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
