Problem (bug ?) with RATE and F1 in $PK
From: Pierre Maitre <maitre@cdg.ch>
Subject: [NMusers] Problem (bug ?) with RATE and F1 in $PK
Date: Thu, 01 Nov 2001 23:00:24 +0100
Dear Nonmem Users
I run into the following problem with NMTRAN
My model is a 2 cpt model with s/c and iv administration.
I use ADVAN4, TRANS4, and my control file for NMTRAN is as follow:
$PROB xxxx 2cpt sc and iv
$DATA ../data/xxxx_PK.nm NOREWIND
$INPUT ID TIME CMT DOSE=AMT RATE CP=DV MDV EVID
$SUBROUTINES ADVAN4 TRANS4
$PK
CALLFL=-2
;
CL = THETA(1)*EXP(ETA(1))
V2 = THETA(2)
Q = THETA(3)*EXP(ETA(2))
V3 = THETA(4)*EXP(ETA(3))
KA = THETA(5)*EXP(ETA(4))
F1 = THETA(6)
S2 = V2
$ERROR etc....
Drug input occurs either as an iv bolus (i.e. in cmpt 2 when using
advan4) or as a long continuous sub-cutaneous infusion (i.e. in
compartment 1 when using advan4).
Bioavailability of the sub-cutaneous depot is probably between 0.3 to
0.5
As long as F1 (the bioavailability for the depot compartment) is
constrained to be 1, there is no problem.
However, when F1 is smaller than 1, say 0.5, strange things happen: the
duration of infusion is reduced by a factor F1.
I found the reason in the NONMEM documentation:
The command:
nmhelp bioavailability
gives the following:
> If the amount is A, and the bioavailability fraction is F, only the
> fraction F of A actually appears in the dose compartment (either
> instantaneously at the time the dose enters the compartment - with a
> bolus dose, or over a period of time - with an infusion).
In other words, if the fraction F1 is 0.5, the amount A entering
compartment 1 is only A*0.5. However the RATE of administration (a known
value, in the data set, see $INPUT above)) is not modified by F1 and is
unchanged. Therefore, the duration of administrations, i.e. A/RATE is
reduced by a factor F1, leading to very strange fits.
Question: is this a bug in the NMTRAN code, or am I missing something?
Pierre Maitre
--
Dr Pierre-O. Maitre
Privat Docent
FMH Anesthésiologie
FMH Pharmacologie Clinique
Cabinet médical / A la Joy
CH-1273 Genolier Switzerland