INDIVIDUALISATION

AND
OPTIMIZATION OF
DRUG DOSAGING
REGIMEN

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 INDIVIDUALIZATION OF DRUG DOSING
REGIMEN

 It 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.

 Same dose of drug may produce large differences in pharmacologic

response in different individuals, this is called as Intersubject
variability.

 In other words it means that the dose required to produce a certain

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response varies from individual to individual.
 The main objective of individualization is aimed at optimizing the dosage
regimen.

 An inadequate therapeutic response calls for a higher dosage whereas drug

related toxicity calls for a reduction in dosage.

 Thus in order to aid individualization, a drug must be made available in dosage

forms of different dose strengths. The number of dose strengths in which a drug
should be made available depends upon two major factors:

1. The therapeutic index of the drug, and

2. The degree of inter subject variability.

 Smaller the therapeutic index and greater the variability, more the
number of dose strengths required.
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 Advantages of Individualization :
 Individualization of dosage regimen help in development of dosage
regimen which is specific for the patient.

 Leads to decrease in Toxicity and sideeffects and increasein

pharmacological drug efficacy.

 Leads to decrease in allergic reactions of the patient for the drug if any.

 Patient compliance increases.

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SOURCES OF VARIABILITY
1. Pharmacokinetic Variability –
 Due to difference in drug concentration at the site of action (as reflected from plasma
drug concentration) because of individual differences in Drug absorption, Distribution,
Metabolism and Excretion.

 Major causes are genetics, disease, age, body wt. & drug-drug interactions

2. Pharmacodynamics Variability –
 Which is attributed to differences in effect produced by a given drug
concentration.
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 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 :
 Estimation of Pharmacokinetic Parameters in individual patients and to evaluate
the degree of Variability.
 Attributing the Variability to some measurable characteristics such as hepatic or
renal diseases, Age, weight etc.
 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.
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A: Dosing of Drugs In Obese Patients:

 The apparent volume of distribution is greatly affected by changes in body

weight since the latter is directly related to vol. of various body fluids.
 The Ideal Body Weight (IBW) for men and women can be calculated from
following formulae:
IBW (Men) = 50 kg +/- 1kg/2.5cm above or below 150cm in height.
IBW (Women) = 45kg +/- 1kg/2.5cm above or below 150cm in height.
 Any person whose body Weight is more than 25% above the IBW is considered
Obese.

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B: 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, TBW and ECF on per kg
body weight basis.
 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 Mosteller’s equation :
SA (in m2) = (Height x Weight)1/2
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 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 (particularly TBW and
ECF) 8

TBW- Total body water. ECF- Extra cellular

 The child's Maintenance dose can be calculated from adult dose by the
following by the following equation :
Child’s dose = SA of child in m2 x Adult dose
1.73
Where 1.73 is surface area in m2 of an avg. 70kg adult.
 Since the surface area of a child is in proportion to the
body weight according to the following equation:
SA(in m2)= Body weight (in kg)
The following relationship can also be written for child’s dose:

Child dose = Wt. of child in kg x Adult dose

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As the TBW in neonates is 30% more than that in adults,
 The Vd for most water soluble drugs is larger in infants and
 The Vd for most lipid soluble drugs is smaller .
Accordingly the dose should be adjusted.

C: Dosing of drugs in Elderly

 Drug dose should be reduced in elderly patients because of
general decline in body function with age.
 The lean body mass decreases and body fat increases by almost 100%
in
elderly persons as compared to adults.
 Vd of water soluble drugs may decrease and that of lipid soluble drugs like
diazepam increases with age.
 Age related changes in renal and hepatic functions greatly alters 10
the
clearance of drugs.
The equation that allows calculation of maintenance dose in such patients is
given as follows :

Patients dose = (weight in Kg) (140 - age in years) x adult dose

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D: DOSING OF DRUGS IN HEPATIC DISEASE
 Disease is a major source of variations in drug response. Both
pharmacokinetics and pharmacodynamics of many drugs are
altered by diseases other than the one which is being treated. The
influence of hepatic disorder on drug availability and disposition is
unpredictable because of the multiple effects that liver disease
produces – effects on drug metabolizing enzymes, on drug
binding and on hepatic blood flow. Hence, a correlation between
altered drug pharmacokinetics and hepatic function is often
difficult. 14
 For example, unlike excretion, there are numerous pathways by which a
drug may be metabolized and each is affected to a different extent in
hepatic disease.
 Therefore the drug dosage should be reduced in patients with hepatic
dysfunction since clearance is reduced and availability is increased in such
a situation.
E: DOSE ADJUSTMENT IN RENAL FAILURE
 Drug in patients with renal impairment have altered
pharmacokinetic profile.
 Their renal clearance and elimination rate are reduced, the
elimination half-
life is increased and apparent volume of distribution altered.
 Since dose must be altered depending upon renal function in such
patient.
 To calculate dose in case of renal failure , the regimen may be adjusted 12

by
OPTIMIZING DOSAGE REGIMENS

 Incorporating the patient's characteristics in the process of initiating a

drug dosage regimen is an important step toward optimization of drug
therapy, but it does not guarantee the success of the therapy.

 We still need to evaluate the outcome of the treatment and we still find
in some cases that the therapeutic objective has not been achieved.

 Traditionally, the management of drug therapy has been accomplished

by monitoring the incidence and intensity of both desired therapeutic
effects and undesired adverse effects.
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CLINICAL EXPERIENCE WITH INDIVIDUALIZATION
AND OPTIMIZATION
BASED ON PLASMA DRUG LEVELS

A: ANTIARRHYTHMIC DRUGS
1- Quinidine : It is useful for treatment of atrial and ventricular
arrhythmia. It is usually administered orally but may be given by
intramuscular or intravenous injection. It has a half-life of about 6 to 7 hrs.
 When usual dosages of quinidine are given to patients on enzyme-
inducing drugs, such as phenobarbital, phenytoin, or rifampin, low sub-
therapeutic blood levels of quinidine are likely to result. Higher than
usual dosages of quinidine are required in these patients.

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 Quinidine concentrations of about 3 to 8µg/ml are considered
therapeutic when nonspecific assay methods are used. With a high
performance liquid chromatography assay procedure antiarrhythmic
effects are associated with serum quinidine levels of 2 to 5 µg/ml.
 The frequency of gastrointestinal disturbances increases with quinidine
levels above 5 µg/ml; cardiovascular disturbances are a concern at
concentrations exceeding 8 µg/ml.
2- Lidocaine
 Lidocaine is the most frequently used intravenous antiarrhythmic agent
for the short term management of ventricular arrhythmias.
 The half-life of lidocaine is about 2 hr.
 In some patients, the clearance of lidocaine decreases with continuous
infusion: dosage reduction may be required during therapy.

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 Coadministration of cimetidine or propranolol. which decreases liver
blood flow and inhibits hepatic metabolism, may also require dosage
reduction of lidocaine.

 Plasma levels of lidocaine less than 1.5 µg/ml are usually ineffective.
The usual therapeutic lidocaine concentration range is 1.5 to 4.0 µg/ml,
but levels up to 8 µg/ml may be needed in some patients. These higher
concentrations may be associate with central nervous system (CNS)
toxicity and cardiovascular depression. Lidocaine levels exceeding 8
µg/ml may be associated with seizures and serious cardiovascular
disturbances.

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B. ANTIBIOTICS
1- Aminoglycoside Antibiotics
 The aminoglycoside antibiotics are effective in treating
pneumonia, urinary tract, soft tissue, burn wound, and other
systemic infections caused by gram-negative organisms.
 All aminoglycosides are ototoxic and nephrotoxic and have a
relatively low therapeutic index.
 The major elimination route for the aminoglycosides is renal
excretion, largely by way of glomerular filtration.
 The half-lives of gentamicin and tobramycin in patients with
normal renal function are variable but avg about 2.5hr.
 Patients with impaired renal function eliminate the
aminoglycosides more slowly and require reduced dosage.
Infants less than 7 days of age and elderly patients also require
lower dosages.
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2- Vancomycin
 Vancomycin is a glycopeptide antibiotic commonly used in the treatment
of serious Gram-positive infections. Nephrotoxicity is often cited as an
adverse effect, especially when high dose therapy is used for a
prolonged duration.
 Nephrotoxicity was found to be significantly higher if the steady-state
vancomycin concentrations were >25–32 μg/mL.
C: ANTICONVULSANTS
 For most epileptic patients, long-term drug therapy is the only practical
form of treatment. Therapy usually continues for at least 3 years and
often for a lifetime. In many clinics and institutions, monitoring of
plasma anticonvulsant levels is a part of the routine management of
patients with epilepsy.

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1- Phenytoin
 No drug has a greater need for therapeutic drug concentration monitoring
and individualized dosing than phenytoin. A relationship between drug
concentration in plasma and daily dose is almost nonexistent because
phenytoin is poorly absorbed, highly plasma protein bound, and subject to
nonlinear, capacity-limited metabolism. Despite these problems, it is the
most frequently prescribed anticonvulsant drug for the management of
grandmal and partial seizures.
 Optimum phenytoin efficacy is achieved in most patients with serum
concentrations in the range of 10 to 20µg/ml.
 Concentration-related CNS toxicity of phenytoin is generally observed at
serum concentrations above 20 µg/ml. As serum levels rise, so do the
frequency and severity of side effects.

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 Children metabolize phenytoin more rapidly than do adults and may
require 2 or 3 times larger mg/kg daily doses (up to 15 mg/kg per day)
than do adults.
 The dosage of phenytoin may need to be increased during pregnancy
because of the increased clearance of the drug during this period.
2- Phenobarbital
 In general, phenobarbital is effective in all convulsive disorders ; it has
been used as an anticonvulsant drug since 1912.
 The half-life of phenobarbital ranges from 50 to 120 hr in adults and from
40 to 70 hr in children. Because of its long half-life, phenobarbital is
usually given to adults once a day at bedtime. Children sometimes require
twice-a-day dosing. Approximately 2 to 3 weeks may be required to reach
steady-state levels of phenobarbital in plasma.

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 Plasma concentrations of 15 to 40 µg/ml are usually required for
adequate therapeutic effect. Plasma phenobarbital levels exceeding 60
µg/ml result in lethargy, coma, but habitual barbiturate abusers may
tolerate much higher concentration.

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