Clinical pharmacokinetics

Pharmacokinetics
• Pharmacokinetics is the study of the time course
of the drug concentration in the body, i.e.,
"what the body does to the drug".

• Parameters calculated from those measures,

such as clearance, half-life, and volume of
distribution

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 Pharmacokinetics…
• Reflect the absorption (A), distribution (D), and
elimination (E) of a drug from the body.
• ADME/ADE

• A proper understanding of these parameters is

required to design an appropriate drug
regimen for a patient,
– Effectiveness is determined by the conc. of the
drug in the body.
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 Pharmacokinetics…
• Ideally the concentration of the drug should be
measured at the site of action of the drug; that
is, at the receptor.
– Possible?
• Inaccessible!
• The drug concentrations are measured in the
whole blood, plasma, urine, saliva, and CSF
and considered as at equilibrium to the site
of action.
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 Applications of Pharmacokinetics

• The bioavailability of a dosage form is

calculated by pharmacokinetic equations.
• The frequency of dosing is calculated from PK
equations.

• To calculate the dose of a controlled release

dosage form pharmacokinetic equations are
required.

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 Applications of PK…
• In case of patients with kidney failure the dose
of a drug should be calculated very cautiously.
– If the rate of absorption of the drug is
greater than the elimination rate
• drug accumulation
– The rate of elimination of the drug from the
body of that patient is calculated with the
help of pharmacokinetic equations.

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 Applications of PK…
• When a potent anticancer drug is administered
to a patient the plasma concentration of the
drug must be very close to MEC.
– Since the therapeutic index of the drug is
very narrow in case of potent drugs so rate
of administration must also be very slow.
– This rate of administration is calculated by
pharmacokinetic principles.

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 Applications of PK…
• Clinical PK is the discipline that describes the
ADME of drugs in patients requiring drug
therapy.

• Clinical PK deals with the application of

pharmacokinetic principles to the safe and
effective therapeutic management of drug
dosage in an individual patient.

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 Time course of a drug in the body
• Drug Administration
• Drug Absorption
• Drug Distribution
• Drug Metabolism
• Drug Excretion

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• Absorption
– When a drug is administered extravascularly to
patients, it must be absorbed across biologic
membranes to reach the systemic circulation.

– If the drug is given orally, the drug molecules must

pass through the gastrointestinal tract wall into
capillaries.

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• Absorption…
– For transdermal patches, the drug must penetrate the
skin to enter the vascular system.
– In general, the pharmacologic effect of the drug is
delayed when it is given extravascularly because time
is required for the drug to be absorbed into the
vascular system.
– The vascular system generally provides the
“transportation” for the drug molecule to its site of
activity.

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Distribution
– After the drug reaches the systemic circulation, it
can leave the vasculature and penetrate the
various tissues or remain in the blood.
– If the drug remains in the blood, it may bind to
endogenous proteins such as albumin or α1-acid
glycoprotein.
– This binding usually is reversible, and an
equilibrium is created between protein-bound drug
and unbound drug.
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• Distribution…
– Unbound drug in the blood provides the driving
force for distribution of the agent to body tissues.
– If unbound drug leaves the bloodstream and
distributes to tissue,
• it may become tissue-bound, and/or it may remain
unbound in the tissue, or
• if the tissue can metabolize or eliminate the drug, it
may be rendered inactive and/or eliminated from the
body.
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• Metabolism
– Certain organs—such as the liver, gastrointestinal
tract wall, and lung—possess enzymes that
metabolize drugs.
– The resulting metabolite may be inactive or have a
pharmacologic effect of its own.
– The blood also contains esterases, which cleave
ester bonds in drug molecules and generally
render them inactive.

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• Metabolism…
– Drug metabolism usually occurs in the liver through
one or both of two types of reactions.
– Phase I reactions generally make the drug molecule
more polar and water soluble so that it is prone to
elimination by the kidney.
– Phase I modifications include oxidation, hydrolysis,
and reduction.

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• Metabolism…
– Phase II reactions involve conjugation to form
glucuronides, acetates, or sulfates.

– These reactions generally inactivate the

pharmacologic activity of the drug and may make
it more prone to elimination by the kidney.

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• Excretion
– Other organs have the ability to eliminate drugs or
metabolites from the body.
– The kidney can excrete drugs by glomerular
filtration or by such active processes as proximal
tubular secretion.
– Drugs also can be eliminated via bile produced by
the liver or air expired by the lungs.

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 Linear Vs Non-linear PK
• When drugs are given on a constant basis, such as a
continuous intravenous infusion or an oral medication
given every 12 hours,
– serum drug concentrations increase until the rate of drug
administration equals the rate of drug metabolism and
excretion.
• At that point, serum drug concentrations become
constant during a continuous intravenous infusion or
exhibit a repeating pattern over each dosage
interval for medications given at a scheduled time.
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• For example, if theophylline is given as a continuous
infusion at a rate of 50mg/h, theophylline serum
concentrations will increase until the removal of
theophylline via hepatic metabolism and renal
excretion equals 50 mg/h.

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• If cyclosporine is given orally at a dose of 300 mg every
12 hours, cyclosporine blood concentrations will follow a
repeating pattern over the dosage interval which will
increase after a dose is given (due to drug absorption
from the GIT) and decrease after absorption is complete.
• This repeating pattern continues and eventually drug
concentrations for each dosage interval become super
imposable
– when the amount of cyclosporine absorbed into the body from
the GIT equals the amount removed by hepatic metabolism
over each dosage interval.
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• Regardless of the mode of drug administration, when
the rate of drug administration equals the rate of
drug removal, the amount of drug contained in the
body reaches a constant value.

• This equilibrium condition is known as steady state and

is extremely important in clinical pharmacokinetics
because usually steady-state serum or blood
concentrations are used to assess patient response.

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• When medications are given on a
continuous basis, serum conc increase
until the rate of drug administration
equals the elimination rate.
• In this case, the solid line shows
serum concentrations in a patient
receiving intravenous theophylline at
a rate of 50 mg/h and oral
theophylline 300 mg every 6 hours
(dashed line).
• Since the oral dosing rate (dose/
interval = 300 mg/6 h = 50 mg/h)
equals the IV infusion rate, the drug
accumulation patterns are similar

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• If a patient is administered several different doses until
steady state is established, and steady-state serum
concentrations are obtained from the patient after each
dosage level, it is possible to determine a pattern of
drug accumulation.
• If a plot of steady state concentration versus dose yields
a straight line, the drug is said to follow linear PK.
• In this situation, steady-state serum concentrations
increase or decrease proportionally with dose.

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• Therefore, if a patient has a steady-state drug
concentration of 10 μg/mL at a dosage rate of 100
mg/h, the steady-state serum concentration will
increase to 15 μg/mL if the dosage rate is increased
to 150 mg/h (e.g., a 50% increase in dose yields a
50% increase in steady-state concentration).

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 Linear pharmacokinetics
• Pharmacokinetic parameters:
– elimination half life, the apparent volume of
distribution and the systemic clearance of most
drugs are not expected to change when different
doses are administered and/or when the drug is
administered via different routes as a single or
multiple doses.

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• The kinetics of such drugs is described as linear, or
dose independent pharmacokinetics and is
characterized by first order process.

• The plasma concentration at a given time at a steady

state and the AUC will both be directly proportional
to the dose administered.

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 Non-linear pharmacokinetics
– While most drugs follow linear pharmacokinetics, in
some cases drug concentrations do not change
proportionally with dose.

– When steady-state concentrations change in a

disproportionate fashion after the dose is altered, a
plot of steady-state concentration versus dose is not
a straight line and the drug is said to follow
nonlinear pharmacokinetics.

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• When steady-state concentrations increase more than
expected after a dosage increase, the most likely
explanation is that the processes removing the drug
from the body have become saturated.
– This phenomenon is known as saturable or Michaelis-
Menten pharmacokinetics.

• When steady-state concentrations increase less than

expected after a dosage increase, there are two
typical explanations.
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– Some drugs, such as valproic acid and
disopyramide saturate plasma protein binding sites
so that as the dosage is increased steady-state
serum concentrations increase less than expected.

– Other drugs, such as carbamazepine, increase their

own rate of metabolism from the body as dose is
increased so steady-state serum concentrations
increase less than anticipated.
• This process is known as autoinduction of drug
metabolism.
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• When doses are increased for most
drugs, steady-state conc increase in a
proportional fashion leading to linear
pharmacokinetics (solid line).

• When steady-state concentrations

increase more than expected after a
dosage increase (upper dashed line),
Michaelis-Menten pharmacokinetics may
be taking place.
• If steady-state concentrations decrease
than expected after a dosage increase
(lower dashed line), saturable PPB
/autoinduction

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• This dramatic increase in the concentration (greater than
directly proportional) is attributed to the non-linear
kinetics of drugs.
– For example, phenytoin.
• For drugs that exhibit non-linear or dose dependent
pharmacokinetics, the fundamental pk parameters, such
as clearance, Vd and elimination half life may vary
depending on the dose administered.
• This is because one or more of the kinetic processes of
the drug may be occurring via a mechanism other than
simple first order kinetics (mixed order kinetics).
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 Bioavailability and Bioequivalences

– When drugs are administered extravascularly, drug

molecules must be released from the dosage form
(dissolution) and pass through several biologic barriers
before reaching the vascular system (absorption).

– The fraction of drug absorbed into the systemic

circulation (F) after extravascular administration is
defined as its bioavailability and can be calculated
after single intravenous and extravascular doses as:

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– where D and Div are the extravascular and intravenous
doses, respectively, and AUCiv,0-∞ and AUC0-∞ are the
intravenous and extravascular areas under the serum- or
blood-concentration-versus-time curves, respectively, from
time zero to infinity.
– The AUC represents the body’s total exposure to the drug
and
• is a function of the fraction of the drug dose that enters
the systemic circulation via the administered route and
clearance (AUC = Dose/CL).

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• When F is less than 1 for a drug administered
extravascularly,
– Either the dosage form did not release all the
drug contained in it, or
– Some of the drug was eliminated or destroyed
(by stomach acid or other means) before it
reached the systemic circulation.

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 Clearance
• Is the volume of serum or blood completely cleared of
the drug per unit time.
• Clearance (CL) is the most important PK parameter
because it determines the steady-state concentration
for a given dosage rate.
• When a drug is given at a continuous IV infusion rate
equal to k0, the steady-state concentration (Css) is
determined by the quotient of k0 and CL:

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• If the drug is administered as individual doses (D) at a
given dosage interval (τ), the average steady-state
concentration (Css) over the dosage interval is given by
the equation:

• where F is the fraction of dose absorbed into the systemic

vascular system.
– Clearance determines the maintenance dose (MD) that is
required to obtain a given Css:
MD = Css ⋅ CL.
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 Volume of distribution
– The volume of distribution (Vd) is a proportionality
constant that relates the amount of drug in the
body to the serum concentration.
• Vd = amount in the body/plasma concentration

• Vd is used to calculate the loading dose (LD) of a drug

that will immediately achieve a desired Css

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– However, in practice, the patient’s own Vd is not
known at the time the loading dose is administered.

– In this case, an average Vd is assumed and used to

calculate a loading dose.

– Because the patient’s Vd is almost always different

from the average Vd for the drug, a loading dose
does not attain the calculated Css, but it hopefully
achieves a therapeutic concentration.
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 Half-life
• Half-life (t1/2) is the time required for serum
concentrations to decrease by one-half after
absorption and distribution are complete.
– Half-life is important because it determines the
time required to reach steady state and the
dosage interval.
– It takes approximately five to seven half-lives to
reach steady-state concentrations during continuous
dosing.

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• Half-life is a dependent kinetic variable because its
value depends on the values of CL and Vd.
• The equation that describes the relationship among
the three variables is

Kel= CL/Vd

– NB:
• Changes in t1/2 can result from a change in either Vd or CL;
• a change in t1/2 does not necessarily indicate that CL has
changed.
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• Half-life can change solely because of changes in Vd.
• The elimination rate constant (Kel) is related to the
half-life by the following equation:

– Both the half-life and elimination rate constant describe how

quickly serum concentrations decrease in the serum or blood.

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 Examples
• A patient with liver failure and a patient with heart
failure need to be treated with a new antiarrhythmic
drug. You find a research study that contains the
following information for patients similar to the ones
you need to treat:
– normal subjects: Cl= 45 L/h, Vd = 175 L;
– liver failure: Cl = 15 L/h Vd= 300 L;
– heart failure: Cl = 30 L/h, Vd = 100 L.

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• Recommend an intravenous loading dose (LD) and
continuous intravenous infusion maintenance dose (MD)
to achieve a steady-state concentration of 10 mg/L
for your two patients based on this data and estimate
the time it will take to achieve steady-state conditions.

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