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Re: Time-varying bioavailability and reproducibility in NONMEM analysis

From: Saeheum Song <ss.pkpdmodel>
Date: Tue, 11 Feb 2020 11:07:08 -0500

Pls check what you have compared. You have used sigma 1 for nonmem not for
mrgsolve.

Even if you use sigma q for Mrgsolve, the results will be
slightly different due to fittong vs. Simulation via random numbers.

Hope it helps


On Tue, Feb 11, 2020, 10:43 AM Le Louedec Felicien <
LeLouedec.Felicien

> Please find below the code for NONMEM analysis and for mrgsolve which is
> the 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 POSTHO=
C FORMAT=
> s1PE16.8E3
> $COV PRINT=E MATRIX=S
> $TABLE ID TIME EVID AMT CMT DV MDV TOLD F1 PRED IPRED IWRES IRES ONEHEADE=
R
> 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 *
> PERIPHERAL ;
> 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
> De 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 Nonme=
m
> 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 whic=
h
> > includes a time-varying bioavailability. Here is a simplified example o=
f
> > 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 line=
s
> > 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 - 11:07:08 EST

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