ADVAN6 coding question

From: "Garry Boswell" gboswell@tanox.com Subject: [NMusers] ADVAN6 coding question Date: Fri, 24 Mar 2006 17:17:09 -0600 NMUsers, I would like to ask the group for some help. I would like to know how to write the NONMEM code for a particular model. In a publication by Bauer et al (J Pharmacokinetics and Biopharmaceutics 27(4), 1999. 397:420) the authors propose a PK/PD model that is equivalent to an indirect response model. The model is a 2 compartment model with first order and MM elimination from the central compartment. Their Model B has the following differential equations: A = amount compound A B = amount CD11a cells dA1/dt = -(k12+k10)*[A1]-Vm*[A1}*[B]/(Km+[A1]) + k21*[A2] + Dose_rate dA2/dt = k12*[A1] - k21*[A2] dB/dt = k03 k30*[B] Vm2*[A1}*[B]/(Km+[A1]) the $DES block should be similar to this (for an IV bolus dose): $DES DADT(1) = -(K10+K12)*A(1) +K21*A(2) -(VM*A(1)*B)/(KM+A(1)) DADT(2) = K12*A(1) -K21*A(2) D??DT = K03 - B*K30 -(VM2*A(1)*B)/(KM+A(1)) Additionally, in previous posting to this group the comment has been made that the Effect compartment needs to be initialized with a dummy AMT = 1 at t=0 for indirect models. Would this also apply to the above case where the measurement in the Effect compartment is not of Compound A but of the number of CD11a cells? TIA Garry

From: Sam Liao liao@pharmaxresearch.com Subject: Re: [NMusers] ADVAN6 coding question Date: Fri, 24 Mar 2006 19:19:18 -0500 Hi Garry: I have a nmv control file and the data set I used to simulate Bauer's PKPD model. Hope this can be helpful to you to write your model and preparing your input file. $PROB A INDIRECT INHIBITION PK/PD MODEL, Raptiva human $INPUT ID AMT TIME RAP=DV CMT $DATA SIM1.PRN $SUBROUTINES ADVAN8 TOL=5 $MODEL NCOMP=3 COMP=(CENTRAL) COMP=(PERI) COMP=(CD11A) $PK CALLFL=1 VC=THETA(1)*EXP(ETA(1)) K12=THETA(2) K21=THETA(3) K10=THETA(4) K03=THETA(5) K30=K03/100 VM=THETA(6) VM2=THETA(7) KM=THETA(8) S1=VC S3=1 F3=100 ;BOUNDARY CONDITION FOR EQUATION 1 ; K30=THETA(9) $DES DADT(1)= K21*A(2) - (K12 + K10)*A(1) -VM*A(1)*A(3)/(KMC*VC +A(1)) DADT(2)= - K21*A(2) + K12*A(1) DADT(3)= K03 - K30*A(3) -VM2*A(1)*A(3)/(KMC*VC +A(1)) $ERROR Y= F + EPS(1) $THETA 0.072 ;1 Vc in L/kg 0.283 ;2 k12 in 1/d 0.506 ;3 k21 in 1/d 0.10 ;4 k10 in 1/d 43.5 ;5 k03 in %CD11a/d .00147 ;6 Vm in mg/kg/d/%CD11a 1.34 ;7 Vm2 in 1/d 0.248 ;8 Kmc in mg/L $OMEGA 0 FIX $SIGMA 0 FIX $SIM (243709) ONLY ;$EST POSTHOC SIG=5 MAXEVAL=9999 PRINT=10 MSFO=MSF1 ;$COV $TABLE ID TIME Y AMT CMT FILE=SIM1 ONEHEADER NOPRINT #ID AMT TIME DV CMT 1 0.3 0 . 1 1 1 0 . 3 1 . 0.5 . 1 1 . 0.5 . 3 1 . 1 . 1 1 . 1 . 3 1 . 1.5 . 1 1 . 1.5 . 3 1 . 2 . 1 1 . 2 . 3 1 . 2.5 . 1 1 . 2.5 . 3 1 . 3 . 1 1 . 3 . 3 1 . 3.5 . 1 1 . 3.5 . 3 1 . 4 . 1 1 . 4 . 3 1 . 4.5 . 1 1 . 4.5 . 3 1 . 5 . 1 1 . 5 . 3 1 . 5.5 . 1 1 . 5.5 . 3 1 . 6 . 1 1 . 6 . 3 1 . 6.5 . 1 1 . 6.5 . 3 1 . 7 . 1 1 . 7 . 3 1 . 7.5 . 1 1 . 7.5 . 3 1 . 8 . 1 1 . 8 . 3 1 . 10 . 1 1 . 10 . 3 1 . 12 . 1 1 . 12 . 3 1 . 14 . 1 1 . 14 . 3 1 . 16 . 1 1 . 16 . 3 1 . 18 . 1 1 . 18 . 3 1 . 20 . 1 1 . 20 . 3 1 . 22 . 1 1 . 22 . 3 1 . 24 . 1 1 . 24 . 3 1 . 26 . 1 1 . 26 . 3 1 . 28 . 1 1 . 28 . 3 1 . 30 . 1 1 . 30 . 3 1 . 32 . 1 1 . 32 . 3 1 . 34 . 1 1 . 34 . 3 1 . 36 . 1 1 . 36 . 3 1 . 38 . 1 1 . 38 . 3 1 . 40 . 1 1 . 40 . 3 1 . 45 . 1 1 . 45 . 3 1 . 50 . 1 1 . 50 . 3 1 . 55 . 1 1 . 55 . 3 1 . 60 . 1 1 . 60 . 3 1 . 65 . 1 1 . 65 . 3 1 . 70 . 1 1 . 70 . 3 1 . 75 . 1 1 . 75 . 3 1 . 80 . 1 1 . 80 . 3 1 . 85 . 1 1 . 85 . 3 1 . 90 . 1 1 . 90 . 3 2 1 0 . 1 2 1 0 . 3 2 . 0.5 . 1 2 . 0.5 . 3 2 . 1 . 1 2 . 1 . 3 2 . 1.5 . 1 2 . 1.5 . 3 2 . 2 . 1 2 . 2 . 3 2 . 2.5 . 1 2 . 2.5 . 3 2 . 3 . 1 2 . 3 . 3 2 . 3.5 . 1 2 . 3.5 . 3 2 . 4 . 1 2 . 4 . 3 2 . 4.5 . 1 2 . 4.5 . 3 2 . 5 . 1 2 . 5 . 3 2 . 5.5 . 1 2 . 5.5 . 3 2 . 6 . 1 2 . 6 . 3 2 . 6.5 . 1 2 . 6.5 . 3 2 . 7 . 1 2 . 7 . 3 2 . 7.5 . 1 2 . 7.5 . 3 2 . 8 . 1 2 . 8 . 3 2 . 10 . 1 2 . 10 . 3 2 . 12 . 1 2 . 12 . 3 2 . 14 . 1 2 . 14 . 3 2 . 16 . 1 2 . 16 . 3 2 . 18 . 1 2 . 18 . 3 2 . 20 . 1 2 . 20 . 3 2 . 22 . 1 2 . 22 . 3 2 . 24 . 1 2 . 24 . 3 2 . 26 . 1 2 . 26 . 3 2 . 28 . 1 2 . 28 . 3 2 . 30 . 1 2 . 30 . 3 2 . 32 . 1 2 . 32 . 3 2 . 34 . 1 2 . 34 . 3 2 . 36 . 1 2 . 36 . 3 2 . 38 . 1 2 . 38 . 3 2 . 40 . 1 2 . 40 . 3 2 . 45 . 1 2 . 45 . 3 2 . 50 . 1 2 . 50 . 3 2 . 55 . 1 2 . 55 . 3 2 . 60 . 1 2 . 60 . 3 2 . 65 . 1 2 . 65 . 3 2 . 70 . 1 2 . 70 . 3 2 . 75 . 1 2 . 75 . 3 2 . 80 . 1 2 . 80 . 3 2 . 85 . 1 2 . 85 . 3 2 . 90 . 1 2 . 90 . 3 3 3 0 . 1 3 1 0 . 3 3 . 0.5 . 1 3 . 0.5 . 3 3 . 1 . 1 3 . 1 . 3 3 . 1.5 . 1 3 . 1.5 . 3 3 . 2 . 1 3 . 2 . 3 3 . 2.5 . 1 3 . 2.5 . 3 3 . 3 . 1 3 . 3 . 3 3 . 3.5 . 1 3 . 3.5 . 3 3 . 4 . 1 3 . 4 . 3 3 . 4.5 . 1 3 . 4.5 . 3 3 . 5 . 1 3 . 5 . 3 3 . 5.5 . 1 3 . 5.5 . 3 3 . 6 . 1 3 . 6 . 3 3 . 6.5 . 1 3 . 6.5 . 3 3 . 7 . 1 3 . 7 . 3 3 . 7.5 . 1 3 . 7.5 . 3 3 . 8 . 1 3 . 8 . 3 3 . 10 . 1 3 . 10 . 3 3 . 12 . 1 3 . 12 . 3 3 . 14 . 1 3 . 14 . 3 3 . 16 . 1 3 . 16 . 3 3 . 18 . 1 3 . 18 . 3 3 . 20 . 1 3 . 20 . 3 3 . 22 . 1 3 . 22 . 3 3 . 24 . 1 3 . 24 . 3 3 . 26 . 1 3 . 26 . 3 3 . 28 . 1 3 . 28 . 3 3 . 30 . 1 3 . 30 . 3 3 . 32 . 1 3 . 32 . 3 3 . 34 . 1 3 . 34 . 3 3 . 36 . 1 3 . 36 . 3 3 . 38 . 1 3 . 38 . 3 3 . 40 . 1 3 . 40 . 3 3 . 45 . 1 3 . 45 . 3 3 . 50 . 1 3 . 50 . 3 3 . 55 . 1 3 . 55 . 3 3 . 60 . 1 3 . 60 . 3 3 . 65 . 1 3 . 65 . 3 3 . 70 . 1 3 . 70 . 3 3 . 75 . 1 3 . 75 . 3 3 . 80 . 1 3 . 80 . 3 3 . 85 . 1 3 . 85 . 3 3 . 90 . 1 3 . 90 . 3 4 10 0 . 1 4 1 0 . 3 4 . 0.5 . 1 4 . 0.5 . 3 4 . 1 . 1 4 . 1 . 3 4 . 1.5 . 1 4 . 1.5 . 3 4 . 2 . 1 4 . 2 . 3 4 . 2.5 . 1 4 . 2.5 . 3 4 . 3 . 1 4 . 3 . 3 4 . 3.5 . 1 4 . 3.5 . 3 4 . 4 . 1 4 . 4 . 3 4 . 4.5 . 1 4 . 4.5 . 3 4 . 5 . 1 4 . 5 . 3 4 . 5.5 . 1 4 . 5.5 . 3 4 . 6 . 1 4 . 6 . 3 4 . 6.5 . 1 4 . 6.5 . 3 4 . 7 . 1 4 . 7 . 3 4 . 7.5 . 1 4 . 7.5 . 3 4 . 8 . 1 4 . 8 . 3 4 . 10 . 1 4 . 10 . 3 4 . 12 . 1 4 . 12 . 3 4 . 14 . 1 4 . 14 . 3 4 . 16 . 1 4 . 16 . 3 4 . 18 . 1 4 . 18 . 3 4 . 20 . 1 4 . 20 . 3 4 . 22 . 1 4 . 22 . 3 4 . 24 . 1 4 . 24 . 3 4 . 26 . 1 4 . 26 . 3 4 . 28 . 1 4 . 28 . 3 4 . 30 . 1 4 . 30 . 3 4 . 32 . 1 4 . 32 . 3 4 . 34 . 1 4 . 34 . 3 4 . 36 . 1 4 . 36 . 3 4 . 38 . 1 4 . 38 . 3 4 . 40 . 1 4 . 40 . 3 4 . 45 . 1 4 . 45 . 3 4 . 50 . 1 4 . 50 . 3 4 . 55 . 1 4 . 55 . 3 4 . 60 . 1 4 . 60 . 3 4 . 65 . 1 4 . 65 . 3 4 . 70 . 1 4 . 70 . 3 4 . 75 . 1 4 . 75 . 3 4 . 80 . 1 4 . 80 . 3 4 . 85 . 1 4 . 85 . 3 4 . 90 . 1 4 . 90 . 3 Best regards, Sam Liao Pharmax Research 201-9882043

From: "Serge Guzy" GUZY@xoma.com Subject: RE: [NMusers] ADVAN6 coding question Date: Sat, 25 Mar 2006 13:58:35 -0800 Hi Garry This model should have the initial conditions in the B-cell compartment: t=0, B=K03/K30 This assumes that at =0, you are at steady state and no drug yet enter the B-cell compartment: Therefore: DBDT = K03 - B*K30 -(VM2*A(1)*B)/(KM+A(1))=0 and A(1)=0 Then, K03-B*K30=0, Therefore, t=0, B=K03/K30 This model is by the way available as a part of the PK/PD libraries in the PDX-MC-PEM program (model name is model56pd). The differential equations are written below for the generalized (up to 3) non linear compartment model linked to the indirect response model you want. Serge Guzy President POP-PHARM SUBROUTINE fcn56pk (N, T, Y, YPRIME) C SPECIFICATIONS FOR ARGUMENTS IMPLICIT real*8 (A-H,O-Z) REAL*8 T, Y(N), YPRIME(N) REAL*8 K10,K12,K21,K01,KA,K13,K31,KM,K42 REAL*8 KIN,KOUT,IC50 REAL*8 TOL C WE PASS THE VALUE OF THE INDEPENDENT VARIABLE (TSAMPLING(I,J)) COMMON/PKINFO/KIN,KOUT,IC50,EC50,EMAX,K10,K12,K21,K01,KA,K13, 1 K31,TLAG,F,KM,VMAX,V,V2,V3,V4,Q,K42,DK42,raterv COMMON/TOTALRATE/SUMRATE COMMON/LINEAR/LIN C IF NON LINEAR pk, not parallel, then lin=2 and k10=0 IF(LIN.EQ.2)THEN K10=0 ENDIF CONTINUE C C C WILL BE OBTAINED FOR EACH T VALUE FROM MNODEL_SELECTION_PK_DIFF CORAL EQUATION C IF K01 IS ZERO, THEN WE FORCE YPRIME(1) TO BE ZERO IF(K01.EQ.0)THEN YPRIME(1)=0 ELSE YPRIME(1)=-K01*Y(1) ENDIF C BLOOD: ORAL INPUT, K10 OUTPUT, K12 OUTPUT, K21INPUT C K13 OUTPUT, K31 INPUT, SATURATED CLEARANCE OUTPUT C IF VMAX =0, THEN WE ARBITRARILY PUT KM=1 TO PREVENT 0/0 IF(VMAX.EQ.0)THEN KM=1 ENDIF YPRIME(2)=K01*Y(1)*F-K10*Y(2)-K12*Y(2)+K21*Y(3)-K13*Y(2)+K31*Y(4) 1 -VMAX*Y(5)*Y(2)/(Y(2)+KM*V)+SUMRATE IF(K12.EQ.0.AND.K21.EQ.0)THEN YPRIME(3)=0 ELSE YPRIME(3)=K12*Y(2)-K21*Y(3) ENDIF IF(K13.EQ.0.AND.K31.EQ.0)THEN YPRIME(4)=0 ELSE YPRIME(4)=K13*Y(2)-K31*Y(4) ENDIF YPRIME(5) = KIN-KOUT*Y(5)-EMAX*Y(5)*Y(2)/(EC50*V+Y(2)) CONTINUE RETURN END _______________________________________________________