- On 24 Sep 2000 at 21:49:19, "viswanath pawar" (vd_pawar.at.rediffmail.com) sent the message

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I am working on a compound which has an half life of about 1.5hrs in

dogs given by I.V route. I need to maintain ceratin therapeutic blood

levels for upto 4 hours.

I would like to give a loading I.V dose followed by constant infusion

for about an hour or so.

How do I calculate the loading dose. And after what time of bolus I

should start the infusion.

Any help I would appreciate.

V.Pawar - On 25 Sep 2000 at 15:51:26, ml11439.at.goodnet.com sent the message

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Dr.Pawar,

In order to determine an appropriate loading dose and

rate of infusion, you would want to determine the drug's

kinetic parameters in the subject(s) of interest. In the

simplest case, one could assume a one compartment model

and determine Ke and Vd.

i) Ke and T1/2

Assuming a one compartment model, at least two plasma

levels could be obtained post IV bolus, and the following

equation could be used to determine Ke:

Ke= [Ln(C1)- Ln(C2)]/[T2-T1]

T1/2= .693/Ke

Optimally, several plasma concentrations could be

obtained and Ke could be solved by linear regression with

Y= LnCp and X= time. With nonlinear regression, Y= Cp

and X= time.

ii) Vd

Once Ke is obtained, you can solve for Vd using the

following fromula for an IV bolus:

Cp= [Xo/Vd]e-Ket

Using the Ke you obtained in step 1, you can extrapolate

the plasma concentration to time zero to obtain Cpo, the

concentration immediately following the bolus:

Cpo= [Xo/Vd]= Cp1e+ket1= Cp2e=Ket2

Vd= Xo/Cpo

Remember to watch your units, such that if the dose was

in mg, then the concentration should be in mg/liter, and the

Vd will be in liters

Alternatively, if you used linear regression, then the

Y intercept of the regression equation would be equal to Cpo.

iii) Loading dose calculation

Once the Vd has been estimated, the IV bolus loading dose

can be calculated using the follwing formula:

Loading dose= Cp(desired mg/l) x Vd (liters)

iv) Maintenance infusion calculation

The infusion rate can be calculated using the following

formula:

Css= Ko/KeVd

Ko= Css(KeVd)

v) Calculation of plasma concentrations

The plasma concentrations can be caculated using the

following formula:

Cp= [Xo/Vd]e-ket' + [Ko/KeVd][1-e-Ket'']

Xo= bolus dose (mg)

t'= time after IV bolus

Ko= infusion rate (mg/hr)

t''= duration of IV infusion

vi) Multicompartment models and fits

In the two compartment case, the same ideas apply but

the plasma levels are fitted by nonlinear regression, and

a Vc along with alpha and beta are calculated. Vc could

be substituted into equation iii for a loading dose calcualtion,

and beta could be substituted into equation iv for Ko calculation.

Mike Leibold, PharmD, RPh

ML11439.-a-.goodnet.com

References

1) Gibaldi, M., Perrier, D., Pharmacokinetics, New York, Marcel Dekker

1975

2) Gibaldi, M., Perrier, D., Pharmacokinetics 2nd ed, New York, Marcel Dekker

1982

3) Wagner, J., Fundamentals of Clinical Pharmacokinetics, Hamilton, Drug

Intelligence Publications 1975

4) Godfrey, Keith, Compartment Models and Their Application, New York,

Academic Press 1983

5) Wagner, J.G., Pharmacokinetics for the Pharmaceutical Scientist, Lancaster,

Technomic Publishing Co 1993

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