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

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