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Re: Time-varying bioavailability and reproducibility in NONMEM analysis

From: Leonid Gibiansky <lgibiansky>
Date: Tue, 11 Feb 2020 09:18:41 -0500

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.felicien
> <mailto:Lelouedec.felicien
>
Received on Tue Feb 11 2020 - 09:18:41 EST

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