Individuals respond differently to the given drugs, some drugs may have no effect on one individual while it may work effectively in others.

1. INDIVIDUALIZATION OF DRUG
DOSAGE REGIMENS
Dr. S P Srinivas Nayak,
PharmD, RPh, MSc., (PGDND) (PhD)
Assistant Professor, Dept. of Pharmacy Practice, PU.
Dr S P NAYAK MED EASY

2. INTRODUCTION
• THERAPEUTIC DRUG MONITORING(TDM):
TDM is a process of measuring drug concentration in
plasma to optimise the therapy for the drugs having
relationship between the plasma drug concentration
and the desired clinical effect or between the plasma
drug concentration and an adverse effect i.e drugs
with a narrow therapeutic window (also known as
critical-dose drugs and narrow therapeutic index (NTI)
drugs), such as
digoxin, aminoglycosides, antiarrhythmics,
anticoagulants, anticonvulsants, and some
antiasthmatics, such as theophylline.

3. • Critical-dose drugs are defined as those drugs
where comparatively small differences in dose or
concentration lead to dose- and concentration-
dependent, serious therapeutic failures and/or
serious adverse drug reactions

4. • For those drugs in which plasma drug concentration
and clinical effect are not directly related, other
pharmacodynamic parameters may be monitored.
• For example, clotting time may be measured directly
in patients on warfarin anticoagulant therapy.
• Glucose concentrations are often monitored in
diabetic patients using insulin products.
• Asthmatic patients may use the bronchodilator,
albuterol taken by inhalation via a metered-dose
inhaler. For these patients, FEV1 (forced expiratory
volume) may be used as a measure of drug efficacy.
• In cancer chemotherapy, dose adjustment for
individual patients may depend more on the severity
of side effects and the patient’s ability to tolerate the
drug.

6. Example, therapeutic range for
theophylline is 10–20 μg/mL.
patients may exhibits various
effects at various drug plasma
levels:
• Mild symptoms of
toxicity included nausea,
vomiting, headache, and
insomnia.
• A potentially serious
effect was sinus
tachycardia.
• severe toxicity shows
life-threatening cardiac
arrhythmias and
seizures.

7. • Many drugs like NSAIDs - ibuprofen,
• CCBs - nifedipine, have a wide therapeutic
range and do not need therapeutic drug
monitoring
• OTC drugs such as various cough and cold
remedies, analgesics, and other products are
also generally safe when used as directed.

8. INDIVIDUALIZATION OF
DRUG DOSAGE REGIMENS
Individuals respond differently to the given
drugs, some drugs may have no effect on one
individual while it may work effectively in
others.
For patients who needs less dose, instead of
using wide therapeutic range, the dosage can
be selected based on each patients individual
need with a low incidence of ADRs

9. VARIABILITY
• Because of interpatient variability in drug
absorption, distribution, and elimination as
well as changing pathophysiologic conditions
in the patient, therapeutic drug monitoring
(TDM) or clinical pharmacokinetic (laboratory)
services (CPKS) have been established in many
hospitals to evaluate the response of the
patient to the recommended dosage regimen.

11. AGE (CHILDREN)
New born have low GFR & tubular transport is not
matured. Similarly, hepatic drug metabolizing
system is inadequate in new born.
BBB is more permeable, hence drugs attain higher
concentration in CNS.
Drug absorption may also be altered in infants
because of lower gastric acidity & slower intestinal
transit.
As skin is thin, transdermal absorption of drugs is
faster & is more permeable.
At one year, drug metabolism is faster than in adults
Ex. Theophylline, Phenytoin, CBZ hence higher dose
may be required.

12. The dose of a drug for children is often
calculated from adult dose
Young’s formula child dose = age/age+12 X AD
Dilling’s formula child dose=age/20 X AD
Clerk’s rule: wt in pounds/150 X AD
Fried’s rule: age in months/150 X AD

13. AGE
As the age progresses, the renal functions are progressively
declines
Decline in liver blood flow & reduction in hepatic microsomal
enzymes results in drug accumulation
Slow absorption due to reduced intestinal motility &
decreased blood flow, decreased plasma protein binding
due to low plasma albumin
Increased chances of drug interactions as a result of
polypharmacy

14. DISEASE
GI disease:
Alter absorption of orally administered drugs
Decreased absorption of amoxycillin in coeliac disease
Decreased absorption in achlorhydria.
Liver disease:
Bioavailability of drugs which have high first pass metabolism is
increased
Decreased serum albumin decreased protein binding of acidic
drugs increased free form of drugs
Decreased metabolism & elimination hence reduce the dose
Prefer alternate drugs that do not depend on hepatic
metabolism for elimination or those have short half-life
Ex. Consider oxazepam or lorazepam instead of diazepam
Avoid prodrugs as they need hepatic metabolism for activation

15. Kidney disease: Clearence of drugs such as
aminoglycosides, digoxin, phenobarbitone
decreases
Altered structure of plasma protein (albumin) in
renal failure results in decreased binding of acidic
drugs
Throid disease:
Hypothyroid patients are more sensitive to digoxin,
morphine & CNS depressants
Hyperthyroid patients are relatively resistant to
inotropic action but more prone to arrhythmic
action of digoxin

16. Body weight:
Influences the concentration of drug at the site
of action
An adult dose refers to an individual of medium
built Hence for obese or lean individuals & for
children the dose must be calculated based on
body weight
Individual dose = BW x Avg.adult dose/70
BSA provides accurate basis for dose calculations
because total body water, ECF volume &
metabolic activity are better paralleled by BSA
Individual dose = BSA X Avg. Adult dose / 1.7

17. Drug interactions:
Pharmacokinetic
Absorbtion
Distribution
Metabolism
Excretion
pharmacodynamic

18. ABSORBTION DRUG INTERACTIONS
INHIBITION OF DRUG ABSORPTION
• Various drugs and dietary supplements can decrease the
absorption of drugs from the GIT. Antacids containing magnesium
and aluminum hydroxide often interfere with absorption of many
drugs. Coadministration of magnesium and aluminum hydroxide
caused a decrease of plasma levels of PERFLOXACIN,
TETRACYCLINS, DIGOXIN, THYROXIN etc.
• These drugs should be given at least 2 hours before the antacid to
ensure sufficient therapeutic efficacy
• Sucralfate used for ulcer, is an aluminum glycopyranoside complex
that is not absorbed but retards the oral absorption of
ciprofloxacin.. Cholestyramine is an anion-exchange resin that
binds bile acid and many drugs in the gastrointestinal tract.
Cholestyramine can bind digitoxin in the GI tract and shorten the
elimination half-life of digitoxin by approximately 30%–40%.
Absorption of thyroxine may be reduced by 50% when it is
administered closely with cholestyramine.

22. • Nonhepatic enzymes can be involved in drug interactions.
For example, drug interactions have been reported for
patients taking linezolid (Zyvox) who are concurrently
taking certain psychiatric medications.
• Linezolid is a reversible monoamine oxidase inhibitor
(MAOI). Serotonergic psychiatric antidepressant drugs such
as citalopram, paroxetine, fluoxetine, sertraline, and other
drugs that affect the serotonergic pathway in the brain.
MAOIs, such as phenelzine and isocarboxazid, are also
contraindicated., linezolid inhibits the action of monoamine
oxidase A responsible for breaking down serotonin in the
brain. It is believed that when linezolid is given to patients
taking serotonergic psychiatric medications, high levels of
serotonin can build up in the brain, causing toxicity. This is
referred to as serotonin syndrome. Its signs and symptoms
include mental changes (confusion, hyperactivity, memory
problems), muscle twitching,

23. Grapefruit–Drug Interactions
• grapefruit juice, can significantly inhibit the
metabolism by gut-wall cytochrome P-450 3A4
(CYP3A4)
• For example, grapefruit juice increases average
felodipine levels about threefold, increases
cyclosporine levels, and increases the levels of
terfenadine, a common antihistamine. In the case of
terfenadine, Spence (1997) reported the death of a 29-
year-old man who had been taking terfenadine and
drinking grapefruit juice 2–3 times per week. Death
was attributed to terfenadine toxicity.
• Grapefruit juice can also affect P-gp-mediated efflux of
some drugs.

24. ALTERED RENAL REABSORPTION DUE
TO CHANGING URINARY pH
• The normal adult urinary pH ranges from 4.8 to
7.5 but can increase due to chronic antacid use.
This change in urinary pH affects the ionization
and reabsorption of weak electrolyte drugs.
• An increased ionization of salicylate due to an
increase in urine pH reduces salicylate
reabsorption in the renal tubule, resulting in
increased renal excretion.
• Basic drugs tend to have longer half-lives when
urinary pH is increased.

26. Genetics:
Genetic differences determine the disposition of
a given drug in an individual
Drug disposition is determined by rate kinetics
of ADME, hence genetic differences
determining various physiological processes
affect the plasma levels of drugs eventually
determining the differences in drug response
by an individual

27. CytP 450 major enz system involved with
metabolism of all xenobiotics.
The metabolic capacity of this enz system is not
equal in all members of a population
Hence we observe a wide inter individual
variations in the rates of metabolism of some
drugs

28. Pantoprazole/omeprazole metabolises in liver
via cyt CYP2C19 & CYP3A48
Antidepressants paroxetine & fluoxatine
extensively metabolised via cyt CYP2D6
Glimipride via cyt CYP2C9
Cyt p typically show large inter individual
differences in activity that lead to differences
in drug response

29. Hence metabolism & excretion of drugs vary
between individuals
3% of caucasians & 15% asians are poor
metabolizers
12% of north indians are poor metabolizers
(pantoprazole)
Collectively several hundred genes & their alleles &
protein products determine the overall drug
disposition in an individual

30. In pharmacogenomics, attempts are made to
determine & quantify these genetic variations &
use them in predicting drug disposition by an
individual
Genotyping techniques for cyt p 450 enz can be
used to predict one’s disposition to a given class
of drugs without doing any evaluation of PK
parameters
Which can be used for deciding choice of drug & its
dose

31. Based on genotyping methods individuals may be
classified as poor , intermediate, extensive & ultra
rapid metabolizers for a group of given drugs
Poor metabolizers will develop higher SDC in comparison
with extensive metabolizers, hence they are at
increased risk of developing concentration dependent
ADRs
Ultra rapid metabolizers will not reach therapeutic SDC
upon treatment with standard doses, hence fail to
respond to treatment

32. If the parent compound is a prodrug, which
requires bio activation by the enz to a active
form, the effect of polymorphism can be quite
complex in poor metabolizers and ultra rapid
metabolizers
Hence these individuals differences in drug
disposition could be compensated by dosage
adjustment according to metabolic capacity,
determination of drug metabolism genotypes

33. • Poor metabolizers and ultra rapid
metabolizers can be identified & dosage could
be tailored to the individual patient in order to
reach therapeutic levels of drug in plasma,
which may help to avoid ADRs or therapeutic
failures

34. Atypical pseudocholinesterase – prolonged
succinylcholine apneoa
G6PD deficiency- hemolysis with primaquine,
sulfonamides, dapsone, quinine, chloroquine etc
Acetylator polymorphism-INH neuropathy, procainamide
& hydralazine induced lupus in slow acetylators
Acute intermittent porphyria- precipitated by
barbiturates due to genetic defects in repression of
porphyrin synthesis

35. THANK YOU