DOSE CALCULATION

Monika Jain ,ICRI, India

CONTENTS Individualization

Intersubject variabilityIntrasubject variability

sources of variabilitysources of variability Causes Dosing of drugs

INDIVIDUALIZATIONBecause of reasonable homogeneity in humans, the dosage regimens are calculated on population basis.

Intersubject variability: same dose of a drug may produce large differences in pharmacologic response in different individuals.

Intrasubject variability : differences in the plasma levels of a given drug in the same subject when given on different occasions.

Rational drug therapy requires individualization of dosage regimen to fit a particular patient’s needs. This require knowledge of pharmacokinetics of drugs.

Two sources of variability in drug Two sources of variability in drug responses areresponses are::

1.Pharmacokinetics variability which is due to differences in drug concentration at the site of action (as reflected from plasma drug conc.) because of interindividual differences in drug absorption, distribution, metabolism and excretion.

2.Pharmacodynamic variability which is attributed to differences in effect produced by a given drug concentration.

CAUSES OF INTERSUBJECT PHARMACOKINETIC VARIABILITY Genetics Disease Age Body weight Drug-drug interaction

The main objective of individualization is aimed at optimizing the dosage regimen.

Thus, in order to aid individualization , a drug must be made available in dosage forms of different strengths.

The number of dose strengths in which a drug should be made available depends upon 2 major factors-

1.the therapeutic index of the drug2.The degree of intersubject variability

Smaller the therapeutic index and greater the variability, more the number of dose strengths required.

Examples of drugs with a narrow therapeutic range, that may require drug monitoring both to achieve therapeutic levels and minimize toxicity, include: dimercaprol, theophylline, warfarin and lithium carbonate.

DOSING OF DRUGS

Dosing of drugs in obese patients

Dosing of drugs in elderly

Dosing of Drugs in Neonates, Infants and children

Dosing of drugs in obese patients

The apparent volume of distribution(vd) is greatly affected by changes in body weight since the latter is directly related to the volume of various body fluids.

The ideal body weight (IBW) for men and women can be calculated from the following formulae:- IBW (Men )= 50kg ± 1 Kg/2.5 cm above or below 150 cm in height

-IBW (Women) =45.5kg ± 1 Kg/2.5 cm above or below 150 cm in height

Any person whose body weight is more than 25% above the IBW is considered obese.

In such patients, the lean to adipose tissue ratio is small because of greater proportion of body fat which alters the Vd of drugs.

Dosing of Drugs in Neonates, Infants and children

The usual dosage regimen calculated on population basis refers to that for adults. Neonates , infants and children require different dosages than adults because of differences in body surface area, TBW and ECF on per Kg body weight basis.

The dose for such patients are preferably calculated on the basis of their body surface area and not on body weight because the body surface area correlates better with dosage requirement , cardiac output, renal blood flow and glomerular filtration in children.

Simple Formula is Mosteller’s equation SA (in m2) = (height * weight)1/2

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Infants and children require larger mg/Kg doses than adult because:

1. Their body surface area per Kg body weight is larger, and hence

2. larger volume of distribution

The child’s maintenance dose can be calculated from adult dose by using the following equation:

child’s Dose = SA of child in m2 × Adult Dose 1.73 Where 1.73 is surface area in m2 of an average

70 Kg adult. Since the surface area of a child is in proportion to the body weight according to equation

SA (in m2 ) = Body weight (in Kg)0.7

The following relationship can also be written for child’s dose:

Child’s Dose = (weight of child in Kg)0.7 × Adult Dose

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As the TBW in neonates is 30 % more than that in adults,

1. the Vd for most water soluble drugs is larger in infants, and

2. the Vd for most lipid soluble drugs is smaller.

Accordingly the dose should be adjusted.

PEDIATRIC CALCULATION Two methods are used to calculate pediatric

dosages:   According to the weight in kilograms (kg)

  According to the child's body surface area (BSA)

Calculations based on body weight The first step is to convert the child's body weight

into kg. The formula is 2.2 lb. = 1 kg. The second step is to calculate the medication dose.

  a. Calculate the daily dose.  b. Divide the daily dose by the number of doses to be administered.  c. Use either the ratio-proportion or formula method to calculate the number of tablets or       capsules or volume to be administered with each dose.

PEDIATRIC DOSAGE CALCULATIONS

Methods used:• According to weight• According to age• Drug dosage per kg of body weight• Body surface area (BSA)

CLARK’S RULEBASED ON WEIGHT Formula:Weight in #s X Adult dose = Child’s dose

150# (avg. adult weight) Ex: Adult dose is 10mg. What is the dose for a child weighing 15#?

FRIED’S RULEBASED ON AGE IN MONTHS (INFANTS)Formula:Age in Months X Adult dose = Child’s dose

150 monthsEx: Adult dose is 100mg. What is the dosefor a 5 month old infant?

YOUNG’S RULEBASED ON CHILD’S AGE IN YEARS Formula:Age of child X Adult dose = Child’s dose

Age of child +12 Ex: Adult dose is 60 minims. What is the dose for a 3 year old child?

BMI= {weight (lb)} × 703 height (in)2

1 lb = 0.454 Kg BMI= {weight (Kg)} × 1000 height (cm)2

CALCULATIONS BASED ON BODY SURFACE AREA (BSA)

BSA is determined from a nomogram using the child's height and weight.

      Child's BSA   X   adult dosage        1.73 M2

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.

Because of smaller volume of body water, higher peak alcohol levels are observed in elderly subjects than in young adults.

Vd of water soluble drugs may decrease and that of a lipid soluble drug like diazepam increases with age.

Age related changes in hepatic and renal function greatly alters the clearance of drugs. Because of progressive decrease in renal function , the dosage regimen of drug that are predominantly excreted unchanged in urine should be reduced in elderly patients.

A general equation that allows calculation of maintenance dose for patient of any age (except neonates and infants) when maintenance of same Css,av is desired is:

Patient’s Dose= Body weight (in Kg)0.7 (140 – Age in Years) ×Adult Dose

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ICRI, Ahmedabad