Individualization of dosage regime

INDIVIDUALIZATION OF
DRUG DOSAGE REGIMEN
Swarna Priya B
STUDENT
DEPARTMENT OF PHARMACY PRACTICE
JAYA COLLEGE OF PHARMACY, CHENNAI

INTRODUCTION
 ALL HUMANS ARE ALIKE - True only as a Species
 Differences exist - including their responsiveness to drugs
 Therefore, there is a frequent need to tailor drug administration to the individual
patient
 A failure to do so lead to ineffective therapy in some patients and toxicity in others
 Therefore, the main challenge in designing a ‘standard’ drug dosage regimen is the
variability in drug handling that exists from patient to patient

INTRODUCTION
 Understanding the sources of this variability and adjusting drug doses accordingly is
an area in which pharmacists can make a major impact on risk management and
patient care
 Average data are useful as a guide; but ultimately, information pertaining to the
individual patient is all-important – interindividual variability
 Intraindividual variability is generally much smaller than interindividual variability
 There are three main sources of variability in pharmacokinetics of drugs and
consequently patient’s response to drugs

STEPS INVOLVED IN INDIVIDUALIZATION OF DOSAGE REGIMEN
Based on the assumption that all patients require the same plasma conc. range for
therapeutic effectiveness, the steps involved in the individualization of dosage
regimen are :
1. Estimation of Pharmacokinetic Parameters in individual patients and to
evaluate the degree of Variability.
2. Attributing the Variability to some measurable characteristics such as
hepatic or renal diseases, Age, weight etc.
3. Designing the new dosage regimen from the collected data.
The design of new dosage regimen involves –
1. Adjustment of dosage or
2. Adjustment of dosing interval or
3. Adjustment of both dosage and dosing interval.

BIOLOGICAL FACTORS
1. Age:
 The factors that affect drug absorption, including gastric pH, gastric emptying,
intestinal motility, and blood flow change with age
 Thus, in the neonate a condition of achlorhydria persists for the first week of life,
and only after 3 years of age gastric acid secretion approaches the adult value
 Gastric emptying is also prolonged and peristalsis is irregular during the early
months of life

These changes tend to be less apparent in the elderly than in the very young
 Children often appear to absorb drugs as completely and, if anything, more rapidly
than adults
 Accordingly, in subsequent calculations of dosage, extent of absorption is assumed
not to vary with age
 A major exception is for some first-pass drugs given to the elderly, where oral
bioavailability increase with age

BIOLOGICAL FACTORS
2. Body Weight:
 Weight, 3.5 kg at birth, increases rapidly in childhood and adolescence and then declines
slowly in the elderly
 As body water spaces, muscle mass, organ blood flow, and organ function are related to
body weight, the volume of distribution, clearance and hence dosage regimens of drugs
also depend on body weight
 However, a weight adjustment is generally thought necessary only if the weight of an
individual differs by more than 30% from the average adult weight (70 kg)
 In practice, then, adjustments for weight are made only for the child and for the adult who
is small, thin, big, or obese

BIOLOGICAL FACTOR
3. Gender:
 Genetic and physiological differences between men and women can influence
both PK and PD
 For example, many genes on the Y chromosome, which are expressed only in
males, have no counterpart on the X chromosome
 The Y chromosome has genes involved in basic cellular function and some genes
on the X chromosome are expressed at higher levels in females
 Gene expression and regulation are likely to be influenced by hormonal
differences between males and females

BIOLOGICAL FACTOR
4. Genetics:
Genetic polymorphism that lead to the production of isoenzyme
with reduced or no activity of to multiple copies of an enzyme with
high activity make a major contribution to the variability in the dose
requirements of drugs that eliminated by hepatic metabolism
Cytochrome P450 (CYP 450) enzymes, P – glycoproteins are
increasingly being recognized for their importance to
pharmacokinetic variability
Most of these genetic differences are complex and are difficult to
determine with any degree of certainty; but a few genetic
differences are well documented (oxidation, S- methylation, and
acetylation)
In future, genetic screening (phenotyping) may be done to
individual patients to design the dose of a drug

BIOLOGICAL FACTOR
5. Disease Conditions:
Disease is a major source of variability in drug response
The PK and PD of some drugs have been shown to be influenced by the
presence of concurrent diseases other than the one for which a drug is used
There are also occasions when the pharmacokinetics of a drug is altered in
the disease for which it is used
Diseases of the kidney, liver, cardio vascular system, respiratory system,
gastrointestinal system and endocrine system are the major cause that
warrant individualized drug therapy

ENVIRONMENTAL FACTORS
1. Drug Interactions:
Many of the clinically significant interactions between drugs are
pharmacokinetic in origin, often due to induction and inhibition of
metabolizing enzymes or transporter proteins
However, interactions can also occur between drugs and food
supplements or herbal remedies
Interactions involving competitive inhibition often occur within two to
three days whereas induction may take anything form hours to weeks
If the interacting drug has a long elimination half life, the interaction
may persist for some time after it has been discontinued

Absorption:
Studies have demonstrated the importance of intestinal
CYP3A4 and P – glycoprotein in drug absorption
Induction of these mechanisms by rifampicin and by St John’s
wort have been shown to reduce the BA of Digoxin
Absorption can also be altered by drug interactions within the
gut that result from binding to other drugs, such as
cholestyramine or antacids, or to enteral feeds, as in the case
of Phenytoin

Distribution:
Drug distribution can be altered by interactions that cause
displacement from plasma protein binding
But, these do not normally alter maintenance dose requirements unless
there is also a reduction in the clearance of unbound drug
Metabolism:
Metabolism can be altered by enzyme induction or inhibition
Due to wide variability in enzyme activity, the clinical significance of
an interaction is often difficult to predict on an individual basis

Other Environmental Factors:
Diet, climate, smoking, alcohol, drugs, pollutants may cause wide
variations in drug response within an individual
Several of these factors can operate simultaneously in the same
individual, thus affecting the processes of ADME and receptor
interaction in different ways and to different degrees
Studies comparing the metabolism of Antipyrine between Asian
Indians in rural Indian villages and Indian immigrants in England
demonstrated that as immigrants adopted the lifestyle and dietary
habits of the British, their drug metabolism accelerated
Light-skinned individuals are subject to drug-induced phototoxicity
after ingesting certain drugs

CULTURAL FACTORS
Cultural or psychosocial factors, such as the attitudes and
beliefs of an ethnic group, may affect the effectiveness of, or
adherence to, a particular drug therapy
Studies have consistently shown that African-American
patients are more likely to be over diagnosed as having a
psychotic illness and are more likely to be treated with
neuroleptics regardless of diagnosis
African-Americans are also more likely to be placed on
implanted or periodically injected rather than oral
medications, reflecting physicians’ concern about adherence

APPROACHES TO DESIGN OF DOSAGE REGIMEN
Various approaches employed in designing of dosage regimen are
1. Empirical Dosage regimen : Is designed by physicians based on empirical
data, Personal experience and Clinical observations. This method is
however not very accurate.
2. Individualization of Dosage regimen : Is the most accurate approach and is
based on the pharmacokinetics of drug in the individual patient. The
approach is suitable for hospitalized patients but is quite expensive.
3. Dosage regimen on population Averages : Most often used approach. The
method is based on one of the two models –
1. Fixed Model.
2. Adaptive model.

Fixed model :
Here, Population average pharmacokinetic parameters are used directly to calculate
the dosage regimen.
Adaptive model :
It is based on both population average pharmacokinetic parameters of the drug as
well as patient variables such as weight, age, sex, body surface area and known
patient pathophysiology such as renal diseases.
Irrespective of the route of administration and complexity of
pharmacokinetic equations, the two major parameters that can be adjusted in
developing a dosage regimen are:
• The Dose Size- Quantity of drug administered at one time
• The Dose Frequency- The time interval between doses.

DOSE SIZE
• The magnitude of both therapeutic and toxic responses depends upon dose size.
• Dose size calculation requires the knowledge of amount of drug absorbed after
administration of each dose. Greater the dose size greater the fluctuations
between Css,max and Css,min during each dosing interval and greater the
chances of toxicity.

DOSING FREQUENCY
• The Dosing Interval (inverse of dosage frequency) is calculated on the basis of
half-life of the drug.
• If the interval is increased and dose is unchanged, Cmax, Cmin, Cav decreases
but the ratio Cmax/Cmin increases.
• Opposite is observed when the dosing interval is reduced or dosing frequency
is increased. It also results in greater accumulation of drug in the body and
toxicity.

CONCLUSIONS
Health care providers should give individualized treatment to each patient
and resist the temptation to apply “cookbook” drug therapy that does not
take into account variations among individual patients
For the practicing physician, each patient represents a unique and dynamic
interaction among determinants that are both genetic and environmental
It is imperative to individualize therapy with respect to the appropriate
choice of both drug and dose
A Clinical pharmacist with adequate pharmacokinetic background can
play a vital role in helping the physician for individualizing drug therapy

Individualization of dosage regime

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Individualization of dosage regime