PharmPK Discussion - Infusion and loading doses

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


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

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


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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