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RE: Time-varying bioavailability and reproducibility in NONMEM analysis

From: Le Louedec Felicien <LeLouedec.Felicien>
Date: Tue, 11 Feb 2020 15:34:18 +0000

Please find below the code for NONMEM analysis and for mrgsolve which is th=
e package I use to perform simulations in R

Thanks you very much

Félicien

;;;;;NONMEM CODE;;;

$PROBLEM TEST F DECREASE
$INPUT ID TIME EVID AMT CMT DV MDV TOLD
$DATA ds_sim_told.csv IGNORE=
$SUBROUTINES ADVAN13 TOL=4
$MODEL COMP=(DEPOT) COMP=(CENTRAL) COMP=(PERIPH)

$PK
TVCL = THETA(1)
TVVC = THETA(2)
TVKA = THETA(3)
TVALAG1 = THETA(4)
TVQ = THETA(5)
TVVP = THETA(6)
TVLAMBDA = THETA(7)
TVMAXDECR = THETA(8)
ERRADD = THETA(9)
ERRPROP = THETA(10)

CL = TVCL
VC = TVVC
KA = TVKA
ALAG1 = TVALAG1
Q = TVQ
VP = TVVP

LAMBDA = TVLAMBDA / 24
MAXDECR= TVMAXDECR
TVF= 1-MAXDECR+MAXDECR*EXP(-LAMBDA*TOLD)
F1 = TVF

K20 = CL/VC
K23 = Q/VC
K32 = Q/VP
S2 = VC

$DES
DADT(1) = - KA * A(1)
DADT(2) = KA * A(1) - K20*A(2) - K23*A(2) + K32*A(3)
DADT(3) = K23* A(2) - K32*A(3)

$ERROR
IPRED=F
W=SQRT(ERRADD**2+(ERRPROP*IPRED)**2)
Y=IPRED+W*EPS(1)
IRES=DV-IPRED
IWRES=IRES/(W+0.001)

$THETA
(0, 0.5) FIX ; 1 CL
(0, 3) FIX ; 2 VC
(0, 0.1) FIX ; 3 KA
(0, 1) FIX ; 4 ALAG
(0, 1) FIX ; 5 Q
(0, 25) FIX ; 6 VP
(0, 0.15) FIX ; 7 LAMBDA
(0, 0.50) FIX ; 8 MAXDECR
(0) FIX ; 9 ADD
(0) FIX ; 10 PROP

$OMEGA 0 FIX
$SIGMA 1 FIX

$ESTIMATION METHOD=1 INTER NOABORT MAXEVAL=0 SIG=3 PRINT=5 POSTHOC =
FORMAT= s1PE16.8E3
$COV PRINT=E MATRIX=S
$TABLE ID TIME EVID AMT CMT DV MDV TOLD F1 PRED IPRED IWRES IRES ONEHEADER =
NOPRINT FILE = run301.TAB FORMAT= s1PE16.8E3

;;;; end of NONMEM CODE ;;;;;

;;;; MRGSOLVE CODE ;;;;;
$PROB test F decrease
  
$PARAM
TVCL : 0.5 : 1 Clearance (L.h-1)
TVVC : 3 : 2 Volume (L)
TVKA : 0.1 : 3 Absorption rate constant (h-1)
TVALAG : 1 : 5 Lag time (h)
TVQ : 1 : 6 Intercompartmental Clearance (L.h-1)
TVVP : 25 : 7 Volume (L)
TVLAMBDA : 0.15 : 8 First-order decay constant (day-1)
TVMAXDECR: 0.50 : 9 Magnitude of decrease constant (%)

TOLD : 0 : default TOLD

$CMT
DEPOT : Depot compartment
CENTRAL : Central compartment
PERIPHERAL : Peripheral compartment

$GLOBAL
double CL, VC, KA, ALAG, Q, VP, LAMBDA, MAXDECR, TVF, K20, K23, K32, F1 ;

$TABLE
double DV = (CENTRAL / VC) ;

$MAIN
CL = TVCL ;
VC = TVVC ;
KA = TVKA ;
ALAG = TVALAG ;
Q = TVQ ;
VP = TVVP ;
LAMBDA = TVLAMBDA / 24 ;
MAXDECR = TVMAXDECR ;

TVF = 1 - MAXDECR + MAXDECR * exp(-LAMBDA*TOLD) ;
F1 = TVF ;

K20 = CL / VC ;
K23 = Q / VC ;
K32 = Q / VP ;

F_DEPOT = F1 ;
ALAG_DEPOT = ALAG ;

$ODE
dxdt_DEPOT = -KA * DEPOT ;
dxdt_CENTRAL = KA * DEPOT - K20 * CENTRAL - K23 * CENTRAL + K32 * PERI=
PHERAL ;
dxdt_PERIPHERAL = K23 * CENTRAL - K32 * PERIPHERAL;

$CAPTURE
DV : Concentration central (mcg/L)
F_DEPOT : F

;;;; end of MRGSOLVE CODE ;;;;







-----Message d'origine-----
De : owner-nmusers
e la part de Leonid Gibiansky
Envoyé : mardi 11 février 2020 15:19
À : nmusers
Objet : 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


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, FRAN=
CE
>
> Team 14: « Dose Individualization of Anticancer Drugs »
>
> +335 31 15 55 69
>
> Lelouedec.felicien
> <mailto:Lelouedec.felicien
>



Received on Tue Feb 11 2020 - 10:34:18 EST

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