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Time-varying bioavailability and reproducibility in NONMEM analysis

From: Le Louedec Felicien <LeLouedec.Felicien>
Date: Tue, 11 Feb 2020 08:52:01 +0000

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 compa=
rtment, where bioavailability is decreasing over time given a maximum in de=
crease (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 su=
re 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 a=
re filled with EVID=0, DV=., and MDV=1.

Then, I estimate these concentrations in maximum a posteriori Bayesian mann=
er (MAXEVAL = 0) with ADVAN 13 (there is no inter-individual nor residual=
 variability).

My problem is that NONMEM found different concentrations in these 28 indivi=
duals, even though they received the same dose. Besides, as excepted, I fou=
nd 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 predic=
tions ?
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.felicien
.fr>



Received on Tue Feb 11 2020 - 03:52:01 EST

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