APPLICATION OF

PHARMACOKINETIC AND
BIOAVAILIBILTY IN CLINICAL
SITUATIONS
SUBJECT: BIOPHARMACEAUTICS
4TH YEAR EVENING
JINNAH UNIVERSITY FOR WOMEN
GROUP 11
MEMBERS: MEMBERS: AREEBA, AYESHA, IQRA,
NIDA, OMAMA, SAFIA, SHEEMA, USRA &
ZAHIDA.
ACKNOWLEDGED BY MISS ASMA MONAZZAM.
 PHARMACOKINETICS
Pharmacokinetics is the movement of the drug
particles inside the body.
Absorption is the movement of the drug from
the site of administration into the bloodstream.
Distribution is the movement of the drug into
the cells.
Metabolism is the conversion of the drug into
another substance or substances.
Excretion is the removal of the drug
of drugs in an individual patient.
 BIOAVAILIBILITY

The rate and extent of absorption of

unchanged drug from its dosage form.
In other words,
Fraction of administered dose that actually
reach systemic circulation.
 MEDICATION THERAPY
MANAGEMENT
Medication Therapy Management is medical
care provided by pharmacists whose aim is,
to optimize drug therapy and improve
therapeutic outcomes for patients. enhance
communication between patients and their
health care team; and optimizes medication use
for enhanced patient outcomes.
 Individualization of drug dosage
regimens:

It means designing of dosage regimen based on

individuals PK charactertics.
All drugs dont require individualization of dosage
regime
For drugs, have large margin of safety i.e. having
exhibit a wide therapeutic window dont require
individualization of dose.
 Continue..
Individualization of dosage regimen are important
for drugs with a narrow therapeutic drugs such as
digoxin, aminoglycosides etc
Objective of the individualization of dosage
regimen design
produce a safe plasma drug concentration.
 Therapeutic drug monitoring
TDM refers to the individualization of dosage by
maintaining plasma or blood drug concentration
within a target range (therapeutic range).
Goal of TDM is to achieve a desired beneficial
effect with minimal adverse effects.
Therapeutic monitoring of plasma drug
concentration is valuable only if a relationship
exists between the plasma drug concentration
and desire clinical effect or between the plasma
drug concentration and adverse effect.
 Continue..
E.g.
1. clotting time may be measured in patients
directly, on warfarin anticoagulant therapy.
2. Glucose concentration are often monitored in
diabetic patients using insulin products.
Major indications for TDM can be
summarized as Low therapeutic index,
Therapeutic failure, Prevention of adverse effects of
life time drugs.
 DOSAGE REGIMEN DESIGNING
For the purpose of dosage Regimen Designing several
methods are use. Generally initial drug dosage is
calculated busing y pharmacokinetic parameters of
average population obtained from literature
.
Then by physical observation monitoring of patient done
for therapeutic response some times drug serum level
measure.

Once patient evaluated dosage Regimens adjusted by

using patent pharmacokinetic parameters and future
therapeutic drug monitoring done.

For dose calculation of drug many software are available

for narrow therapeutic index drugs For example [ASHSP].
Dosage designing is based on pharmacokinetic principals
of drugs.
 By use of computer software and accuracy of
calculation improved less chance of errors and
proper maintenance of record.
Calculation of dose based on pharmacokinetic of
drug is most accurate approach for designing of
dosage Regimen.
DOSAGE REGIMEN BASED ON
POPULATION AVERAGE:
In this method pharmacokinetic parameter
obtained from research that had published in
literature. This method is based on fix of adaptive
model.
I n fix model we assume that average
pharmacokinetic parameter directly use for dose
Regimen without any change.

Adaptive model use patient variables for

dosage design like weight, age, sex, BSA, etc. In
this model also assume some pharmacokinetic
parameter like drug clearance not change from
dose to next dose.
 PARTIAL PHARMACOKINETIC
PARAMETER FOR DESIGNING
DOSAGE REGIMEN:
For some drug complete profile of drug is unknown so
assumptions are made for dose calculations. E.g. we
assume bioavailability factor F=1 or 100 but if drug not
fully absorbed.

The patient will be under medicated. Some

assumptions are based on safety and efficacy of drug
use.
 DOSAGE REGIMEN DESIGNING
EMPERICALLY:
In this physician choose a dosage Regimen
without using pharmacokinetic variables.

In this condition physician use empirical clinical

data for making decisions.
 CONVERSION FROM IV ROUTE TO
ORAL DOSING:
Once the patient condition is controlled by IV
ROUTE medication go to Oral route to continue the
medication of the patient when IV infusion stopped.

Serum concentration level go to down following 1st

Oder elimination kinetics. In oral Dosing time for
achieving steady state depend on rate constant of
elimination of drug.

When go from IV to Oral controlled release oral

drug give once or twice daily is common.
 DOSE DETERMINATION:
Dose of a drug is estimated to achieve desirable
therapeutic level of drug in body .

Most of drugs have desirable drug dose and

pharmacokinetic available in literature but in some
condition complete information not found in literature so
some necessary assumptions are made in accordance
with information available.

If the drug is given in multiple dose for long period of

time. Dosage Regimen calculation is necessary for
average steady state
EFFECT OF CHANGING DOSE ON CMax,
Cmin, AND Cav
EFFECT OF CHANGING DOSING INTERVAL ON
CMax, Cmin, AND Cav
 DETERMINATION OF DRUG
ADMINISTRATION FREQUENCY:
Drug dose is related to the frequency of drug
administration, if the drug administered more frequently
smaller the dose is needed to obtain the same Cav.

Though, as longer the dosing interval, larger the dose

required to maintain the steady state concentration the
dosing intervals get longer.

When chosen an very long dosing interval peak

plasma level may result due to the larger dose that are
toxic drug concentration and trough plasma
concentration both are below the minimum effective
concentration , even while Cavy will remain the same.
 When chosen an very long dosing interval peak plasma
level may result due to the larger dose that are toxic drug
concentration and trough plasma concentration both are
below the minimum effective concentration , even while
Cav will remain the same.

Dosing interval of most of the drug is determined through

elimination half life for e.g. penicillin have low toxicity, may
be its interval become longer than elimination half life
without any problem related to toxicity.

A narrow therapeutic drug such as digoxin , to overcome

its peak and trough fluctuations in the level of blood for
example the digoxin . Therefore a drug having a large
margin of safety or large therapeutic index drug given in
large doses and having a long dosing interval.
 DOSE REGIMEN AND DOSE AND
DOSE INTERVAL DETERMINATION:

On the design of dosing regimen, choice of drug and

drug product can lead to the success of drug therapy.

At receptor site a particular concentration of drug is

achieved by properly design of the dose regimen to give
maximum therapeutic response with minimum adverse
effect .

But difficulty occur due to variation in

pharmacokinetics from individual to individual therefore
proper clinical evaluation required during dosage
regimen.
 Appropriate dosage regimen design to
provide a drug dose and interval to get a
target drug concentration at the site of
action.

Dosage regimen do not require for the

drug having a large therapeutic index

While it is very important for the narrow

therapeutic index drug like digoxin to
achieve the effective plasma concentration
have not exceed to minimum toxic
concentration
 PURPOSE OF ROUTE OF
ADMINISTRATION:

In drug therapy it is very important to select the proper

route of administration.

The absorption of drug and its duration of activity are

influenced by the route of administration of drug.

Drug are applied topically or administered systemically

but the most convenient and acceptable route is oral route
they are design to dissolve the drug in lumen for e.g.intra-
arterial route of administration and intra-athecal route of
administration are not must safe as other route of
administration.
 Those drugs which are unstable in the GIT like
protein and other drug which are passing through
first pass effect are not suitable to given through
oral route.

For example degradation of insulin in GIT by the

enzyme known as proteolytic enzyme because
insulin is protein in nature. While nitroglycerine has
high first pass effect cannot administer through oral
administration.

Drugs that are administered through the IV route

are directly reached to systemic circulation. It is
convenient for the drug having a short half life.
 Through this route drug is administered into the
circulatory system in a very fastest way.
Elimination can also occur immediately if IV bolus
is administered.
But these drug cannot administer through
intramuscular route because it can local irritation
and pain at the sight of injection

But the absorption through this route is also fast

and injected to prolong the drug action but the rate
of drug absorption will affect due to the anatomic
site of drug de position .
Slower absorption may occur at the site of
injection due to the precipitation of an insoluble
drug therefore, to achieve proper drug therapy a
particular route should be selected.
 DOSING OF DRUGS IN
NEONATES, INFANTS AND
CHILDREN:
Neonates, Infants and children require different
dosages than that of adults because of differences
in the body surface area.

Dose for such patients are calculated on the

basis of their body surface area not on body
weight basis.

The surface area in such patients are calculated

by Mostellers equation.
SA (in m2) = (Height x Weight) 1/2 /60

Infants and children require larger mg/kg doses

than adults because: Their body surface area
per kg body weight is larger and hence Larger
volume of distribution
 DOSING OF OBESE PATIENT:-

Obesity is a big problem in all over the world .In obesity

increases mortality resulting increase the risk of
hypertension. Coronary artery disease, and diabetes.

Athletes patient are obese because have greater body

weight due to greater muscle mass. .obesity is defined by
body mass index (BMI).

BMI is measure as body weight( Kg).If patient ( BMI ) is

high then 30 so accumulation of fats occur in body
 DOSING OF DRUG IN ELDERLY
PATIENT:-

Drug dose should be reduced in elderly patients

because of general decline in body function with
age.

Age related changes in renal and hepatic

functions greatly alters the clearance of drugs.
 PHARMACOKINETICS OF DRUGS
INTERACTION

Usually the interaction of different kinds of drugs

cause when there is an administration of more than
one drug by the patient with no changes in time
means the patient is taking two or more drugs at
once. The administration of several drugs at once is a
common issue in our surroundings .

A variety of dietary and disease conditions can

influence the enormity of these connections of drugs
with each others . Drug interactions influencing
pharmacokinetics can have pharmacodynamics
consequences, in such a way by increasing or
decreasing the efficiency of the drug. It can also
increase the chances of toxicity in the body.
These interactions also affected by the genetics and
the disease state if the patient .

Drug interactions can influence drug incorporation by

disturbing the suspension of the medicine in the
gastrointestinal tract by affecting the emptying of the
stomach or intestinal blood flow, or by reserve of
active transport and passive transport processes.

Numerous medicinal interactions influencing the

absorption of paracetamol can provide as illustrations
of medicinal relations as of influence on gastric
emptying rate.
 The medicine of ulcer propantheline decreases the rate of
paracetamols absorption but has no effect on the amount of
incorporation The medicine of heartburn metoclopramide
enhances the rate of incorporation of paracetamol.

More than one drug that are two or more medicines can
contend with one another for the same protein- binding site,
which can cause dislocation of the medicine with the inferior
attraction from the required site of the protein. drug interaction
can leads to allosteric or non competitive interaction as a
medicine -induced conformational change in the requisite site
which can cause the disarticulation of the medicine which is in
the bound form
 DRUG METABOLISM INDUCTION:

Cytochrome P-450 iso enzymes are often involved in the

metabolic oxidation of many drugs. Many drugs can
simulate the production of hepatic enzymes.

Therapeutic doses of Phenobarbital and other

barbiturates accelerate the metabolism of coumarin
anticoagulant such as warfarin and substantially reduce
the hypoprothrombinemic effect.

Fetal hemorrhagic episodes can result when

Phenobarbital is withdrawn and warfarin dosage maintain
at previous level. Other drugs known to induce drug
metabolism include carbamazipine, rifampin, valporic acid
and phenytoin.
 Enzymatic stimulation can shorten the elimination half life
of the affected drug. For example Phenobarbital can result
in lower levels of dexamethasone in asthmatic patients
taking both drugs.

St. john wort a herbal supplement also induce

cytochrome P-450 iso enzyme and is known to reduce
plasma drug concentrations of digoxin , indinavir and other
drugs .

FOR EXAMPLE:
Mechanism of anti coagulant , anti depressant ,
corticosteroids can induce by phenobarbitone therefore the
efficacy of these drug is reduced therefore its effect the
drug kinetics.
INHIBITION OF DRUG ABSORPTION
Various drugs and dietary supplements can
decrease the gastrointestinal tract. Antacids containing
magnesium and aluminum hydroxide often with
absorption of many drugs.

Co administration magnesium and aluminum

hydroxide cause decrease of plasma levels of
perfloxacin.

The drug interaction is caused by the formation of

chelate complexes and is possibly due to absorption
of the quinolone to aluminum hydroxide gel. Perffloxin
should be given at least 2 hours before the antacid to
ensure suffient therapeutic efficacy.
FOR EXAMPLE :

The metabolism of drug phenytoin can inhibit by

isoniazid due to the same metabolic enzyme like
inhibitor of xanthine oxidase and MAO can directly
inhibit the enzyme activity.
INHIBITION OF BILIARY EXCRETION:

The interaction between digoxin and verapamil was

studies in six patients with chronic atrial fibrillation the
effects of adding verapamil on steady-state plasma
concentration s of digoxin were studied.

Verapamil induced increase in steady-state plasma

concentrations of digoxin. The biliary clearance of
digoxin was determined by a duodenal perfusion
technique.
For example:
Urinary and biliary of digoxin are mediated by p-gp
while qunidine is inhibitor of p-gp result in interaction
occur and biliary excretion decrease .
 1.EFFECT OF FOOD ON DRUG
DISPOSITION
Food components can promote or retard the disposition
of drugs.

The extent of foods effect on the absorption or

metabolism of drugs depends on the characteristics of
the food,

When the food is consumed, whether fluids are taken

with the food, and on the characteristics of the individual
consuming the food .
 A. GRAPEFRUIT DRUG
INTERACTION

Grapefruit juice increases the oral bioavailability of

felodipine.

Flavanoids present in the form of glycoside in

grapefruit juice.

After ingestion, by the action of intestinal flora

,these are converted into aglycones and sugars,
these compounds inhibit the CYP enzyme .
 B. DIET-THEOPHYLLINE
INTERACTIONS

A protein rich diet will increase theophylline

clearance.

Average theophylline half lives in subjects on a low

carbohydrate, high protein diet increased from 5.2 to
7.5 hours

When subjects were changed to a high-carbohydrate

,low-protein diet.
 POPULATION
PHARMACOKINETICS

In the diagnosis of disease ,the physician may

make a preliminary diagnosis based on symptoms
and physical examinations.

Later the laboratory test are received .

The clinician then make a new diagnostic procedure
on both sets of information.
Bayesian theory provides a method to weigh the
prior information and new information to estimate a
new probability for predicting the disease.
3.REGIONAL PHARMACOKINETICS

Regional pharmacokinetics is based on the

study of the factors influencing drug
concentrations in specific regions (tissues, organs)
of the body

Due to the movement of drug from blood into

and out of the region (drug uptake and elution,
respectively).