Prof Henny Lucida Phd Apt Calculation of Dosesppt
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Transcript of Prof Henny Lucida Phd Apt Calculation of Dosesppt
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Calculation of Doses
Henny Lucida, PhD, Apt
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Conversion from iv infusion to oral
dosing
After the patients condition is controlled by ivinfusion, it is often desirable to convert to theoral route of same medication
in patient out patient to minimize fluctuation, when iv infusion stop
(the Cp decreases according to first orderelimination) then oral dosage regimen starts
directly the exponential decline of Cpfrom iv infusion should be matched by theexponential increases in Cp from the oralproduct
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A conversion from iv infusion to a
controlled release oral medication given
once or twice daily has become most
common, exp: theophylline & quinidine
Two methods for the calculation of
appropriate oral dosage regimen for a
patient whose condition has beenstabilized by an iv infusion
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Method 1
Assume: Css after iv infusion = C
av desiredafter multiple oral doses of the drug
SF
CLC
Dthen,kVCL
SF
kVC
D
kV
SFDC
Tav0DT
Dav0
D
0av
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Example
An adult asthmatic patient (age 55,78 kg)has been maintained on an iv infusion of
aminophylline at a rate of 34 mg/hr.The
steady-state theophylline drug
concentration was 12 mg/mL and total
body clearance was calculated as 3.0 L/hr.
Calculate an appropriate oral dosage
regimen of theophylline for this patient.
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Solution
S = 0.85 (cause aminophylline, a soluble salt which contains 85%
theophylline)
F = 1 (theophylline is 100% bioavailable)
Do/ or the dose rate =34 mg/hr. To convert to oral theophylline, S
& F should be considered :
28.9mg/hr
1
3410.85
SFDratedoseneTheophylli 0
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Solution (contd)
To convert the theophylline oral dose rate (28.9 mg/hr) to
a reasonable schedule for the patient with a
consideration of the various commercially theophylline
drug products:the total daily dose = 28.9 mg/hr x 24 hr = 693.6 mg/day
possible theophylline dosage schedule:
700 mg/day or 350 mg every 12 hrs or 175 mg every 6
hrs.The dose of 350 mg every 12 hrs could be given in
sustained-release form to avoid fluctuations.
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Method 2
Assumes that the rate of iv infusion (mg/hr) isthe same desired rate of oral dosage
Using the example in method 1, the solution:
iv infusion rate = 34 mg/hr
the total daily dose of aminophylline = 34 mg/hr
x 24 hr = 816 mg, which equivalent to 816 x 0.85
= 693.6 mg of theophylline.
Thus 700mg of theophylline per day or 350 mgcontrolled-release theophylline every 12 hours
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Determination of dose
The drug dose is estimated to deliver a
desirable (target) therapeutic level of drug
to the body. The dose of a drug is
estimated with the objective of delivering a
desirable therapeutic level of the drug tothe body.
For many drugs, the desirable therapeutic
levels and pharmacokinetic parametersare available in the clinical literature.
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For a drug given in multiple doses for an
extended period of time, the dosage regimen is
usually calculated, so that the average Css(Cav) is within the therapeutic range.
The dose can be calculated with eq.:
Where Do = dose, t = dosing interval
V
Ft1.44DC
D
210
av
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Equations for Cssmax and Css
min
k
k
D
0
min
k
D
0
max
e
e1
1
V
DC
e1
1
V
DC
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Effect of changing dose and dosing interval on
Cssmax and Css
min and Css
av
Cssav is most often used for dosage calculation
Cssav Cannot be measured directly but obtained
by AUC/ during multiple dosage regimen
Cssav as an indicator for deciding therapeuticblood level.
When dosing interval is changed, the dose may
be proportionally increased to keep Css
avconstant
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Examples;
Diazepam is given either 10 mg tid or 15 mg bid,
the same is obtained as shown by equation;
Cssav = SFDo/kVD
In fact: if the daily dose is the same, the Cssavshould be the same.
The dosing interval must be set with the
elimination half-life of the drug
drugs with narrow therapeutic window must be
monitored to ensure safety and efficacy
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Determination of frequency of drug
administration
The more frequently a drug isadministered, the smaller the dose mustbe to obtain the same Cssav.
Thus a dose of 250 mg every 3 hourscould be changed to 500 mg every 6 hourswithout affecting Cssav .
However, as the get longer, the size ofdose to maintain Cssav getscorrespondingly larger
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For narrow therapeutic window
drugs
When an excessively long is chosen, the
large dose may results in Cp above MTC
although the Cssav will remain the same.
Thus, must be given relatively frequently
to minimize excessive peak and trough
fluctuation in blood levels.
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Look at the example
Penicillins, have relatively low toxicity, may begiven at intervals much longer than their twithout any toxicity problems
Penicillin G: 250 mg every 6 hrs ( 8x its t, ie0.75 hrs), the TC >>100 times its EC
Digoxin: 0.25 mg/day (0.59 x its t, ie 1.7 days),the TC is only 1.5 times its EC
Therefore, a drug with a large therapeutic index(a large margin of safety) can be given in largedoses and at relatively long .
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Determination of both dose and
dosage interval
For intravenous multiple dosage regimen:
k
min
max
e1
CC
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Practice problem
The t elimination of an antibiotic is 3 hrs
with VDapp equivalent to 20% of BW. The
usual therapeutic range is between 5 and
15 mg/mL. Adverse toxicity for this drug isoften observed at serum conc greater than
20 mg/mL. Calculate a dosage regimen
(multiple iv doses) that will maintain thetherapeutic range.
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Solution
-0.231 = -1.10, = 4.76 hrThe dose was determine by eq:
Let VD= 20%BW = 200mL/kg
Then Do = 2 mg/kg
So, the dose should be
2 mg/kgBW every 4.76 hrs
The should be made as convenient as
Possible, let take 6 hrs, then we
Should calculate the Do again
k
D0max
e1
/VDC
k
min
max
e
1
C
C
333.0
1515
231.0
)3/693.0(
t
t
e
e
76)(0.231)(4.
0
e1
/200D
15
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Using nomograms and tabulation in
designing dosage regimensExp: Maintenance dose of theophylline when the Cp is not measured
Age Dose Dose/12hrs
6-9 yrs 24 mg/kg/day 12 mg/kg
9-12 yrs 20 mg/kg/day 10 mg/kg
12-16 yrs 18 mg/kg/day 9 mg/kg
> 16 yrs 13 mg/kg/day or 900 mg 6.5 mg/kg
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Dosing of drugs in infants and
children
Life stages:
Neonates (newborn baby)
Infants children
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Altered pharmacokinetic of drugs
Newborn babies / neonates:
Drug disposition, erratic: distrib from
placenta
exp: opiates (for maternal pain and relief)
benzodiazepines (for maternal
eclampsia/preeclampsia)
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Neonates: Drug absorption
Drug absorption, erratic & unavailable in
the ill body. An iv route is recommended,
im route is avoided
exp: paraldehyde & diazepam (neonatal
seizures) and paracetamol suppos
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Neonates: Drug distribution
Absolute GFR increases logarithmically withpost-conceptional age irrespective of the lengthof a babys gestation
Extracelluler fluids is highest at birth & falls dueto the post-natal diuresis over the first 48 hrs ofpost-natal life
The amount of adipose tissue vary substantially
(diabetic mother) Protein binding in plasma is influenced by theamount of albumin (2/3 of adult concentration)
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Neonates: Drug metabolism
Not quantitatively different but the
efficiency of the process
Drug metabolism is affected by
physiological hyperbilirubinemia of the
new-born. Bilirubin competes both for
enzyme binding sites & for glucuronate
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Neonates: Drug elimination
Immaturity of hepatic and renal function:slow elimination of most drugs (advantage:dont need a maintenance dose). Ex :
phenobarbitone, a loading dose of 20mg/kgBW is adequate to maintain thetherapeutic level for days. Drugs withnarrow therapeutic window (gentamycin,
vancomycin) should be given lessfrequently and plasma blood level must beasssayed to avoid toxicity
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A guide to administration of low therapeutic
index antibiotics for neonates
Use narrow spectrum & short courses antibiotics
Use cephalosporins (cefotaxime & ceftadizime)
for blind treatment (should be stopped after 48
hrs if cultures negative) rather thanaminoglycosides due to lower toxicity and no
TDM needed.
A routine TDM is required for aminoglycosides
and vancomycin ( also theophylline and
aminophylline)