Hello everyone!
This is giving me great deal of headache. If you can please help me with this,
my subsequent models will start working too. Please take your extremely
valuable time to help me, if you can.
I am trying to relate THC concentration in the central compartment to heart
rate, and in the effect compartment to psychological highness. So, there are
two PD effects, heart rate and highness. My model is successfully converging
and giving me physiologically relevant parameters when I run those models
separately i.e. simultaneous estimation of PK parameters and PD parameters
related to heart rate OR simultaneous estimation of PK parameters and PD
parameters related to highness. However, when I try to estimate all of them all
at once, my model is just not running. Errors are:
1. My final parameters are same as initial parameters
2. "OCCURS DURING SEARCH FOR ETA AT A NONZERO VALUE OF ETA NUMERICAL
DIFFICULTIES WITH INTEGRATION ROUTINE.
NO. OF REQUIRED SIGNIFICANT DIGITS IN SOLUTION VECTOR TO DIFFERENTIAL
EQUATIONS, 6, MAY BE TOO LARGE."
I have tried ADVAN 6, 8 AND 13 and have mostly used FOCE as estimation. Couple
of things to be noticed in NONMEM control stream below:
1. I am fixing THETA and OMEGAS for PK parameters derived from poppk model.
2. There are two emax equations, one for heart (EMAX) and one for effect
compartment in brain (EMAXB).
3. I am not estimating ETA around effect compartment rate constant and EC50.
4. I have 4 observations per subject for heart rate and highness.
5. TYPE 1 (=1) relates to highness, TYPE2(=1) relates to heart rate and TYPE
3 (=1) relates to Cp
So, you can see that overall, I am estimating very few parameters. Below is the
dataset and control stream
ID
TIME
AMT
DV
CMT
MDV
TYPE1
TYPE2
TYPE3
1402
9:39
40000
0
1
1
0
0
1
1402
9:39
.
0
3
0
1
0
0
1402
9:39
.
0
1
0
0
1
0
1402
9:50
.
271.8
1
0
0
0
1
1402
9:50
.
6
3
0
1
0
0
1402
9:50
.
34.4
1
0
0
1
0
$INPUT C ID TIME AMT DV CMT MDV TYPE1 TYPE2 TYPE3
$SUBROUTINE ADVAN6 TRANS1 TOL=6
$MODEL NCOMP = 3
COMP = (CENTRAL)
COMP = (PERIPH1)
COMP = (EFFTHC)
$PK
TVV1 = THETA(1) ;Central Volume of distribution in L
V1 = TVV1*EXP(ETA(1))
TVCL = THETA(2)
CL = TVCL*EXP(ETA(2)) ;Clearance
TVQ = THETA(3)
Q = TVQ*EXP(ETA(3)) ;Intercompartment Clearance
TVV2 = THETA(4)
V2 = TVV2*EXP(ETA(4))
KE01= THETA(5)
EC50H = THETA(6)
EMAXH = THETA(7)*EXP(ETA(5))
EC50B = THETA(8)
EMAXB = THETA(9)
HILL = THETA(10)
S1 = V1
A_0(1)=0
A_0(3)=0
$DES
C1 = A(1)/V1
C3 = A(3) ;effect compartment for THC
DADT(1) = (Q/V2)*A(2) - (Q/V1)*A(1) - (CL/V1)*A(1)
DADT(2) = (Q/V1)*A(1) - (Q/V2)*A(2)
DADT(3) = KE01*C1 - KE01*A(3)
$ERROR
CP = A(1)/V1
CE1 = A(3)
CONC = CP*(1 + ERR(1)) + ERR(3)
H = EMAXH*(((CP**HILL))/((EC50H**HILL)+(CP**HILL)))
B = EMAXB*(((CE1**HILL))/((EC50B**HILL)+(CE1**HILL)))
EFF1 = B + ERR(2)
EFF2 = H + ERR(4)
IF(TYPE1.EQ.1) IPRED = B
IF(TYPE2.EQ.1) IPRED = H
IF(TYPE3.EQ.1) IPRED = CP
Y = (EFF1*TYPE1) + (EFF2*TYPE2) + (CONC*TYPE3)
$THETA
16.5 FIX ; [V1]
255 FIX ; [CL]
33.5 FIX ; [Q]
29.7 FIX ; [V2]
(0, 1, 10) ; [KEO1]
(0.01,16.3) ; EC50H
(0, 79) ; EMAXH
(0.01,16.3) ; EC50B
10 FIX ; EMAXB
1 FIX ; HILL
$OMEGA
0.085 FIX ; [V1]
0.159 FIX ; [CL]
0.140 FIX ; [Q]
0.191 FIX ; [V2]
(0.001, 0.1) ; EMAXH
$SIGMA
0.0672 ;ERR1
178 ;ERR2
100 ;ERR4
$SIGMA
0.00004 FIX ;[ERR3]
$COV MATRIX=R UNCONDITIONAL
$ESTIMATION METHOD=1 MAXEVAL=99999 SIG=3 NOABORT PRINT=5 MSFO=simultaneous.MSF
Regards,
Sumeet K. Singla
Ph.D. Candidate
Division of Pharmaceutics and Translational Therapeutics
College of Pharmacy | University of Iowa
Iowa City, Iowa
[email protected]<mailto:[email protected]>
518.577.5881
Final Parameter is same as initial parameter - integrated PK-PD models with two PD parameters
ERR3 and ERR4 are mixed up, should be in order (in the ERROR block). Can it be the reason?
Leonid
Quoted reply history
On 12/8/2019 2:24 PM, Singla, Sumeet K wrote:
> Hello everyone!
>
> This is giving me great deal of headache. If you can please help me with this, my subsequent models will start working too. Please take your extremely valuable time to help me, if you can.
>
> I am trying to relate THC concentration in the central compartment to heart rate, and in the effect compartment to psychological highness. So, there are two PD effects, heart rate and highness. My model is successfully converging and giving me physiologically relevant parameters when I run those models separately i.e. simultaneous estimation of PK parameters and PD parameters related to heart rate OR simultaneous estimation of PK parameters and PD parameters related to highness. However, when I try to estimate all of them all at once, my model is just not running. Errors are:
>
> 1. My final parameters are same as initial parameters
> 2. “OCCURS DURING SEARCH FOR ETA AT A NONZERO VALUE OF ETA NUMERICAL
>
> DIFFICULTIES WITH INTEGRATION ROUTINE. NO. OF REQUIRED SIGNIFICANT DIGITS IN SOLUTION VECTOR TO DIFFERENTIAL EQUATIONS, 6, MAY BE TOO LARGE.”
>
> I have tried ADVAN 6, 8 AND 13 and have mostly used FOCE as estimation. Couple of things to be noticed in NONMEM control stream below:
>
> 1. I am fixing THETA and OMEGAS for PK parameters derived from poppk
> model.
> 2. There are two emax equations, one for heart (EMAX) and one for
> effect compartment in brain (EMAXB).
> 3. I am not estimating ETA around effect compartment rate constant and
> EC50.
> 4. I have 4 observations per subject for heart rate and highness.
> 5. TYPE 1 (=1) relates to highness, TYPE2(=1) relates to heart rate and
> TYPE 3 (=1) relates to Cp
>
> So, you can see that overall, I am estimating very few parameters. Below is the dataset and control stream
>
> ID
>
> TIME
>
> AMT
>
> DV
>
> CMT
>
> MDV
>
> TYPE1
>
> TYPE2
>
> TYPE3
>
> 1402
>
> 9:39
>
> 40000
>
> 0
>
> 1
>
> 1
>
> 0
>
> 0
>
> 1
>
> 1402
>
> 9:39
>
> .
>
> 0
>
> 3
>
> 0
>
> 1
>
> 0
>
> 0
>
> 1402
>
> 9:39
>
> .
>
> 0
>
> 1
>
> 0
>
> 0
>
> 1
>
> 0
>
> 1402
>
> 9:50
>
> .
>
> 271.8
>
> 1
>
> 0
>
> 0
>
> 0
>
> 1
>
> 1402
>
> 9:50
>
> .
>
> 6
>
> 3
>
> 0
>
> 1
>
> 0
>
> 0
>
> 1402
>
> 9:50
>
> .
>
> 34.4
>
> 1
>
> 0
>
> 0
>
> 1
>
> 0
>
> $INPUT C ID TIME AMT DV CMT MDV TYPE1 TYPE2 TYPE3
>
> $SUBROUTINE ADVAN6 TRANS1 TOL=6
>
> $MODEL NCOMP = 3
>
> COMP = (CENTRAL)
>
> COMP = (PERIPH1)
>
> COMP = (EFFTHC)
>
> $PK
>
> TVV1 = THETA(1) ;Central Volume of distribution in L
>
> V1 = TVV1*EXP(ETA(1))
>
> TVCL = THETA(2)
>
> CL = TVCL*EXP(ETA(2)) ;Clearance
>
> TVQ = THETA(3)
>
> Q = TVQ*EXP(ETA(3)) ;Intercompartment Clearance
>
> TVV2 = THETA(4)
>
> V2 = TVV2*EXP(ETA(4))
>
> KE01= THETA(5)
>
> EC50H = THETA(6)
>
> EMAXH = THETA(7)*EXP(ETA(5))
>
> EC50B = THETA(8)
>
> EMAXB = THETA(9)
>
> HILL = THETA(10)
>
> S1 = V1
>
> A_0(1)=0
>
> A_0(3)=0
>
> $DES
>
> C1 = A(1)/V1
>
> C3 = A(3) ;effect compartment for THC
>
> DADT(1) = (Q/V2)*A(2) - (Q/V1)*A(1) - (CL/V1)*A(1)
>
> DADT(2) = (Q/V1)*A(1) - (Q/V2)*A(2)
>
> DADT(3) = KE01*C1 - KE01*A(3)
>
> $ERROR
>
> CP = A(1)/V1
>
> CE1 = A(3)
>
> CONC = CP*(1 + ERR(1)) + ERR(3)
>
> H = EMAXH*(((CP**HILL))/((EC50H**HILL)+(CP**HILL)))
>
> B = EMAXB*(((CE1**HILL))/((EC50B**HILL)+(CE1**HILL)))
>
> EFF1 = B + ERR(2)
>
> EFF2 = H + ERR(4)
>
> IF(TYPE1.EQ.1) IPRED = B
>
> IF(TYPE2.EQ.1) IPRED = H
>
> IF(TYPE3.EQ.1) IPRED = CP
>
> Y = (EFF1*TYPE1) + (EFF2*TYPE2) + (CONC*TYPE3)
>
> $THETA
>
> 16.5 FIX ; [V1]
>
> 255 FIX ; [CL]
>
> 33.5 FIX ; [Q]
>
> 29.7 FIX ; [V2]
>
> (0, 1, 10) ; [KEO1]
>
> (0.01,16.3) ; EC50H
>
> (0, 79) ; EMAXH
>
> (0.01,16.3) ; EC50B
>
> 10 FIX ; EMAXB
>
> 1 FIX ; HILL
>
> $OMEGA
>
> 0.085 FIX ; [V1]
>
> 0.159 FIX ; [CL]
>
> 0.140 FIX ; [Q]
>
> 0.191 FIX ; [V2]
>
> (0.001, 0.1) ; EMAXH
>
> $SIGMA
>
> 0.0672 ;ERR1
>
> 178 ;ERR2
>
> 100 ;ERR4
>
> $SIGMA
>
> 0.00004 FIX ;[ERR3]
>
> $COV MATRIX=R UNCONDITIONAL
>
> $ESTIMATION METHOD=1 MAXEVAL=99999 SIG=3 NOABORT PRINT=5 MSFO=simultaneous.MSF
>
> Regards,
>
> *Sumeet K. Singla*
>
> *Ph.D. Candidate*
>
> *Division of Pharmaceutics and Translational Therapeutics*
>
> *College of Pharmacy | University of Iowa*
>
> *Iowa City, Iowa*
>
> *[email protected] <mailto:[email protected]>*
>
> *518.577.5881*