Transcript DOSAGE REGIMEN Prof. Dr. Basavaraj K. Nanjwade M.Pharm., Ph. D Department of Pharmaceutics KLE University’s College of Pharmacy BELGAUM – 590010, Karnataka, India Cell No:

DOSAGE REGIMEN
Prof. Dr. Basavaraj K. Nanjwade M.Pharm., Ph. D
Department of Pharmaceutics
KLE University’s College of Pharmacy
BELGAUM – 590010, Karnataka, India
Cell No: 0091 9742431000
E-mail: [email protected]
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Multiple dosing with respect to
I.V. and Oral
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CONTENTS
• Dosage regimen
• General concepts
• Multiple dosing with respect to I.V.
• Multiple dosing with respect to Oral route.
• Concept of loading dose, maintenance dose,
• Accumulation, Adjustment of dosage in renal
and hepatic impairment
• Individualization of therapy
• References.
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Dosage regimen
It is defined as the manner in which a drug is
taken. For certain analgesics, hypnotics, antiemetics etc. a single dose may provide an
effective treatment. But the duration of most
illness is longer than the therapeutic effect
produced by a single dose. In such cases drugs
are required to be taken on a repetitive basis
over a period of time.
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Thus an “optimal multiple dosage regimen” is
the one in which the drug is administered in
suitable doses, by suitable route, with
sufficient frequency that ensures maintenance
of plasma concentration within the
therapeutic window without excessive
fluctuation and drug accumulation for the
entire duration of therapy.
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Two major parameters that can be adjusted in developing a
dosage regimen are:
1. The dose size :- It is the quantity of the drug administered
each time. The magnitude of therapeutic & toxic responses
depend upon dose size. Amount of drug absorbed after
administration of each dose is considered while calculating
the dose size. Greater the dose size greater the fluctuation
between Css,max & Css,min (max. and min. steady state
concentration) during each dosing interval & greater
chances of toxicity.
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2. Dose frequency :- It is the time interval between
doses. Dose interval is inverse of dosing frequency.
Dose interval is calculated on the basis of half life of
the drug. When dose interval is increased with no
change in the dose size ,Cmin, Cmax & Cav decrease,
but when dose interval is reduced, it results in
greater drug accumulation in the body and toxicity.
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Certain concepts
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B) Time to reach steady state during multiple
dosing:
The time required to reach steady state
depends primarily upon the half life of the
drug. Provided Ka>>Ke, plateau is reached in
approximately 5 half lives. The time taken to
reach steady state is independent of dose size,
dose interval & no. of doses. It is determined
only by Ke
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Multiple dosing with respect to I.V.
On repeated drug administration, the plasma
conc. will be added upon for each dose
interval giving a plateau or steady state with
the plasma conc. fluctuating between a
minimum and maximum
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Css max
Plsama drug conc.
Steady state
Css min
time
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Multiple dosing with respect to oral
route
When an oral multiple dosing regimen is followed,
plasma conc. will increase, reach a maximum and
begin to decline. A 2nd dose will be administered
before all of the absorbed drug from 1st dose is
eliminated. Consequently plasma conc. resulting
from 2nd dose will be higher than from 1st dose.
This increase in conc. with dose will continue to
occur until a steady state is reach at which rate of
drug entry into the body = rate of exit
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Plasma drug conc.
C max
C min
time
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Concept Of Accumulation Index, Loading
Dose And Maintenance Dose
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Loading Dose
• A drug dose does not show therapeutic activity unless it
reaches the desired steady state.
• It takes about 4-5 half lives to attain it and therefore time
taken will be too long if the drug has a long half-life.
• Plateau can be reached immediately by administering a
dose that gives the desired steady state instantaneously
before the commencement of maintenance dose X0.
• Such an initial or first dose intended to be therapeutic is
called as priming dose or loading dose X0,L.
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Size And Administration
• After e.v. administration, Cmax is always smaller than
that achieved after i.v. and hence loading dose is
proportionally smaller.
• For the drugs having a low therapeutic indices, the
loading dose may be divided into smaller doses to be
given at a various intervals before the first maintenance
dose.
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Calculation Of Loading Dose
• A simple equation for calculating loading dose is :
X0,L = Css,av Vd
F
• When Vd is not known, loading dose may be calculated
by the following equation :
X0,L =
1
X0
(1 – e-KEt) (1 – e-Kat)
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Calculation Of Loading Dose
• Given equation applies when Ka >> Ke and drug is
distributed rapidly. When drug is given i.v. or when
absorption is extremely rapid, the absorption phase is
neglected and the above equation reduces to :
X0,L
1
= Rac
X0 = (1 – e-KEt)
•
The ratio of loading dose and maintenance dose X0,L/X0
is called as dose ratio.
• As a rule when T (dosing interval) = t1/2 dose ratio
should be 2
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Calculation Of Loading Dose
• When T > t1/2 dose ratio is smaller than 2.0
• When T< t1/2 dose ratio is greater than 2.0
• If the loading dose is not optimum either too low or too
high, the steady state is attained within a 4-5 half lives in
a manner similar to when no loading dose is given.
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Dose ratio >2
loading dose X0,L
maintenance dose X0
T
X
0
T
X
0
T
X
0
T
X
0
T
Dose ratio 2
MSC
Cp
MEC
dosing interval in hrs
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Maintenance Of Drug
Within The Therapeutic Range
• The ease or difficulty in Maintaining drug concentration
within the therapeutic window depends upon –
- Therapeutic index of the drug
- Half life of the drug
- Convenience of dosing.
• For a drug with low half-life and TI it is extremely
difficult. Example – heparin
• However the drug with low half-life (0.9 hrs) and high
TI can be given less frequently every 4-6 hrs) provided
maintenance dose is large.
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• Drugs with half-lives greater than 8 hrs are more
convenient to dose. Given once every half life.
• For drugs with very long half-lives 24 hrs e.g.
amlodipine, once daily dose is very convenient
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Accumulation Index
(multiple dose regimen of i.v bolus)
• drug accumulation during multiple dosing
X0+1/2X0
(½+1/4) X0
1/2X0
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• After administration of first dose X0 at t=0 the amount of
drug in the body X=1X0.
• At the next dosing interval X=1/2X0, the amount of drug
remain in the body, administration of next i.v dose raises
the body content to X=X0 + ½ X0 i.e. drug accumulation
occurs in the body.
• Accumulation occurs because drug from previous doses
has not been removed completely.
• As the amt. of drug gradually rises in the body rate of
elimination also rises proportionally until plateau is
reached.
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• Thus the extent to which a drug accumulates in the body
is a function of its dosing interval and elimination of
half-life and is independent of dose size.
• The extent to which any drug accumulate with any
dosing interval in a patient can be derived from
information obtained with a single dose and is given by
accumulation index Rac as :
Rac
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=
1
(1 – e-KEt)
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Therapeutic
drug
monitoring
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Therapeutic drug monitoring
• It specializes in the measurement of medication levels
in blood. Its main focus is on drugs with a
narrow therapeutic range, i.e. drugs that can easily be
under- or overdosed.
• Therapeutic drug monitoring is important as
Insufficient levels of drug in the plasma will lead to
under treatment or resistance, and excessive levels can
lead to toxicity and tissue damage.
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Indications for Therapeutic
Drug monitoring include:
• There is narrow therapeutic window.
• There are potential patient compliance problems.
• The drug dose cannot be optimized by clinical observation
alone.
• Knowledge of the drug level influences management.
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Sampling and drug analysis
• Usually, plasma or serum is used for drug assays.
• Drug assay methods should have adequate sensitivity, be
specific for the drug (or metabolite) to be measured and have
appropriate accuracy and precision.
• Automated immunoassay methods, High performance liquid
chromatography (HPLC) and Gas liquid chromatography (GLC)
(e.g. amiodarone, perhexiline) can be used.
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Examples of drugs analysed by
therapeutic drug monitoring :
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Drugs commonly monitored
Drug
Therapeutic range mg/L
Digoxin
0.5 - 2.11
Amiodarone
1.0 - 2.5
Lignocaine
2.0 - 5.0
Quinidine
2.0 - 5.0
Flecainide
0.2 - 0.9
Mexilitine
0.5 - 2.5
Salicylate
150 - 300
Perhexiline
0.15 - 0.6
Theophylline
10 - 20
Phenytoin
10 - 20
Carbamazepine
5.0 - 12
Sodium valproate
50 - 100
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Reference
•
Biopharmaceutics And Pharmacokinetics A Treatise,
Brahmankar DM Vallabh prakashan page no. 309-314.
 “Text Book Of Biopharmaceutics & Pharmacokinetics”, Dr.
Shobha Rani R. Hiremath..
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THANK YOU
Cell No: 0091 9742431000
E-mail: [email protected]
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