4 replies to this topic

[18963422692]

Dear all,

 

I am trying to write a QSP model  (See "Betts A, Haddish-Berhane N, Shah DK, van der Graaf PH, Barletta F, King L, Clark T, Kamperschroer C, Root A, Hooper A, Chen X. A Translational Quantitative Systems Pharmacology Model for CD3 Bispecific Molecules: Application to Quantify T Cell-Mediated Tumor Cell Killing by P-Cadherin LP DART®. AAPS J. 2019 May 22;21(4):66. doi: 10.1208/s12248-019-0332-z. Erratum in: AAPS J. 2019 Jun 4;21(4):73. PMID: 31119428; PMCID: PMC6531394. "). The model text is below. When running the model, I consistently get an error "Model execution failed. Initial fcntheta1 value NaN". I tried different initial estimates and different algorithms without success. Any suggestion?

 

Thank you

 

test(){

    TV = (4/3 * 3.14 * Rtumor^3) / 1000

 

    TD = (2 * P * Rcap/Rkrogh^2 + 6*D/Rtumor^2) * (C1 - C3/eps)

 

    Tot41BBp = (Tcellsp *BB/NA) * 10^9 

 

    TotPDL1t = (Tumorcellst * mPDL1/NA) * 10^9

    

    Tot41BBt = (Tcellst * BB/NA) * 10^9

 

    ksyn = kdeg * sPDL1_0

    

dosepoint(A1, idosevar = A1Dose, infdosevar = A1InfDose, infratevar = A1InfRate)

  

deriv(A1 = (-CL*C1 -CLd* C1 + CLd * C2  - (kon_41BB * C1 * (Tot41BBp - D41BBp) + koff_41BB * D41BBp - kon_PDL1 *C1 * sPDL1 + koff_PDL1 * DPDL1p -TD* TV/V1)*V1))

    

      

        deriv(A2= (CLd * C1  - CLd * C2))

    

 

    deriv(A3= (TD-(kon_PDL1* C3 * (TotPDL1t - DPDL1t-Trimer)/eps) + (koff_PDL1 * DPDL1t) - (kon_41BB * C3 * (Tot41BBt-D41BBt-Trimer)/eps) + (koff_41BB * D41BBt)))

 

 

 

 

    deriv(A4 = (ksyn-kdeg*sPDL1-kon_PDL1 * C1 * sPDL1 + koff_PDL1*DPDL1p))

 

    deriv(A5 = (kon_PDL1 * C1 * sPDL1 - koff_PDL1 * DPDL1p- kdegcx * DPDL1p))

    

    deriv(A6 = (kon_41BB * C1 * (Tot41BBp - D41BBp) - koff_41BB * D41BBp))

 

 

    deriv(A7 = (kon_41BB * C3 * (Tot41BBt - D41BBt - Trimer)/eps - koff_41BB * D41BBt - kon_PDL1 * D41BBt * (TotPDL1t-DPDL1t- Trimer)/eps + koff_PDL1 * Trimer))

  

    deriv(A8 = ((kon_PDL1 * C3 * (TotPDL1t - DPDL1t - Trimer)/eps - koff_PDL1 * DPDL1t - kon_41BB * DPDL1t * (Tot41BBt - D41BBt - Trimer)/eps + koff_41BB * Trimer - kint * DPDL1t)))

  

    deriv(A9 = ((kon_41BB * DPDL1t * (Tot41BBt - D41BBt - Trimer)/eps - (koff_41BB + koff_PDL1) * Trimer + kon_PDL1 * D41BBt * (TotPDL1t - DPDL1t - Trimer)/eps)))

    

 

    

    #M1

   deriv(A10 =  kg0 * (1 - w/Mmax) * M1 / ((1 + (kg0/kg * w)^psi)^(1/psi)) - kkill * mPDL1)

   deriv(A11 = kkill * M1 - M2/tao)

   deriv(A12 = (M2 - M3) / tao)

   deriv(A13 = (M3 - M4) / tao)

    kkill = kmax * Trimer / (kc50 + Trimer)

    w = M1 + M2 + M3 + M4

    TSC = kg0 * kc50 / (kmax - kg0)

 

 

 

#Plasma_conc = C1*MW/1000 ; convert from nM to ng/mL

#Tumor_conc = C3*MW/1000 ; convert from nM to ng/mL

#Trimer_conc = trimer/50

 

 

 

 

 

 

    C1 = A1/V1

    C2 = A2/V2

C3 = A3

sPDL1= A4

DPDL1p= A5

    D41BBp= A6

    D41BBt= A7

DPDL1t= A8

Trimer= A9

M1=A10

M2=A11

M3=A12

M4=A13

    #CL = kel*V1

#kel=CL/V1

    #CLd= k12 *V1

    #k21 = CLd/V2

#k12 = CLd/V1

 

    sequence{C1 = A1Dose/V1;C2 = 0;C3 = 0;D41BBp = 0;D41BBt = 0;DPDL1t = 0;Trimer = 0;sPDL1 = sPDL1_0;DPDL1p =0;M1 = TV*1000000; M2 = 0;M3 = 0;M4 = 0;}

   

    error(CEps = 0.1)

    

    observe(CObs = C1 + C1*CEps)

    

      fixef(V1 = c(, 40.2, ))

      fixef(V2 = c(,211, ) )

        fixef(CL= c(, 4.61, ))

          fixef(CLd= c(, 25.2, ))

           fixef(kon_41BB = c(, 1.72, ))

            fixef(koff_41BB = c(, 193.66, ))

             fixef(kon_PDL1 = c(, 1.57, ))

              fixef(koff_PDL1 = c(, 0.74, ))

             

    fixef(kdeg = c(, 0.15, ))

    fixef(kdegcx =  c(, 0.115, ))

    fixef( kint =c(0,0.1728,))

    fixef(Rtumor(freeze) = c(,1,))

    fixef(Rkrogh(freeze) = c(,75,))

    fixef(P(freeze) = c(,13.9,))

    fixef(D(freeze) = c(,0.000916,))

    fixef(eps(freeze) = c(,0.24,))

    fixef(Rcap(freeze) = c(,8,))

    fixef(mPDL1(freeze) = c(,28706,))

    fixef(NA(freeze) = c(,6.02*10^23,))

    fixef(ETRatio(freeze) = c(,5000000000,))

    fixef(Tumorcellst(freeze) = c(,100000000000,))

    fixef(Tcellsp(freeze) = c(,1,))

    fixef(Tcellst(freeze) = c(,6.02*10^23,))

    fixef(BB(freeze) = c(,64900000000,))

    fixef(sPDL1_0(freeze) = c(,1.1,))

    fixef(kg0(freeze) = c(,0.0125,))

    fixef(kg(freeze) = c(,4.37,))

    fixef(Mmax(freeze) = c(,3800,))

    fixef(psi(freeze) = c(,20,))

    fixef(kmax(freeze) = c(,0.03,))

    fixef(kc50(freeze) = c(,0.0004,))

    fixef(tao(freeze) = c(,0.199,))

 

}

Edited by 18963422692, 20 March 2023 - 08:35 AM.

[smouksassi1]

you equations has NA not sure you can use NA as it might be a special word

 

try building your model little by little make sure things are working at every step

 

can you share a project that reproduce the error in our end ?

[18963422692]

Thank you for the suggestions.

I replaced NA, but it still doesn't work。

 

warnings and Errors：

 

Error in Population: 

Error reading file C:\UsersAppData\Local\Temp\Phoenix\DME_SI~1.842\out000001.txt: File does not exist

 Eng 6 process            1  of            1  is alive

 entering naive pooled engine 6, iteration limit=        1000

 

 READFLAGS

 environmental flags and variables

           0  iflagnp 

           0  iflagrestart

           1  norderAGQ

           1  iflagfocehess

           1  iflagverbose

           1  Allow Gaussian Fit

           1  METHODblup

          13  NDIGITblup

           1  METHODlagl

          13  NDIGITlagl

           1  iflagIEXP

   2.0000000949949026E-003  tolmodlinz

           0  nrep_pcwres

         500  Nsample

         200  Nburn

           0  iflaganagrad

           3  iodelevelused

 NorderAGQ not applicable to this engine            6

 NorderAGQ set to 1 but unchanged in nlmeflags.asc

 

 Initial thetas and bounds

    i      Thetalo(i)      Thetainit(i)    Thetahi(i)

    1     -0.1000+101      0.4020E+02      0.1000+101

    2     -0.1000+101      0.2110E+03      0.1000+101

    3     -0.1000+101      0.4610E+01      0.1000+101

    4     -0.1000+101      0.2520E+02      0.1000+101

    5     -0.1000+101      0.1720E+01      0.1000+101

    6     -0.1000+101      0.1937E+03      0.1000+101

    7     -0.1000+101      0.1570E+01      0.1000+101

    8     -0.1000+101      0.7400E+00      0.1000+101

    9     -0.1000+101      0.1500E+00      0.1000+101

   10     -0.1000+101      0.1150E+00      0.1000+101

   11      0.0000E+00      0.1728E+00      0.1000+101

   12      0.0000E+00      0.1000E+00      0.1000+101

 sigmaLchol=  0.10000000000000001     

 

 initial packed param vector and typx vector

         i        packed(i)        typx(i)

         1       40.200000       40.200000

         2      211.000000      211.000000

         3        4.610000        4.610000

         4       25.200000       25.200000

         5        1.720000        1.720000

         6      193.660000      193.660000

         7        1.570000        1.570000

         8        0.740000        0.740000

         9        0.150000        0.150000

        10        0.115000        0.115000

        11        0.172800        0.172800

        12        0.100000        0.100000

 

 Initial fcntheta1 value                       NaN

 

 Nsub from initxtheta=          21

 Nobstotal =          232

 

 corresponding ELSobj with zeroed blups=                       NaN

 

 Initial parameter values result in -LL = NaN

 Restart from new values

Error: Model Exception: Fortran Exception

NlmeErrorExit: close files and exit(0)

 

 

Model execution failed.

[kniefort]

In addition to renaming the NA variable, try the following:

 

• Move your variable definitions above your de's
• Comment out Cl and Cld definitions
• Change CL to Cl in your definitions
• Comment out ETratio in fixef

The following should run: 

 

test(){

 

dosepoint(A1)

 

C1 = A1/V1

        C2 = A2/V2

C3 = A3/TV

Rtumor = 1

D41BBp= A6/V1

    sPDL1= A4/V1

DPDL1p= A5/V1

    ksyn = kdeg * sPDL1_0

#Cl = kel*V1

kel=Cl/V1

#    Cld= k12 *V1

    k21 = Cld/V2

k12 = Cld/V1

D41BBt= A7/TV

DPDL1t= A8/TV

Trimer= A9/TV

Rkrogh = 75 

    Rtumor = 1

              P = 334/24

                 D = 0.022/24

           eps = 0.24

            Rcap = 8

mPDL1 = 28706

AVOG=6.02*10^23

 

deriv(A1 = (-kel*C1 -k12* C1 + k21 * C2 * V2/V1 - kon_41BB * C1 * (Tot41BBp - D41BBp) + koff_41BB * D41BBp - kon_PDL1 *C1 * sPDL1 + koff_PDL1 * DPDL1p -TD* TV/V1)*V1)

 

    deriv(A2= (k12 * C1 * V1/V2 - k21 * C2)*V2)

 

    TV = (4/3 * 3.14 * Rtumor^3) / 1000

 

    deriv(A3= (TD-(kon_PDL1* C3 * (TotPDL1t -DPDL1t-Trimer)/eps) + (koff_PDL1 * DPDL1t) - (kon_41BB * C3 * (Tot41BBt-D41BBt-Trimer)/eps) + (koff_41BB * D41BBt)*TV))

 

TD = (2 * P * Rcap/Rkrogh^2 + 6*D/Rtumor^2) * (C1 - C3/eps)

 

Tot41BBp = (Tcellsp *BB/AVOG) * 10^9 

    deriv(A4 = (ksyn-kdeg*sPDL1-kon_PDL1 * C1 * sPDL1 + koff_PDL1*DPDL1p)*V1)

    

    deriv(A5 = (kon_PDL1 * C1 * sPDL1 - koff_PDL1 * DPDL1p- kdegcx * DPDL1p)*V1)

    deriv(A6 = (kon_41BB * C1 * (Tot41BBp - D41BBp) - koff_41BB * D41BBp)*V1)

 

TotPDL1t = (Tumorcellst * mPDL1/AVOG) * 10^9

    

    Tot41BBt = (Tcellst * BB/AVOG) * 10^9

    

    deriv(A7 = (kon_41BB * C3 * (Tot41BBt - D41BBt - Trimer)/eps - koff_41BB * D41BBt - kon_PDL1 * D41BBt * (TotPDL1t-DPDL1t- Trimer)/eps + koff_PDL1 * Trimer)*TV)

    

    deriv(A8 = ((kon_PDL1 * C3 * (TotPDL1t - DPDL1t - Trimer)/eps - koff_PDL1 * DPDL1t - kon_41BB * DPDL1t * (Tot41BBt - D41BBt - Trimer)/eps + koff_41BB * Trimer - kint * DPDL1t)*TV))

    

    deriv(A9 = ((kon_41BB * DPDL1t * (Tot41BBt - D41BBt - Trimer)/eps - (koff_41BB + koff_PDL1) * Trimer + kon_PDL1 * D41BBt * (TotPDL1t - DPDL1t - Trimer)/eps)*TV))

    

    

    sequence{C2 = 0

             C3 = 0

             D41BBp = 0

             D41BBt = 0

             DPDL1t = 0

             Trimer = 0

     sPDL1 = sPDL1_0

             DPDL1p = 0

             mPDL1 = 28706

             sPDL1_0 = 1.1

             Rkrogh = 75 

             Rtumor = 1

             P = 334/24

             D = 0.022/24

             eps = 0.24

             Rcap = 8

     }

 

             

    

    error(CEps = 0.1)

    

    observe(CObs = C1 + C1*CEps)

    

    fixef(V1 = c(, 0.05, ), V2 = c(, 0.1, ), Cl = c(, 0.001, ), Cld = c(, 0.003, ), sPDL1_0 = c(, 12, ),kon_41BB = c(, 0.824, ),

koff_41BB = c(, 10.944, ),kon_PDL1 = c(, 4.54, ),koff_PDL1 = c(, 1.5588, ),kdeg = c(, 0.15, ), kdegcx =  c(, 0.115, ),

Tcellsp(freeze)=c(, 5000000000, ),Tumorcellst(freeze)= c(, 100000000000, ), Tcellst (freeze)=  c(, 6.4900000000, ), BB (freeze)=  c(, 100000, ),

#ETRatio  (freeze)=  c(, 150 , ),

kint =c(0,0.1728,))

}

[18963422692]

<full quote removed for brevity>

 

Thank you very much for your help!

Edited by Simon Davis, 21 March 2023 - 09:08 AM.
full quote removed for brevity