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CHAPTER 2

DESIGN OF DOSAGE REGIMENS

NOMOGRAMS AND TABUIAllONS IN DESIGNING DOSAGE REGIMENS
For ease of calculation of dosage regimens, many clinicians rely on nomograms to calculate
proper dosage regimen for their patients. The use of a the
nomogram may give a quick dosao
regimen adjustment for patients with characteristics requiring adjustments such sage
as
weight and physiological state. In general, the nomogram of a age, body
drug is based on population
pharmacokinetic data collected and analysed using a specific pharmacokinetic model.
To keep the dosage
regimen calculation simple, complicated equations are often solved
results and the
are
displayed diagrammatically on
special scaled axes to
produce simple dose a
recommendation based on patient information. Some make
monograms use of
specific physiologic
parameters such as serum creatinine concentration to help
to renal function.
modify the dosage regimen according
For many marketed
drugs the manufacturer provides tabulated general
establishing a dosage regimen for patients including loading and maintenance guidelines for use in
doses.
For drugs with a narrow
therapeutic range such as theophylline, a guide for monitoring serum
drug concentrations is given. Another
example is the aminoglycoside antibiotic, tobramycin
sulphate USP (Nebcin, Eli Lilly) which is eliminated
of primarily by renal clearance. Thus, the dosage
tobramycin sulphate should be reduced in direct
clearance. proportion to a reduction in creatinine
The manufacturerprovides a nomogram for estimating the percent of the normal dose or
tobramycin sulphate assuming the serum creatinine level (100
mg/ mL) has been obtained.
1 CONVERSION F RUM INikAVENOUS
P'atients
INFUSION TO ORAL DOSING
dosing is
controlled by intravenous infusion.
It is often undesirable to medicae the
patient continuously with the same
drug using oral route of administration. When the ver ous
infusion is nudv
stopped the serum drug concentration nation
kinetics. decreases according to the tirst oraer
eu
The time to reach
steady-state depends on the first-order elimination rate oral
drug products. Therefore, if the constant for n .
patient starts the dosage regimen with the oral drug ct at the
same time as the
intravenous infusion is prouu
from the intravenous stopped, then the exponential deciine serum levels
infusion should be o
from the oral matched by the exponential increase in serum
drug product.

10
Design of Dosage Regimens
11
The conversion from
intravenous infusion to a
controlled-release oral medication given once or
twice daily has
become more familiar
with the availability of controlled-release
such as theophyllfne and quinidine. drug products
Comptter for the
simulation conversion of intravenous
theophylline (aminophylline) therapy to oral controlled-telease
oral therápy should be started at theophylline demonstrated that
the same time as the intravenous infusion is
stopped.
With this method, minimal fluctuations are observed between the
peak
theophylline levels. Moreover, giving the first oral dose when IV infusion
and trough serum
is stopped may make it
easier for the nursing staff
patient to comply with the dosage regimen. Either of these methous
or

may be used to calculate an appropriate oral dosage regimen for a patient whose condition has

been stabilized by an intravenous drug infusion. Both methods assume that the patient's plasma
drug concentration is at steady state.

2.1.1 METHOD 1
Method 1 assumes that the steady-state plasma drug concentration, Css, after IV infusion isS
identical to the desired Cav multiple oral doses of the drug. Therefore, the following equation may
be used:

CavSFD,/KvpT
Do/TC"av KVD
Where S is the salt form of the drug and D, o/t is the dosing rate.

EXAMPLE:
An adult male asthmatic patient (age 5, 78 kg) has been maintained on an intravenous infusion of

aminophylline at a mg/hr. The steady-state theophylline drug

rate of 34 concentration was 12

8/mL, and total body clearance was calculated as 3.0 L/hr.

Calculate an appropriate oral dosage regimen of theophylline for this patient?

Solution:
Aminophylline is a soluble salt of theophylline and contains
85% theophylline (S = 0.85).
oral dose. Because total body clearance, C/T=
Theophylline is 100% bioavailable (F= 1) after an
kV D,
The equation may be expressed as

Do/t= C"av ClT/ SF

based on aminophylline. The patient, however,

The dose rate, D o/t (34 mg/hr), was calculated
convert to oral theophylline,
S and F should be considered.
Will be given theophylline orally. To
 PVA TextBook of CinicalPharmacokinetics&Pharmacotherapeutic Druag M.
Monitoring
Theophylline dose rate -
SFD»/t -

(0.85) (1) 34) / 1 -289mg/hr

The theophylline dose rate of 28.9 mg/hr must be converted to a reasonable schedul
patient with a consideration of the various commercially available theophylline druo n for the
Therefore, the total daily dose is 28.9 mg/hr x 24 hr or 693.6
mg/day. Possible theophvlline do
schedules might be 700 mg/day, 350 my9 every 12 hours, or 175 mg every 6 hours dosage
Each of these dosage regimens would achieve the same C but different C max and C min which
l
should be calculated. The dose of 350 mg every 12 hours could be given in the
sustained-relesws
form to avoid any excessive-high drug concentration in the body.

2.1.2 METHOD 2
Method 2 assumes that the rate of intravenous infusion
(mg/hr) is the same desired rate of oral
dosage
EXAMPLE:
Using the example in method 1, the following calculations may be used.

Solution:
The aminophylline is given
by IV infusion at a rate of 34 mg/hr.
The total daily dose of
aminophylline is 34 mg/hr x 24 hr 816mg. =

The equivalent daily dose in terms of

theophylline is 816 x 0.85=693.6 mg. Thus, the patient should
receive
approximately 700 mg of theophylline per day or 350 mg controlled-release theophylline
every 12 hours.

2.2 DETERMINATION OF DOSE

The drug dose is estimated to deliver
a desirable
(target) therapeutic
level of the drug to the body
The dose of a drug is estimated with the objective of delivering a desirable therapeutic level of the
drug in the body.
For many drugs, the desirable
therapeutic drug levels and pharmacokinetic parameters d
available in the clinical literature.
However, the literature, in some cases, may not yield plete
drug intormation, or the information available
conp the
may be partly equivocal. Theretore
pharmacOkinetics must make certain necessary assumptions in accordance with the best
pharmacokinetic intormation available.
For a
drug that is sualy
given in multiple doses for an extended
calculated so that the average period, the dosage
regi
steady state blood level is within the therapeutiC range *he dose
can be calculated with al
Equation, which expresses the Cay in terms of dose (Do), dosing n
the volume of distribution (Vo), and the elimination
half-life of the drug. F is the tract
absorbed and is equal to 1 or
drugs administered ntravenously.

C'=144 DoteF/ Vpt

Design of Dosage Regimens 13

2.2.1 PRACTICE PROBLEMS

1. Pharmacokinetic data for clindamycin were reported as follows:

k =0.247hr
t 1/2 2.81hr
Vp=43.91L/1.73m2
every
of the drug is given orally
What is the steady-state concentration of the drug after 150 mg
hours week? (Assume the drug is 100%% absorbed.)

Solution

Ca 1.44 Doti/2 F /VpT

144x 150,000 x
2.81 x 1 ug/ml
43,900 x 6

=2.3 ug/ml

ADMINISTRATION
DETERMINATION OF FREQUENCY OF DRUG
2.3 administration. The more

often related to the frequency of drug

dose is Thus, a
The size of drug be to obtain the s a m e Cav.
a
the smaller the dose must
administered,
drug is without affecting the
frequently a to 500 mg every 6 hours
3 hours could be changed intervals get
dose of 250 mg every However, as the dosing
concentration of the drug.

average steady-state
plasma plasma drug
concentration gets
to maintain the average
the size of the
dose required large dose may
longer, interval is chosen, the
When an excessively long dosing Will
though Cav
remain
correspondingly larger. concentration, e v e n
levels that are above toxic drug
peak plasma
result in

the same (see). the elimination half-life. Drugs

most drugs is
determined by
interval for at intervals much longer
In general, the dosing low toxicity may be given
which have relatively
such as the penicillin's toxicity problems.
half-lives
without any
than their elimination must be given relatively
such as digoxin and phenytoin, the
narrow therapeutic range, in blood levels. For example,
Drugs having a
"peak-and-trough"
tluctuations

excessive elimination half-lite of digoxin

to minimize the
frequently 0.25 mg/day, and
schedule for digoxin is elimination half-life
Common
maintenance
every 6 hours, while the
is given at 250 mg
is 1.7 days. In contrast, penicillin G
hour.
of penicillin G is 0.75
 PVA Text Book of Clinical Pharmacokinetics & Pharmacotherapeutic Drur
14 rug Monitorin
Penicillin is given at a dosage interval equal to 8 times its elimination half-life, whereas.
eas digoxinis
piven at a dasing interval only 0.59 times its elimination half-life. The toxic plasma concent
ofpenicillin Gis over 100 times greater than its effective concentration. tion

MINATION OF BOTH DOSE AND DOSAGE INTERVAL

Dose and thedosage interval should be considered in the dosage regimen calculations. Ideallv
the
calculated dosage regimen should maintain the serum drug cpncentrations between C.
and
For intravenous multiple-dosage
Cmin. regimens, the ratio of C at max/C at min
by which can be simplified to
may beexpressed

max C1-e*)
min Cp 1(1-e*")

C max 1

min eKT

From the above Equation a maximum dosage

interval may be calculated that will maintain the
serum concentration between Cmin and Cmax. After the
dosage interval is calculated, then a dose
may be calculated.

25 DOSING OF DRUGS IN INFANTS AND CHILDREN

Infants and children have different
dosing requirements than adults. Newborn usually reters to a
baby from birth to about 2 months of age. Infants can be considered children anywhere from birtn
to 1
yeaf* old:-Dosing of drugs in this population requires
differences in the
a thorough considerationu or

pharmacokinetics and pharmacology of a specific drug in the preterm new-o

infant, new-born infant (birth to 28
days), infant (28 days to 23 months), young child (2 to 5 yeats
older child (6 to 11
years), adolescent (12 to 18 years), and the adult (FDA Guidance tor ry
2000), Inau
he
pharmacokinetics and pharmacodynamics of most drugs are not well known in
under 12 years of age. The variation in body composition and the maturity of liver anac
cidney
function are potential sources of differences in pharmacokinetics ence
concerning age. For
conve
infants" are here arbitrarily defined as children 0 to 2 yearsof age. within zroup,
special consideration is necessary for However, tu neir
infants less than four weeks (1 month) old, becaus
ability to handle drugs often differs from that of
more mature intants.
Design of Dosage Regimens 15

In addition to ditterent dosing requirements for the paediatric population, there is a need to

consider the use ot paediatric dosage forms that permit more accurate dosing and patient

compliance. For example, liquid paediatric drug products may come with a calibrated dropper or

a premeasured teaspoon (5 mL) for accurate dosing and have a cherry flavour for paediatric
Paediatric drug formulations may also contain different drug concentrations
Ppatient compliance.
compared to adult drug formulation. Furthermore, alternative drug delivery such as an
intramuscular antibiotic drug injection into the gluteus Medius muscle that is considered tor
paediatric patient, as opposed to the deltoid muscle for an adult patient.
In general, the complete hepatic function is not attained until the third week of life. Oxidative

are deficient. Also

processes are relatively well
developed in infants, but conjugative enzymes
many drugs exhibit reduced binding to plasma albumin in infants.
New born show only 30-50% of the renal activity of adults based on activity per unit of body

renal excretion will have a sharply decreased

weight. Drugs that are heavily dependent on

elimination half-life

2.6 DOSING OF DRUGS IN THE FI DERLY

as patients who
Defining "Elderly" geriatric population is often arbitrarily defined
is difficult. The
of these people live active and healthy lives. Also, there
is an
are older than 65 years, and many
for more than 85 years, who are often considered as
increasing number of people who are living
is more often associated with physiologic
the "older elderly" population. The ageing process
The elderly has been classified as the
changes during ageing rather than purely chronological age.
the old (ages 75-85 years), and the old (age> 85 years)
young-old (ages 65-75 years),
homeostatic reserve decreases with advanced age but occurs
Performance capacity and the loss of
patient. Physiologic and cognitive functions tend
to
to a different degree in each organ and each
and etficacy
and can attect compliance and the therapeutic safety
change with the ageing process
also tends to be o n multiple drug therapy due
to c o n c o m i t a n t
of a prescribed drug. The elderly
ftunction in some geriatric patientsS, complicated drug dosage
illness. Decreased cognitive
result in poor drug compliance, resulting in lack
schedules, and the high cost of drug therapy may
interactions, and drug intoxication.
of drug efficacy, possible drug
related to age by markers show that renal plasma
as measured
Several vital physiologic functions
and breathing capacity can drop trom 10% to 30% in
flow, glomerular filtration, cardiac output,
Ihe physiologiC changes due to ageing may
compared to those at age 30.
elderly subjects n the elderly. For some drugs, an age-
considerations in administering drugs
necessitate special
reactions or toxicity may be observed. This aPparent increased
dependent increase in adverse drug
be due to pharmacodynamic and/or pharmacokinetic changes.
drug sensitivity in the elderly may
assumes that age causes alterations in the and quality
quantity
The pharmacodynamic hypothesis the number of drug
to enhanced drug response. Quantitatively,
of target drug receptors leading in the affinity for the drug may
with age, whereas qualitatively, a change
receptors may decline
 16 PUA Text Book of Clinical Pharmacokinetics &Pharmacotherapeutic Drua
occur. Alternatively, the pharmacokinetic hypothesis assumes that age-dependent inc
lonitoring
adverse drug reactions are due to physiologic changes in drug absorption, distribuiin increases
elimination, including renal excretion and hepatic clearance. ribution, and
In the elderly, age-dependent alterations in drug absorption may incude a declino
splanchnic blood flow, altered gastrointestinal motility, an increase in gastric pH, and alterati. e
the gastrointestinal absorptive surface. The incidence of achlorhydra in the
elderly mav affo
dissolution of certain drugs such as weak bases and certain dosage forms that the
require ann acid
environment for disintegration and release.
From a distribution consideration, drug-protein binding in the plasma
may decrease because of a
decrease in the albumin concentration, and the apparent volume of distribution
may change dte
to a decrease in muscle mass and an increase in
body fat. Renal drug excretion generally declines
with age because of a decrease in the
glomerular filtration rate and active tubular secretion
Moreover, the activity of the enzymes responsible for drug biotranstormation
may decrease with
age, leading to a decline in hepatic drug clearance.
Elderly patients may have several different pathophysiologic conditions that require
multiple
drug therapy that increases the likelihood of a drug interaction. Moreover, increased adverse
reactions and toxicity may result from
drug
poor patient compliance. Both penicillin and kanamycin
show prolonged to in the aged
patient, because of an age-related gradual reduction in the kidneyY
size and function.

2.7 DOSING OF DRUGS IN THE OBESE PATIENT

Obesity is a significant problem in the United States and is also becoming a problem in other
countries. Overweight and obesity are defined as abnormal or excessive fat accumulation that
presents a risk to health. A body mass index (BMI) over 25 is considered overweight, and over 30
is obese. Obesity has been associated with increased mortality resulting from increases in the
incidence of hypertension, atherosclerosis, coronary artery disease, diabetes, and other conditions
compared to non-obese patients.
A patient is considered obese if actual body weight exceeds ideal or desirable
body weight by 20
according to Metropolitan Life. Ideal or desirable body weights are based on average b0ay
weights and heights for males and females considering age. Athletes who have a higher bouy
weight due to greater muscle mass are not considered obese.
Obesity often is defined by body mass index (BMI), a value that normalises body weight baseu
height. BMI is
expressed as
body weight (kg) divided by the square of the person's height rs)
or
kg/m2. BMI is calculated (e
according to the following two equations:

BMI = weight(lb)x 703

LHeight(inJ
 7
Design ofDosegeRegiorens

BMI=Weight(kg)
x 10.000
LHeight(cm)
tor
tissue than is necessary
The obese patient (BMI> 30) has a more significant accumulation of fat
to muscle
functions. Adipose (fat) tissue has smaller proportion of water compared
normal body a

water to total body weight

tissue. Thus, the obese patient has a smaller proportion of total body of
the apparent volume
compared to the patient of ideal body weight, which could affect
distribution of the drug.
distribution of antipyrine
For example, significant difference in the apparent volume of
showed a
(0.62 L/kg) based on actual
(0.46 L/kg) compared to ideal-body-weight patients
in obese patients weight for a male
(1Bw) refers to the appropriate or normal
total body weight. Ideal body weight obtained
a r e generally
female based on height, weight, and frame size; ideal body weights
or age,
the Metropolitan Life
latest table of desirable weights for men and w o m e n compiled by
from the
Insurance Company.
the
in the obese patient,
water per kilogram bodyweight
body
In addition to differences in total the drug's
to distributional changes in
fat in these patients could lead
greatest proportion of body
pharmacokinetics.

awiau Quesions
LONG ANSWER QUESTIONS form? (Reter 2.2)
intravenous infusion to oral dosage
to convert
Q.1. What are the steps dosing three neonates? (Refer 2.5, 2.6, 2.7)
Write note and steps to be followed while studies with examples? Give
Q.2 a
their applications with pharmacokinetic
nomograms? Explain
Q.3 What are
2.1.1, 2.12)
their advantages and disadvantages? (Refer2.1,
SHORT ANSWER QUESTIONS
(Refer 2.3)
short note on dosing frequency?
Q1 Write a elderly? (Refer
26)
on dosing of drugs to
Write a short note of drugs to
obese patients? (Refer
2.7)

Q.3. Write a short note on doing (Reter 2.5)

to paediatrics?
Write a short note o n dosing of drugs
4