ERR3 and ERR4 are mixed up, should be in order (in the ERROR block). Can
it be the reason?
Leonid
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*
*sumeet-sin...@uiowa.edu <mailto:sumeet-sin...@uiowa.edu>*
*518.577.5881*
