Back to the Top
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.
Back to the Top
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]
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.
Once Ke is obtained, you can solve for Vd using the
following fromula for an IV bolus:
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
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
v) Calculation of plasma concentrations
The plasma concentrations can be caculated using the
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
1) Gibaldi, M., Perrier, D., Pharmacokinetics, New York, Marcel Dekker
2) Gibaldi, M., Perrier, D., Pharmacokinetics 2nd ed, New York, Marcel Dekker
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
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (email@example.com)