From:Sophie.Glatt@serono.com
Subject:[NMusers] Endogenous drug
Date:Fri, 12 Jul 2002 11:01:46 +0100
Dear all,
I am modelling, multiple dose, 2-compartments IV and SC pharmacokinetics
of a drug X which exhibits endogenous plasma levels. Endogenous production
appears constant on the time scales (placebo).
In each subject, the baseline concentration of X was measured in one
pre-dose sample, and samples were measured for X post-dose, exhibiting a
return to the endogenous levels.
I know how to write the code for an endogenous baseline drug concentration,
and used the following code for the residual error:
$ERROR
FTOT=F+CBAS, FTOT is the total plasma concentration estimate, comprising
the sum of the exogenous (F) and endogenous (CBAS) drug concentrations.
W=FTOT
Y=FTOT+W*(EPS(1))
IPRED=FTOT
IRES=CP*IPRED
IWRES=IRES/W
The PK model is ADVAN 4 TRANS 4
In other software, one can initialize each compartment to the ratio of
Rin/CL, thereby generating a steady-state in the body. In above case,
NONMEM code only adds to the amount (once) in the central compartment
(CBAS) ignoring the peripheral compartment.
Is there some way of coding the model to place a constant amount in all
compartments.
Thanks in advance.
Sophie.
Endogenous drug
From:eonid Gibiansky
Subject:Re: [NMusers] Endogenous drug
Date:Fri, 12 Jul 2002 09:00:26 -0400
Sophie,
To place a constant amount in any compartment you need to have a source (a
steady-state infusion-type input into some compartment) that would results
in the appropriate endogenous level. I am not sure that you need this
complication. I your model, you do not add addition amount to the central
compartment but subtract (from DV) the endogenous concentration level.
(The description:
> In above case,
>NONMEM code only adds to the amount (once) in the central compartment
>(CBAS) ignoring the peripheral compartment.
is not quite correct)
Assuming linearity, you model "extra dose", ignoring natural level. If you
really need endogenous levels in the other compartments, you may look for a
steady-state solution of the system that you find in your modeling process.
For sure, concentrations in the other compartment can be expressed via the
model parameters and endogenous level in the central compartment (assume
that all DADT=0). You also may find corresponding source (as a free term in
the equation for the central compartment if the source is in the central
compartment).
For a two compartment model, equations for the "endogenous part" of the
concentration are as follows:
DA1DT=p1-(k12+k10) A1+k21 A2
DA2DT=k12 A1 - k21 A2
where p1 is "endogenous source", A1, A2 are endogenous amounts (A1=CBAS*V1)
Assuming DA1DT=DA2DT=0, A2 (or C2) and p1 can be expressed as a function of
CBAS and model parameters.
Of course, if you have reasons to believe that your endogenous source is in
the compartment 2, you will need to solve for
-(k12+ k10) A1+k21 A2 = 0
k12 A1 - k21 A2+p1=0
Leonid