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

From: Leonid Gibiansky <lgibiansky>
Date: Sun, 8 Dec 2019 14:46:10 -0500

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-singla
>
> *518.577.5881*
>
Received on Sun Dec 08 2019 - 14:46:10 EST

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