Introduction of Dosage regimen, Approaches for design of dosage regimen, Individualization, Advantages, Dosage in neonates, Geriatrics, Renal and Hepatic impaired Patients.
2. Introduction to Dosage Regimen.
Approaches to design dosage regimen.
Dose size, Frequency and Accumulation.
Individualization.
Steps Involved in Individualization of Dosage Regimen.
Dosing of Drugs in Neonates, Infants and Children.
Dosing in Geriatrics.
Dose adjustment in Renal and hepatic impairment.
3. Introduction
Dosage Regimen - Dosage regimen is defined as the manner in
which the drug is taken.
For some drugs like analgesics single dose is efficient for optimal
therapeutic effect however the duration of most illnesses are longer
than the therapeutic effect produced by a single dose, In such cases
drugs are required to be taken on a repetitive bases over a period of
time depending upon the nature of illness.
An optimal multiple dosage regimen is the one in which the drug is
administered in suitable doses with sufficient frequency that ensures
maintenance of plasma conc. Within the therapeutic window for
entire duration of therapy.
4. 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.
5. 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.
6. 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.
7. For drugs administered chronically, dose size calculation is based on
average steady state blood levels and is computed from the above
equation :
Xss,av = 1.44FX0t1/2
ז
Where
X0 = Maintenance dose,
F = Fraction of dose absorbed,
ז = Dosing interval
t1/2 = Half life
1.44 = Reciprocal of 0.693
8. 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.
9. A proper balance should be obtained between dose frequency and
size to attain steady state conc. And with minimum fluctuations to
ensure therapeutic efficacy and safety.
For drugs with wide therapeutic index such as penicillin's, Larger
doses may be administered at longer intervals (more than half life of
drug) without any toxicity effects.
For drugs with narrow therapeutic index such as digoxin, small
doses with frequent intervals (less than half life of drug) is better to
obtain a profile with least fluctuations which is similar to that
observed with controlled drug release systems.
10. Drug Accumulation during Multiple Dosing :
Accumulation occurs because drug from previous doses has not been
removed completely.
As the amount of drug in the body increases due to accumulation, the
rate of elimination also rises proportionally until a steady state or
plateau is reached when the rate of drug entry into the body equals
the rate of exit.
Thus, the extent to which a drug accumulates in the body during
multiple dosing is independent of dose size and is the function of
a. Dosing Interval and
b. Elimination half-life.
The extent to which a drug will accumulate in the body with any dose
interval in a patient can be derived from information obtained with a
single dose and is given by Accumulation Index Rac .
12. Loading and Maintenance Dose :
A drug does not show therapeutic activity unless it reaches the
desired steady state. Plateau can be reached immediately by
administering a dose that gives the desired steady state
instantaneously before commencement of maintenance dose Xo.
Such an Initial dose or first dose intended to be therapeutic is called
as loading dose or priming dose Xo,L. Equation for calculating
Loading dose is
Xo,L = Css,av Vd
F
For drugs having low therapeutic indices the loading dose maybe
divided into smaller doses to be given at various intervals before the
first maintenance dose. When Vd is not known the loading dose can
be calculated by the following equation :
13. Xo,L = 1
(1-e – Ka 1- )( ז e – KE ( ז
When the drug is given I.V. or when absorption is extremely rapid,
the absorption phase is neglected and the above equation reduces to
accumulation index :
Xo,L = 1 = Rac
Xo (1-e – KE ( ז
The ratio of loading dose to maintenance dose Xo,L/Xo is called as
dose ratio. As the rule when
ז = t1/2 , dose ratio equals 2.0, ז > t1/2 , dose ratio is smaller than 2.0
ז < t1/2 , dose ratio is grater than 2.0 .
14.
15. Maintenance Dose :
A maintenance dose is the maintenance rate [mg/h] of drug
administered equal to the rate of elimination at steady state. It is also
defined as the amount of drug required to keep a desired mean steady
state concentration in the tissues. It is administered after L.D.
Calculation of Maintenance Dose :
The required maintenance dose may be calculated as :
MD = CpCL
F
Where,
MD – Maintenance dose rate (mg/L)
Cp – desired peak Conc. Of drug (mg/l)
CL – Clearance of drug in body and F – Bioavailability.
16. Rational drug therapy requires Individualization of Dosage regimen to
fit a particular patient’s needs. The application of Pharmacokinetic
principles in the dosage regimen design for the safe and effective
management of illness in individual patient is called as Clinical
Pharmacokinetics.
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
response varies from individual to individual.
17. 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 side effects and increase
in pharmacological drug efficacy.
Leads to decrease in allergic reactions of the patient for the
drug if any.
Patient compliance increases etc.
18. 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.
2. Pharmacodynamics Variability –
Which is attributed to differences in effect produced by a given drug
concentration.
The Major cause of variability is Pharmacokinetic variability.
Difference in the plasma conc. levels of given in the same individual
when given on different occasions is called as “Intersubject
Variability”
19. It is rarely encountered in comparison to Inter-individual variations.
The differences in variability differ for different drugs. Some drugs
shows greater variability than others
Major causes of Intersubject Pharmacokinetics Variability are –
1. Genetics.
2. Diseases.
3. Age.
4. Body Weight and
5. Drug-Drug Interactions.
Less important Causes are :
1. Pharmaceutical formulations
2. Route of administration
3. Environmental factors and Patient non-compliance.
20. 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 strengths. The number of dose strengths
in which the drug should be made available depends upon 2 Major
Factors -
1. The Therapeutic index of the drug and
2. The degree of Inter-subject Variability.
Smaller the therapeutic index greater the variability, more the number
of dose, strengths required.
21. 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.
22. 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.
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) foe 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.
23. Any Person Whose body Weight Is more than 25% above the IBW is
considered Obese.
Generalizations regarding drug distribution and dose distribution
in obese patients :
For drugs such as Digoxin that do not significantly distribute in
excess body space, Vd do not change and hence dose should be
calculated on IBW basis.
For polar drugs like antibiotics (Gentamicin) which distribute in
excess fat of obese patients to less extent then other tissues the dose
should be lower than per kg total body weight basis but more than
that on IBW basis.
24. 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
60
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)
TBW- Total body water. ECF- Extra cellular fluid.
25. 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’s dose = weight of child in kg
x adult dose
70
26. 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.
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 the
clearance of drugs.
27. 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
1660
Dosing of drugs in Hepatic diseases :
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 accumulation in obstruction jaundice)
28. Impaired Hepatic blood flow leading to an increase in bioavailability
caused by a reduction in first pass metabolism
(e.g. Bioavailability's 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.
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.
29. Examples of drugs who's drug conc. Changes due to hepatic
impairment :
High extraction ratio
Antidepressants
Chlorpromazine/haloperidol
Calcium channel blockers
Morphine
Glyceryl trinitrates
Levodopa
Propranolol
30. Low extraction ratio
Non-steroidal anti-inflammatory drugs
Diazepam
Carbamazepine
Phenytoin
Warfarin
Extraction Ratio – is the measure in renal physiology, Primarily used
to calculate renal plasma flow in order to evaluate renal function. It is
the amount of compound entering the kidney that got excreted into the
final urine. Extraction ratio of the drugs ranges from 0 -1.5 l/min.
High Extraction Ratio - Less than 0.3
Low Extraction Ratio - More than 0.7
31. Dosing of drugs in Renal Disease
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
insufficiency if the Vd change is assumed to be negligible.
The adjustment of drug dosage in case of renal disease are carried out
by mainly three approaches :
Dose adjustment based on Total body clearance.
Dose adjustment based on Elimination rate constant or Half life.
Dose adjustment in renal failure
32. 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 ז & clearance Cl T of the drug.
Css,av = Fx0/ClT ז
Css,av = F x 1/ClT x x0ז/
To be kept Assumed Decreased Needs
Constant Constant due to Disease adjustment
33. If ClT' , X0 ' & ז ' represents the values for the renal failure patient,
then the eq. for dose adjustment is given as
Css,av = x0/ClT ז = x0 / Cl’T ‘ז
Rearranging in terms of dose & dose interval to be adjusted, the eq.
is
’ = Cl’
Xo
T Xo
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.
34. 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 ז & volume of distribution vd & t1/2 of the drug.
Css,av = 1.44 F X0 t1/2
Vd ז
Where, the coefficient 1.44 is the reciprocal of 0.693.
35. Css,av = 1.44 F X t1/2 X X0
Vd ז
To be kept Assumed Decreased Needs
Constant Constant due to Disease adjustment
If t1/2 ' , X0 ז & ' ' represents the values for the renal failure
patient, then the eq. for dose adjustment is given as
Css,av = t1/2 Xo = t1/2 ‘ Xo’
'ז ז
36. Rearranging in terms of dose & dose interval to be adjusted, the eq.
is
Xo’ = t1/2 Xo
ז ‘ t‘1/2 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.
37.
38. Antiviral drugs
Renal clearance is the major route of elimination for many antivirals.
In patients with renal impairment, renal clearance of these drugs is
reduced and the elimination half-life is significantly prolonged. As a
result, normal doses will accumulate and may lead to neurological
signs such as dizziness, confusion, hallucinations, somnolence and
convulsions etc.
Hypoglycemic drugs
Metformin
Metformin has been associated with rare but potentially fatal lactic
acidosis. This is thought to result from accumulation of metformin
when renal impairment reduces renal clearance.
39. Insulin
Renal elimination accounts for up to half of the clearance of insulin, so
as renal failure progresses, less insulin is excreted so smaller doses are
required.
Allopurinol
Allopurinol is used in the management of gout to lower serum and
urinary uric acid concentrations. As allopurinol, and its active principal
metabolite oxypurinol, are mainly excreted in the urine, they
accumulate in patients with poor renal function so the dose should be
reduced.
40. Diseases are the major source of variation in drug response. Both
pharmacokinetic and Pharmacodynamics of many drugs are altered
by disease other than the one which is being treated.
Disease state :
Renal dysfunction
Uremia
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 etc.
41. 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.
42. References
Bio pharmaceutics and Pharmacokinetics – A Treatise by
D.M Brahmankar and Sunil B. Jaiswal.
Bio pharmaceutics and Pharmacokinetics by P.L Madan
JAYPEE Publication.
Internet sources : Google
: www.astralianprescriber.com Volume 32
Number 2 April 2009.
Applied Bio pharmaceutics and Pharmacokinetics Vth
Edition by Leon Shargel.