could you show equations? Bioavailability is treated differently in
Nonmem and R, so code should reflect it.
Thanks
Leonid
On 2/11/2020 3:52 AM, Le Louedec Felicien wrote:
Dear NONMEM users,
I’m struggling for a couple of weeks against contradictory results
between NONMEM and R analysis of the same data with the same model which
includes a time-varying bioavailability. Here is a simplified example of
my issue:
On the one hand, let’s introduce a bicompartmental model with a depot
compartment, where bioavailability is decreasing over time given a
maximum in decrease (MAXDECR) and a first-order decay constant (LAMBDA).
Instead of the variable TIME, I use a covariate TOLD (Time Of Last Dose)
in order to be sure that the value of F1 computed by NONMEM will be
independent of the time used for computation:
---
$INPUT CID TIME EVID AMT CMT DV MDV TOLD
$MODEL COMP=(DEPOT) COMP=(CENTRAL) COMP=(PERIPH)
$PK
MAXDECR = THETA(1)
LAMBDA = THETA(2) / 24 ; TIME is in hour, Lambda in day-1
F1 = 1 - MAXDECR + MAXDECR * EXP(-LAMBDA * TOLD)
$THETA
(0, 0.5, 1) FIX
(0, 0.15 ) FIX
---
On the other hand, we have a dataset of 28 IDs with:
-the same dosing regimen of 400 mg qd for 28 days (one line with EVID=1
per administration, no ADDL).
-different “sampling occasions” at 0h, 6h, 12 and 18h post-dose; at day
1 for ID1, at day 1&2 for ID2, at day 1&2&3 for ID3, and so on until
ID28 who has a complete PK exploration from day 1 to 28. All these lines
are filled with EVID=0, DV=., and MDV=1.
Then, I estimate these concentrations in maximum a posteriori Bayesian
manner (MAXEVAL = 0) with ADVAN 13 (there is no inter-individual nor
residual variability).
My problem is that NONMEM found different concentrations in these 28
individuals, even though they received the same dose. Besides, as
excepted, I found that all individuals had the same value for F1 (at a
given time point).
Would any of you have an idea of why NONMEM does not return the same
predictions ?
Thank you very much in advance
Kind regards
Félicien LE LOUEDEC, PharmD
PhD student
Centre de Recherches en Cancérologie de Toulouse (CRCT), Toulouse, FRANCE
Team 14: « Dose Individualization of Anticancer Drugs »
+335 31 15 55 69
lelouedec.felic...@iuct-oncopole.fr
<mailto:lelouedec.felic...@iuct-oncopole.fr>
