# Re: [NMusers] Time-varying bioavailability and reproducibility in NONMEM analysis

could you show equations? Bioavailability is treated differently in Nonmem and R, so code should reflect it.
```Thanks
Leonid
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On 2/11/2020 3:52 AM, Le Louedec Felicien wrote:
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```Dear NONMEM users,

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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:
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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:
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---

\$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:

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-the same dosing regimen of 400 mg qd for 28 days (one line with EVID=1 per administration, no ADDL).
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-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.
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Then, I estimate these concentrations in maximum a posteriori Bayesian manner (MAXEVAL = 0) with ADVAN 13 (there is no inter-individual nor residual variability).
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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).
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Would any of you have an idea of why NONMEM does not return the same predictions ?
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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

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lelouedec.felic...@iuct-oncopole.fr <mailto:lelouedec.felic...@iuct-oncopole.fr>
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