Hi Everyone,
I am trying to relate my compound, THC and metabolite, THC-OH, concentrations
to psychological highness (on scale of 0-10) using effect compartment approach.
This effect compartment model is well validated in literature for these two
compounds. When I run my model, I get the following error. I have tried ADVAN
6,8 AND 13 but no success so far. I have attached sample of my dataset and the
control stream. Both THC and THC-OH has peripheral compartments. TYPE 3 equates
to THC conc, TYPE2 equates to metabolite conc, and TYPE 1 equates to highness.
CMT 1 and CMT4 denote THC and THCOH concentration in central compartment,
respectively.
Please let me know of any possible solutions.
"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, 3, MAY BE TOO LARGE. "
ID TIME
DV CMT TYPE1 TYPE2 TYPE3 MDV
1204
9:38
21138
79.9
1
0
0
1
1
1204
9:38
.
7
.
1
0
0
0
1204
9:38
.
10.1
4
0
1
0
0
$SUBROUTINE ADVAN6 TRANS1 TOL=3
$MODEL NCOMP = 6
COMP = (CENTRAL)
COMP = (PERIPH)
COMP = (EFFTHC)
COMP = (METABOL)
COMP = (METABOL2)
COMP= (EFFTHCOH)
$PK
Q1 =THETA(1)*EXP(ETA(1)) ; Inter-compartment clearance
for THC
V1 =THETA(2)*EXP(ETA(2)) ; V - THC - Central Comp
V2 =THETA(3)*EXP(ETA(3)) ; V - THC - Peripheral Comp
K14 =THETA(4)*EXP(ETA(4)) ; Metabolite conversion
Q2 =THETA(5)*EXP(ETA(5)) ; Inter-compartment clearance
for THC-OH
V4 =THETA(6)*EXP(ETA(6)) ; V - THCOH - Central Comp
V5 =THETA(7)*EXP(ETA(7)) ; V - THCOH - Peripheral Comp
CL =THETA(8)*EXP(ETA(8)) ; Clearance
KE01 =THETA(9)*EXP(ETA(9)) ; rate constant for THC effect
compartment
KE02 =THETA(10)*EXP(ETA(10)) ; rate constant for THCOH effect
compartment
S1=V1
S4=V4
A_0(1)=0
A_0(3)=0
A_0(4)=0
A_0(6)=0
$DES
C1=A(1)/V1
C3=A(3)
C4=A(4)/V4
C6=A(6)
DADT(1) = (Q1/V2)*A(2) - (Q1/V1)*A(1) - K14*A(1)
DADT(2) = (Q1/V1)*A(1) - (Q1/V2)*A(2)
DADT(3) = KE01*C1 - KE01*A(3)
DADT(4) = K14*A(1) - (CL/V4)*A(4) - (Q2/V4)*A(4) + (Q2/V5)*A(5)
DADT(5) = (Q2/V4)*A(4) - (Q2/V5)*A(5)
DADT(6) = KE02*C4 - KE02*A(6)
$ERROR
CE1=A(3)
CP=A(1)/V1
CE2=A(6)
CM=A(4)/V4
EMAX = THETA(11)*EXP(ETA(11))
EC50 = THETA(12)*EXP(ETA(12))
HILL = THETA(13)*EXP(ETA(13))
CONC = CP*(1 + ERR(1)) + ERR(2)
CONCMET = CM + ERR(3)
E = EMAX*(((CE1**HILL)+(CE2**HILL))/((EC50**HILL)+((CE1**HILL)+(CE2**HILL))))
EFF = E + ERR(4)
IF(TYPE3.EQ.1) IPRED = CP
IF(TYPE2.EQ.1) IPRED = CM
IF(TYPE1.EQ.1) IPRED = E
Y = (CONC*TYPE3) + (EFF*TYPE1) + (CONCMET*TYPE2)
$THETA
(0, 6.964) ;[Q1]
(0, 20) ;[V1]
(0, 50) ;[V2]
(0, 10) ;[K14]
(0, 10) ;[Q2]
(0, 40) ;[V4]
(0, 50) ;[V5]
(0, 102.95) ;[CL]
(0,5,50) ;[KE01]
(0,5,50) ;[KE02]
10 FIX ;[EMAX]
(1, 50, 400) ;[EC50]
(0.1, 1,5) ;[HILL]
$OMEGA
0.0152 ; [P] omega(1,1)
0.005 ; [P] omega(2,2)
0.06 ; [P] omega(3,3)
0.04 ; [P] omega(4,4)
0.03 ; [P] omega(5,5)
0.06 ; [P] omega(6,6)
0.03 ; [P] omega(7,7)
0.07 ; [P] omega(8,8)
0.06 ; [P] omega(9,9)
0.05 ; [P] omega(10,10)
0.05 ; [P] omega(11,11)
0.06 ; [P] omega(12,12)
0.06 ; [P] omega(13,13)
$SIGMA
0.5 ; [ERR1]
0.5 ; [ERR3]
0.5 ; [ERR4]
$SIGMA
0.00001 FIX ;[ERR2]
$EST METHOD=1 MAXEVAL=9999 PRINT=5 SIG=3 NOABORT MSFO=2010-2013.MSF
$COV
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
