could you try models without ALAG? will they also differ? Not sure how
MRGsolve treats time-dependent covariates for F1. Nonmem will use the
next value of TOLD. In this case, TOLD at dose records should be equal
to the time of the previous dose (assuming that ALAG < inter-dose
interval), is this how it was coded?
Leonid
On 2/11/2020 10:34 AM, Le Louedec Felicien 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 : owner-nmus...@globomaxnm.com [mailto:owner-nmus...@globomaxnm.com] De la
part de Leonid Gibiansky
Envoyé : mardi 11 février 2020 15:19
À : nmusers@globomaxnm.com
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
lelouedec.felic...@iuct-oncopole.fr
<mailto:lelouedec.felic...@iuct-oncopole.fr>
