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 < [email protected]> wrote: > 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 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 @annotated > 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 @annotated > 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 @annotated > DV : Concentration central (mcg/L) > F_DEPOT : F > > ;;;; end of MRGSOLVE CODE ;;;; > > > > > > > > -----Message d'origine----- > De : [email protected] [mailto:[email protected]] > De la part de Leonid Gibiansky > Envoyé : mardi 11 février 2020 15:19 > À : [email protected] > 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, FRANCE > > > > Team 14: « Dose Individualization of Anticancer Drugs » > > > > +335 31 15 55 69 > > > > [email protected] > > <mailto:[email protected]> > > > > > > >
