This document discusses approaches to adjusting drug dosages for patients with impaired renal or hepatic function. It outlines three main approaches to adjusting dosage based on total body clearance, elimination rate constant or half-life, and methods used in renal failure. It also discusses dose adjustment considerations for obese, pediatric, elderly, and individual patients based on pharmacokinetic variability between individuals. The document emphasizes monitoring drug therapy through therapeutic drug monitoring to evaluate patient response and adjust dosages accordingly.

1. Seminar on…
Dosage Regimen
By
Amruta S. Sambarekar
Dept. Of Pharmaceutics
Maratha Mandal’s
College of Pharmacy
Belgaum.

2. Table of Contents
PART -II
Adjustment of Dosage in Renal Impairment.
Adjustment of Dosage in Hepatic
Impairment.
Individualization.
Therapeutic Drug Monitoring.

3. Adjustment of Dosage in Renal Impairment
In patient with renal failure, the half life of the drug is
increase and its clearance drastically decreases if it is
predominantly eliminated by way of excretion.
Hence, dosage adjustment should take into account the
renal function of the patient and the fraction of
unchanged drug excreted in urine.
There are two additional method for dose adjustment
in renal insuffiency if the Vd change is assumed to be
negligible.

4.  General Approach…
 No change in the desired or target plasma
concentration.
 Diminished renal clearance but unchanged
non-renal clearance.
 Unaltered drug protein binding & volume of
distribution in the renally impaired patient.
 Unchanged drug absorption from the GIT.

5. Three Major Approaches are…
 Dose adjustment based on Total body clearance.
 Dose adjustment based on Elimination rate
constant or Half life.
 Dose adjustment in renal failure.

6. Dose adjustment based on Total body clearance
 The average drug conc. at steady-state css,av is a
function of maintenance dose X0 , the fraction of
dose absorbed F, the dosing interval ‫ & ז‬clearance
Cl T of the drug.
Css,av F X0
Cl T ‫ז‬
X0
Css,av F
1
(‫)ז‬
Cl T ‫ז‬
X X
4

7.  If ClT' , X0 ' & ‫ז‬represents the values for the renal failure
'
patient, then the eq. for dose adjustment is given as…
X0 X0 '
Css,av
ClT ‫ז‬ ClT' ‫' ז‬
 Rearranging in terms of dose & dose interval to be adjusted,
the eq. is…
X0 ' ClT' X0
‫'ז‬ ClT ‫ז‬
 From the above eq., the regimen can be adjusted by
reduction in dosage or increase in dosing interval or a
combination of both.
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8. Dose adjustment based on Elimination
rate constant or Half life
 The average drug conc. at steady-state css,av is a
function of maintenance dose X0 , the fraction of
dose absorbed F, the dosing interval ‫ & ז‬volume
of distribution vd & t1/2 of the drug.
1.44 F X0 t1/2
Css,av
Vd‫ז‬
 Where, the coefficient 1.44 is the reciprocal of
0.693.
6

9. 1.44 F X0
Css,av X t1/2 X
Vd ‫ז‬
To be kept Assumed increased due Needs
normal constant to disease adjustment
If t1/2 ' , X0 ' & ‫ ' ז‬represents the values for the renal failure
patient,
then the eq. for dose adjustment is given as…
t1/2 X0 t1/2 ' X0 '
Css,av
‫ז‬ ‫'ז‬

10.  Rearranging in terms of dose & dose interval to
be adjusted, the eq. is…
X0 ' t1/2 X0
‫'ז‬ t1/2 ' ‫ז‬
 Because of prolongation of half life of a drug due
to reduction in renal function, the time taken to
achieve the desired plateau takes longer if the
more severe is dysfunction, hence such patient
sometimes need loading dose.
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11. Diseases are the major source of variation in drug response.
Both pharmacokinetic and Pharmacodynamic of many drugs
are altered by disease other than the one which is being
treated.
Disease state :
Renal dysfunction
Uremia

12. Renal dysfunction :
It greatly impair the elimination of drug especially those that
are primarily excreted by the kidney.
Causes of renal failure are hypertension, diabetes mellitus
Uremia :
It is characterized by impaired Glomerular filtration and
accumulation of fluid and protein metabolism.
In both the cases the half life of the drug are increased as a
consequences drug accumulation and toxicity increases.

13. Adjustment of Dosage in Hepatic Impairment.
The influence of Hepatic disorder on the drug
bioavailability & disposition is unpredictable
because of the multiple effects that liver produces.
The altered response to drugs in liver disease
could be due to decreased metabolizing capacity of
the hepatocytes, impaired biliary elimination, due to
biliary obstruction (e.g. Rifampicin accumulates in
obstruction jaundice)

14.  Impaired Hepatic blood flow leading to an
increase in bioavailability caused by a reduction
in first pass metabolism (e.g Bioavailabilities of
Morphine and Labetalol have been reported to
double in patients with Cirrhosis)
 Decreased protein binding and increased
toxicity of drugs highly bound to plasma protein
(e.g. Phenytoin, Warfarin) due to impaired
albumin production, altered volume of
distribution of drugs due to increased
extracellular fluid.
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15.  Oedema in liver disease may be increased by
drugs that cause fluid retention (e.g.
Acetylsalicylic acid, Ibuprofen, Prednisolone,
Dexamethasone).
 Generally, drug doses should be reduced in
patients with hepatic dysfunction since clearance
is reduced & bioavailability is increased in such
a situation.
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16. Renal function determination
Glomerular filtration rate can be determined by
following two methods :
Insulin clearance
Creatinine clearance

17. For children (1-20 years) :
Clcr =0.48 H X [W] 0.7
Scr [70]
For Adult (above 20 years) :
Males, Clcr = (140 – age) W
72 x Scr
Females, Clcr =(140 – age) W
85 x Scr

18. A direct method for determining creatinine
clearance is :
Clcr = Rate of creatinine excretion
Serum creatinine in mg %
Renal function. RF is calculated by following
equation :
RF= Clcr of patient
Clcr of a normal person

19. Dose required by the patient with renal impairment :
Normal dose X RF
Dosing interval :
Normal interval/RF
Dose adjustment in renal failure when drug is
eliminated both by renal and non renal mechanism :
Normal dose = RF X [ fraction excreted X fraction eliminated]
in urine non renally

20. Conclusion
 Ideally in planning ‘Dosage regimen’ drug
dosage adjustment is important in all critically ill
patients with organ failures.
 In treating such critically ill patients, drug
treatment should be so carefully done in order to
achieve steady state plasma concentration
required within a known and safe effective
therapeutic range.
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21. Individualization of Therapy
 Same dose of drug may produce large
differences in pharmacologic response in
different individuals, this is called as intersubject
variability.
 For the rational drug therapy, requires
individualization of dosage regimen.
 To achieve optimum dosage regimen.
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22. Sources of Variability
1) Pharmacokinetic Variability :
 Due to differences in drug conc. at the site of
action.
 Major causes are genetics, disease, age, body wt.
& drug-drug interactions.
2) Pharmacodynamic Variability :
 Due to differences in effect produce by a
given drug conc.

23.  For individualization of drug therapy, a drug
must be available in dosage forms of different
dose strengths.
 Depends on two major factors…
i) Therapeutic Index &
ii) The degree of intersubject variability.
Hence, smaller the therapeutic index & greater
the variability, more the no. of dose strengths
required.

24. Steps involved in Individualization of
Dosage regimen
 Estimation of pharmacokinetic parameters in
individual patient & determining their deviation
from the population values to evaluate the
extent of variability.
 Attributing the variability to some measurable
characteristics such as hepatic or renal disease,
age, wt. etc.
 Designing the new dosage regimen from
collected data.
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25. Dosing of Drug in Obese Patient :
IBW (men)=50Kg + 1Kg/2.5 cm above or below150
cm
in height
IBW (women)=45Kg +1Kg/2.5 cm above or below
150cm in height
Any person whose body weight is more than 25%
above the IBW is considered as obese.

26. Dosing of drug in Neonates, Infants &
Children
Mosteller’s equation:
SA (in m2)=( height X weight )1/2
60
Child’s maintenance dose can be calculated from
adult dose by using the following equation :
Child’s dose= SA of Child in m2 X Adult Dose
1.73
SA (in m2) = Body weight (Kg)0.7

27. The following relationship can also be written for child’s dose :
Child’s dose= [weight of child in Kg] 0.7 X Adult dose
70
Dosing of drug in elderly :
A general equation that allows calculation of maintenance dose
of any age except neonates & infants:
Patient’s dose=(weight in Kg)0.7(140- age in years)XAdult Dose
1660

28. Therapeutic Drug Monitoring
 Management of drug therapy in individual
patient often requires evaluation of the response
of the patients to the recommended dosage
regimen, known as Therapeutic drug
monitoring.
 Depending on the drug & the disease to be
treated, for management of drug therapy in
individual patient, we need…
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29. I. Monitoring Therapeutic effect :
E.g. prevention of an anticipated attack of
angina or shortening of duration of pain
when attack occurs, through the use of
Glyceryl trinitrate.
II. Monitoring Pharmacologic actions :
E. g. Blood glucose lowering with Insulin.
III. Monitoring plasma drug conc. :
E.g. Digoxin, Phenytoin etc.
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30. Conclusion
 Successful application of this monitoring therapy
requires complete knowledge of pharmacokinetic
parameter of the drug, the situation in which this
parameters are likely to be altered & the extent to
which they could be altered, & a sensitive, specific
& accurate analytical method for determination of
drug concentration.

31. References
 ‘Biopharmaceutics & Pharmacokinetics’, A
Treatise, D. M. Brahmankar & Sunil B. Jaiswal,
Vallabh Prakashan, Pitampura, Delhi.
 ‘www.google.com
 ‘Text Book Of Biopharmaceutics &
Pharmacokinetics”,
Dr. Shobha Rani R. Hiremath.
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32. Thank You !