, or Cu).
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• It can vastly exceed any physical volume in the body because it is the volume
apparently necessary to contain the amount of drug homogeneously at the
concentration found in the blood, plasma, or water.
1. Drugs with very high volumes of distribution have much higher concentrations
in extravascular tissue than in the vascular compartment, i.e, they are not
homogeneously distributed.
2. Drugs that are completely retained within the vascular compartment, on the
other hand, would have a minimum possible volume of distribution equal to
the blood component in which they are distributed.
E.g. 0.04 L/kg body weight or 2.8 L/70 kg for a drug that is restricted to the plasma
compartment.
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https://sepia2.unil.ch/pharmacology/parameters/volumeofdistribution/

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High Volume of distribution Low Volume of distribution

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• If a patient is obese, drugs that do not readily penetrate fat (Lipid
insoluble) (e.g. gentamicin, digoxin, tacrolimus, gemcitabine) should
have their volumes calculated from fat-free mass (FFM) as shown
below.
Total body weight (WT) is in kilograms and height (HTM) is in meters.
• For women: FFM (kg) = 37.99 x HTM2 x WT/35.98 x HTM2 + WT
• For men: FFM (kg) = 42.92 x HTM2 x WT/30.93 x HTM2 + WT
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• Patients with edema, ascites, or pleural effusions offer a larger
volume of distribution to hydrophilic drugs (e.g, gentamicin) than is
predicted by body weight.
In such patients, the weight should be corrected as follows:
• Subtract an estimate of the weight of the excess fluid accumulation
from the measured weight.
• Use the resultant “normal” body weight to calculate the normal
volume of distribution.
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16. V depends on
1. Binding to tissues : Decreases plasma concentration and makes the apparent volume
larger.
2. Binding to plasma proteins : Increases plasma concentration and makes the apparent
volume smaller.
3. Age : Older people have a relative decrease in skeletal muscle mass and tend to have a
smaller apparent volume of distribution. (E.g. digoxin which binds to muscle proteins).
4. Obese patients : The volume of distribution may be overestimated in if based on body
weight if the drug does not enter fatty tissues well (Lipid insoluble) e.g. digoxin.
5. Pathological state : Edema, ascites, pleural effusion—can markedly increase the
volume of distribution of drugs such as gentamicin that are hydrophilic and have small
volumes of distribution.
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17. Importance of Volume of distribution
• Loading dose depend on volume of distribution
• Drugs having high V are difficult to be removed by dialysis e.g.
digoxin.
• Drug with high V will have longer t1/2. ex. Chloroquine have
• Lipophilic drug will have high V while hydrophilic drug will have small
V.
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18. Calculation
Q: A 60 kg patient is given a 1000 microgram dose of Drug A. On
measuring the steady state plasma concentration, we get a value of 2
micrograms per L. Volume of distribution for this drug will be ?
A: V = Dose/Plasma concentration
= 1000 μg /2 μg/L
= 500 L/60 kg
= 8.33 L/kg
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19. CLEARANCE
• It is the theoretical volume of plasma from which the drug is
completely removed in unit time
• It predicts the rate of elimination in relation to the drug concentration
(C)
CL= Rate of elimination/C
• Clearance is defined with respect to blood (CLb), plasma (CLp), or
unbound in water (CLu), depending on where and how the
concentration is measured.
• Expressed in ml/min.
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• Additive character of clearance : Elimination of drug from the body may
involve processes occurring in the kidney, the lung, the liver, and other
organ
• Dividing the rate of elimination at each organ by the concentration of drug
presented to it yields the respective clearance at that organ.
• The two major sites of drug elimination are the kidneys and the liver.
Clearance of unchanged drug in the urine represents renal clearance.
Within the liver, drug elimination occurs via biotransformation of parent
drug to one or more metabolites, or excretion of unchanged drug into the
bile, or both.
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21. First-order elimination
• A constant fraction of drug in the body is eliminated per unit of time.
• For most drugs, clearance is constant over the concentration range
encountered in clinical settings.
• This is true because metabolizing enzymes and transporters usually
are not saturated; thus, the absolute rate of elimination of the drug is
essentially a linear function of its concentration in plasma.
• However, if the dose is high enough, elimination pathways of all drugs
will get saturated.
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22. Zero-order elimination
• If mechanisms for elimination of a given drug become saturated, the
kinetics approach zero order (the case for ethanol and high doses of
phenytoin).
• In which case a constant amount of drug is eliminated per unit of time.
• So, clearance will vary depending on the concentration of drug that is
achieved.
• It’s also known as capacity limited elimination, saturable, dose- or
concentration-dependent, nonlinear, and Michaelis Menten elimination.
• Warfarin, Alcohol or ethanol and Aspirin, Theophylline, Tolbutamide and
Phenytoin.
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23. Time (Hours) Cp (mg/L) Drug remaining
0 16 100 %
1 8 50 %
2 4 25 %
3 2 12.5 %
4 1 6.25 %
5 0.5 3.125 %
Time (Hours) Cp (mg/L) Drug remaining
0 16 100 %
1 14 87.5 %
2 12 75 %
3 10 62.5 %
4 8 50 %
5 6 37.5 %
FIRST ORDER KINETICS
(Drug A)
ZERO ORDER KINETICS
(Drug B)
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24. First Order kinetics
(Linear kinetics)
Zero Order kinetics
(Non linear kinetics)
1. Constant fraction of drug is eliminated per
unit time.
2. Rate of elimination is proportional to
plasma concentration.
3. Clearance remains constant.
4. Half life remain constant.
5. Most of the drugs follow first order
kinetics.
1. Constant amount of the drug is
eliminated per unit time.
2. Rate of elimination is independent of
plasma concentration.
3. Clearance is more at low concentrations
and less at high conc.
4. Half life is less at low conc. and more at
high conc.
5. Very few drugs follow pure zero order
kinetics e.g. alcohol.
6. Any drug at high conc. (when metabolic
or elimination pathway is saturated)
May show zero order kinetics.
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25. Comparative pharmacokinetic parameters with
first order and zero order elimination
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26. Importance of clearance
• Abnormal clearance may be anticipated when there is major
impairment of the function of the kidney, liver, or heart.
• Creatinine clearance is a useful quantitative indicator of renal
function.
• Hepatic disease has been shown to reduce the clearance and prolong
the half-life of many drugs. However, for many other drugs known to
be eliminated by hepatic processes, no changes in clearance or half-
life have been noted with similar hepatic disease.
• This reflects the fact that hepatic disease does not always affect the
hepatic intrinsic clearance.
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27. HALF-LIFE
• Time required to change the amount of drug in the body by one-half (50%) during
elimination (or during a constant infusion)
• Time course of drug in the body will depend on both the volume of distribution
and the clearance:
Elimination t½ = ln2/k
• Where ln2 is the natural logarithm of 2 (or 0.693)
• Because drug elimination can be described by an exponential process, the time
taken for a two fold decrease can be shown to be proportional to the natural
logarithm of 2.
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• k is the elimination rate constant of the drug, i.e. the fraction
of the total amount of drug in the body which is removed
per unit time
So, K= Cl/V
t1/2 = 0.693 x V/CL
• Units = ml/min or L/hr
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• During absorption: Fifty percent of the steady-state
concentration is reached after one half-life, 75% after
two half-lives, and over 90% after four half-lives.
• During elimination: Fifty percent of the drug is lost
after one half-life, 75% after two half-lives, etc.
• The “rule of thumb” that four half-lives must elapse
after starting a drug-dosing regimen before full
effects will be seen is based on the approach of the
accumulation curve to over 90% of the final steady-
state concentration.
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30. Calculation :
Q: The 70 kg patient is taking prescribed paracetamol for treatment of
fever. The volume of distribution and clearance for paracetamol are 67
L and 21 L/h/70 kg, respectively.
What will be the half-life of the paracetamol in this patient ?
A: Half life t½ = 0.693 x V/CL
= 0.693 x 67 L/21 L/hour
= 2.21 hour
t1/2 ~ 2 hour
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31. Importance of half-life of drug
• Most useful in designing drug dosage regimens
• Dosage regimen design is the selection of drug dosage, route, and
frequency of administration in an informed manner to achieve
therapeutic objectives.
Ex. For paracetamol t1/2 = 2 hour so 2 x 4 t1/2 =8 hour
So, paracetamol is given at every 8 hour or TDS.
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32. STEADY STATE
• In most clinical situations, drugs are administered in such a way as to
maintain a steady state of drug in the body, ie, just enough drug is
given in each dose to replace the drug eliminated since the
preceding dose.
• Clearance is the most important pharmacokinetic term to be
considered in defining a rational steady-state drug dosage regimen.
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• At steady state, the dosing rate (“rate in”) must equal the rate of
elimination (“rate out”).
Dosing rate ss = Rate of elimination ss = CL x TC
Thus, if the desired target concentration is known, the clearance in that
patient will determine the dosing rate.
• If the drug is given by a route that has a bioavailability(F) less than
100% e.g. For oral dosing,
Dosing rate oral = Dosing rate/F oral
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• Dose rate-Cpss relationship is linear
only in case of drugs eliminated by first
order kinetics.
• For drugs which follow Michaelis
Menten kinetics, elimination changes
from first order to zero order kinetics
over the therapeutic range.
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36. Importance of Steady state
• β-lactams, glycopeptides and macrolides produce ‘time dependent
inhibition’, i.e. antimicrobial action depends on the length of time the
concentration remains above the MIC; division of daily dose improves the
effect. So drug is given given after each plasma half life so SSPC will
develop in 4-5 t1/2
• Most antibiotics are given at 2 to 4 half-life intervals— thus attaining
therapeutic concentrations only intermittently. For many organisms,
aminoglycosides, fluoroquinolones and metronidazole produce
‘concentration-dependent inhibition’, i.e. inhibitory effect depends on the
ratio of peak concentration to the MIC
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37. LOADING DOSE
• When the time to reach steady state is appreciable Long, as it is for
drugs with long t1/2, it may be desirable to administer a loading dose
that promptly raises the concentration of drug in plasma to the target
concentration.
• The volume of distribution is the proportionality factor that relates
the total amount of drug in the body to the concentration; if a loading
dose is to achieve the target concentration
Loading dose = Amount in the body immediately following the
loading dose = V x TC
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• If the rate of absorption is rapid relative to distribution (this is always
true for rapid intravenous administration), the concentration of drug
in plasma that results from an appropriate loading dose—calculated
using the apparent volume of distribution—can initially be
considerably higher than desired and severe toxicity may occur.
• Thus, slow administration of an intravenous drug (over minutes rather
than seconds) is almost always prudent practice.
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39. MAINTENANCE DOSE
• This dose is one that is to be repeated at specified intervals after the
attainment of target Cpss so as to maintain the same by balancing
elimination.
• If intermittent doses are given,
Maintenance dose = Dosing rate x Dosing interval = CL x TC x Dosing
interval
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40. Calculation :
Q: A target plasma theophylline concentration of 10 mg/L is desired to
relieve acute bronchial asthma in a patient. If the patient is a non
smoker and otherwise normal except for asthma, the mean clearance is
2.8 mg/h/70kg. Since the drug will be given as an intravenous infusion,
F=1. calculate the dosing or infusion rate.
A : Dosing rate = CL x TC
= 2.8 L/h/70kg x 10 mg/L
= 28 mg/h/70 kg
• So in this patient the infusion or dosing rate would be 28 mg/h/70kg.
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41. Calculation:
Q: In above case If the asthma attack is relieved, the clinician might
want to maintain this plasma level using oral theophylline, which might
be given every 12 hours using an extended- release formulation to
approximate a continuous intravenous infusion. Its bioavailability is
0.96. When the dosing interval is 12 hours the size of each
maintenance dose would be ?
A: Maintenance dose = Dosing rate/Bioavailability x Dosing interval
= 28 mg/h/0.96 x 12 h
= 350 mg
if dosing interval is 8 hour = 28 mg/h/0.96 x 8 h =233 mg
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42. Calculation
Q: Target plasma concentration of theophylline to relieve acute
bronchial asthma is 10 mg/L. The loading dose for the theophylline for
a 70-kg person would be ? [ Volume of distribution is 35 L ]
A: Loading dose = V x TC
= 35 L × 10 mg/L
= 350 mg
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43. THERAPEUTIC DRUG MONITORING
• Measurement of plasma drug concentration can give an estimate of
the pharmacokinetic variables in that patient and the magnitude of
deviation from the ‘average patient’, so that appropriate adjustments
in the dosage regimen can be made.
In case of drugs obeying first order kinetics:
Revised dose rate = Previous dose rate × Target Cpss /Measured Cpss
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44. Use of TDM :
1. Drugs with low safety margin, e.g. —digoxin, anticonvulsants,
antiarrhythmics, theophylline, aminoglycoside antibiotics, lithium,
tricyclic antidepressants.
2. If individual PK variations are large, e.g.—antidepressants, lithium
3. Potentially toxic drugs used in the presence of renal failure, e.g. —
aminoglycoside, vancomycin.
4. In case of poisoning.
5. In case of failure of response without any apparent reason, e.g. —
antimicrobials.
6. To check patient compliance, e.g. —psychopharmacological agents.
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45. Calculation:
Q: The 84-kg patient given 0.125 mg digoxin every 24 hour. If the
measured minimum (trough) steady state concentration(Cpss) were
found to be 0.35 ng/mL rather than the predicted level of 0.7 ng/mL,
an appropriate, practical change in the dosage regimen would be ?
A: Revised dose rate = Previous dose rate × Target Cpss /Measured
Cpss
= 0.125 mg × 0.7 ng/mL/ 0.35 ng/mL
= 0.25 mg
So, to increase the daily dose by 0.125 mg to 0.25 mg digoxin daily.
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46. SUMMARY
• Volume of distribution (V) = Amount of drug in the body/C
• Clearance (CL) = Rate of elimination/C
• Elimination t½ = 0.693 x V/CL
• Dosing rate ss = Rate of elimination ss = CL x TC
• Loading dose = = V x TC
• Maintenance dose = Dosing rate x Dosing interval = CL x TC x Dosing
interval
• Revised dose rate = Previous dose rate × Target Cpss /Measured
Cpss
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47. References
• Bertram G Katzung, “Basic & clinical pharmacology”, 14th edition.
• Goodman and Gilman’s “The Pharmacological Basis of Therapeutics”,
14th edition.
• K. D. Tripathi, “Essentials of Medical Pharmacology,” 5th edition.
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