prof henny lucida phd apt calculation of dosesppt

7/30/2019 Prof Henny Lucida Phd Apt Calculation of Dosesppt

1/27

Calculation of Doses

Henny Lucida, PhD, Apt


2/27

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


3/27

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


4/27

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


5/27

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.


6/27

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


7/27

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.


8/27

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


9/27

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.


10/27

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


11/27

Equations for Cssmax and Css

min

k

k

D

0

min

k

D

0

max

e

e1

1

V

DC

e1

1

V

DC


12/27

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


13/27

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


14/27

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


15/27

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.


16/27

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 .


17/27

Determination of both dose and

dosage interval

For intravenous multiple dosage regimen:

k

min

max

e1

CC


18/27

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.


19/27

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


20/27

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



> 16 yrs 13 mg/kg/day or 900 mg 6.5 mg/kg


21/27

Dosing of drugs in infants and

children

Life stages:

Neonates (newborn baby)

Infants children


22/27

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)


23/27

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


24/27

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)


25/27

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


26/27

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


27/27

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)

prof henny lucida phd apt calculation of dosesppt

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