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Final Parameter is same as initial parameter - integrated PK-PD models with two PD parameters

From: Singla, Sumeet K <sumeet-singla>
Date: Sun, 8 Dec 2019 19:24:16 +0000

Hello everyone!

This is giving me great deal of headache. If you can please help me with th=
is, 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 a=
re two PD effects, heart rate and highness. My model is successfully conver=
ging and giving me physiologically relevant parameters when I run those mod=
els separately i.e. simultaneous estimation of PK parameters and PD paramet=
ers related to heart rate OR simultaneous estimation of PK parameters and P=
D parameters related to highness. However, when I try to estimate all of th=
em 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 DI=
FFICULTIES WITH INTEGRATION ROUTINE.

NO. OF REQUIRED SIGNIFICANT DIGITS IN SOLUTION VECTOR TO DIFFERENTIAL EQU=
ATIONS, 6, MAY BE TOO LARGE."

I have tried ADVAN 6, 8 AND 13 and have mostly used FOCE as estimation. Cou=
ple of things to be noticed in NONMEM control stream below:

  1. I am fixing THETA and OMEGAS for PK parameters derived from poppk mod=
el.
  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 E=
C50.
  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 distributi=
on 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=sim=
ultaneous.MSF

Regards,

Sumeet K. Singla
Ph.D. Candidate
Division of Pharmaceutics and Translational Therapeutics
College of Pharmacy | University of Iowa
Iowa City, Iowa
sumeet-singla
518.577.5881


Received on Sun Dec 08 2019 - 14:24:16 EST

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