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- [NMusers] problem about enterohepatic circulation model. Thanks!!!!

breakfast COMP GB4ON dummy cmt to turn on GB exit at lunch COMP GB4OFF dummy cmt to turn off GB exit at lunch COMP GB8ON dummy cmt to turn on GB exit at dinner COMP GB8OFF dummy cmt to turn off GB exit at dinner COMP GB12ON dummy cmt to turn on GB exit at post dinner COMP GB12OFF dummy cmt to turn off GB exit at post dinner PK CALLFL 2 KA THETA 1 TVCL THETA 2 CL TVCL EXP ETA 1 TVVC THETA 3 V2 TVVC EXP ETA 2 K23 THETA 4 K32 THETA 5 K24 THETA 6 K41 THETA 7 GBL THETA 8 ALAG5 0 0001 ALAG6 ALAG5 GBL ALAG7 4 5001 ALAG8 ALAG7 GBL ALAG9 8 0001 ALAG10 ALAG9 GBL ALAG11 12 0001 ALAG12 ALAG11 GBL S2 V2 IF NEWIND LT 2 THEN JON 1 JOFF 0 ENDIF IF JON EQ 1 Z 1 IF JOFF EQ 1 Z 0 JON 0 JOFF 0 IF DOSREC CMT EQ 5 OR DOSREC CMT EQ 7 JON 1 IF DOSREC CMT EQ 9 OR DOSREC CMT EQ 11 JON 1 IF DOSREC CMT EQ 6 OR DOSREC CMT EQ 8 JOFF 1 IF DOSREC CMT EQ 10 OR DOSREC CMT EQ 12 JOFF 1 DES K10 CL V2 DADT 1 KA A 1 K41 Z A 4 DADT 2 RATE KA A 1 K32 A 3 K23 A 2 K24 A 2 K10 A 2 DADT 3 K23 A 2 K32 A 3 DADT 4 K24 A 2 K41 Z A 4 DADT 5 0 DADT 6 0 DADT 7 0 DADT 8 0 DADT 9 0 DADT 10 0 DADT 11 0 DADT 12 0 ERROR Y F 1 EPS 1 THETA 0 1 KA theta 1 0 30 clearance theta 2 0 300 Vc theta 3

Original URL path: http://nonmem.org/nonmem/nm/99feb132005.html (2016-04-25)

Open archived version from archive - [NMusers] WinNonmix code

of the model Changing the initials does not help I ve attached the code below Can somebody tell me if there is an error in the model Any help would be highly appreciated Thanks for your help Nele Nele Plock Freie Universitaet Berlin Institute of Pharmacy Dept Clinical Pharmacy Kelchstr 31 D 12169 Berlin Germany tel 49 0 30 838 50625 fax 49 0 30 838 50711 email nplock zedat fu berlin de The used model is as follows PK3 f90 DESCRIPTION This subroutine describes an two compartment model with zero order input first order output elimination from a peripheral cmt and lag time REQUIRED FORTRAN COMPILERS 1 DIGITAL VISUAL FORTRAN 2 MICROSOFT FORTRAN POWERSTATION 4 0 INPUT 1 mode index describing the type of calculation to be performed mode 2 for predicted values mode 3 for differential equations mode 4 for starting values of differential equations mode 5 for secondary parameters 2 p vector containing structural model parameters where p 1 V p 2 cl p 3 ti p 4 tlag p 5 q p 6 v2 p 7 cl2 3 con vector containing constants requried in the model where con 1 doses con 2 dose 1 con 3 time of dose 1 etc subroutine usrmod mode funcno dta f p dz s con x z wt y objfn implicit none integer mode funcno real 8 p 1 con 1 x f s 1 z 1 dz 1 dta 1 wt 1 y objfn real 8 v cl k10 t sum dose auc cmax tmax k0 ti tlag k12 k21 real 8 k20 INP q v2 cl2 integer nn ndose k i v p 1 cl p 2 ti p 3 tlag p 4 q p 5 v2 p 6 cl2 p 7 if mode 2 then f z

Original URL path: http://nonmem.org/nonmem/nm/98feb102005.html (2016-04-25)

Open archived version from archive - [NMusers] new buglist for NMTRAN 07FEB2005

DV A LOG D XIII Steady state kinetics will not be computed when 1 there are multiple problem specifications 2 with the second or subsequent problem specification SS is listed first in the INPT record 3 an SS routine is not listed in the SUBROUTINES record Work around Construct a new data set such that 2 above will not happen That is the new data set will be exactly like the old data set except for having a new column that is exactly like the first column in the original data set and the new column will be placed after the first column Actually the first column itself can be deleted but if it is not use DROP with the first column Work around Include the name of the SS routine in the SUBROUTINES record XIV NM TRAN translation of clock times to elapsed times can be faulty All elapsed times resulting from clock time translation should have two digits to the right of the decimal point Certain elapsed times greater than 999 99 hours 41 6 days are unpredictably and mistakenly truncated so that they contain only one digit to the right of the decimal point See discussion in the NONMEM Archive http www cognigencorp com nonmem nm 99apr192002 html Fix In routine READ3 replace the line ELSEIF VALUE KK J GE 1000 0 AND WIDE NE Y THEN with ELSEIF VALUE KK J GE 1000 0 AND WIDE NE Y AND NSP EQ 1 THEN XV The error message DATA WIDE CANNOT BE USED FILE CONTAINS MORE THAN 9999 RECS may appear but it should not appear when 1 the WIDE option appears on the DATA record 2 there are more than 9999 records in the data set 3 the control stream consists of a single problem Fix In routine READF insert these two statements anywhere among the other declaration statements COMMON COMEND ENDFIL LOGICAL ENDFIL and change the statement IF INOBS GT 9999 AND WIDE EQ Y CALL ERRMSG 283 1 to IF INOBS GT 9999 AND WIDE EQ Y AND NOT ENDFIL X CALL ERRMSG 283 1 In routine GETITM insert this statement anywhere among the other declarations COMMON COMEND ENDFIL In routine CHKDAT change the statement IF MKFDAT AND INOBS GT K9999 THEN to IF MKFDAT AND INOBS GT K9999 AND WIDE NE Y THEN XVI NM TRAN translation of TIME data items is faulty when 1 NM TRAN infers that the data are single subject data 2 the name ID is listed in the INPUT record as ID or ID L1 3 some synonym A B and or DATE DROP preceeds ID in the INPUT record Time translation occurs when either clock times are present in the NM TRAN data set or DATE items appear Usually when time translation occurs with single subject data ID does not appear in the INPUT record though L1 may appear in which case the TIME data item on the first record of the data set is translated to 0 and subsequent TIME data items are translated to times relative to 0 When ID is listed in the INPUT record with every data record where the ID data item changes value the TIME data item is translated to 0 and subsequent TIME data items up to the next change in ID value are translated to times relative to 0 Due to the bug if ID is listed near the beginning of the INPUT record different data from the ID data items are used in the process of time translation If the ID is listed near the end of the INPUT record the ID data items are ignored in the process of time translation i e all TIME data items subsequent to the one on the first data record are translated to times relative to 0 Work around Construct a new data set such that 3 above will not happen That is the new data set will be exactly like the old data set except for having a new column that is exactly like the column in the original data set with the ID data items column C and the new column will be placed before the columns with the A type data items and or the DATE data items Actually column C itself can be deleted but if it is not give this column a name N different from ID and use N DROP Work around Avoid using the synonym A B XVII The constant LNP4 in files TSIZES is set at installation time to the default value of 1000 An error occurs during compilation of generated code when LNP4 is set to a value greater than 9999 However a value greater than 9999 is of little practical value When the option COMRES n n 0 is used in the ABBREVIATED record or when verbatim code is used and when LNP4 is set to a value greater than 1000 an error occurs during compilation of generated code Fix In routine GENCOM replace the two lines of code WRITE LINE A I4 4 A DIMENSION COM COMMAX LL 19 with WRITE LINE A I6 6 A DIMENSION COM COMMAX LL 21 XVIII The data may be mistakenly interpreted as single subject data when 1 there are multiple problem specifications 2 in the second or subsequent problem specification a MSFI record appears without the NPOP option With the problem specification where the MSFI record appears without the NPOP option the data are misinterpreted as single subject data An error message will make it clear that the data are being misinterpreted Work around Include the NPOP option XIX Fatal error message 386 spuriously arises when abbreviated code such as IF condition statement is used where 1 the condition includes a test of ICALL or COMACT and either 2a the statement is a WRITE PRINT statement that uses either ICALL or COMACT in the output list or 2b the statement is an assignment statement that uses either ICALL or COMACT as a right

Original URL path: http://nonmem.org/nonmem/nm/99feb102005.html (2016-04-25)

Open archived version from archive - [NMusers] $DES and T

event time increases Does this mean that CONC is only recomputed at observed time points I do not have any dosing events What happens between these time points When I print out to a table the first CONC value is 0 even if TIME 0 Results change if I add new data records to the data set with MDV 1 and new TIME points Thanks in advance Lars SUBROUTINES ADVAN6 TOL 5 MODEL COMP EFFECT PK TVKIN THETA 1 KIN EXP TVKIN TVKOUT EXP THETA 2 KOUT TVKOUT EXP ETA 1 TVTH THETA 3 TH EXP TVTH K 6 41 V 0 127 KA 1 35 ERROR IPRE A 1 Y 1 IPRE ERR 1 DES CONC DOSE KA K KA V EXP KA T EXP K T KIN1 0 IF CONC GT TH KIN1 1 DADT 1 KIN KIN1 KOUT A 1 From Sam Liao sliao pharmaxresearch com Subject Re NMusers DES block and T Date Wed February 9 2005 6 38 pm Hi Lars You do need to have the MDV record with time equal to zero in order to solve the differential equation correctly You ve done the right thing paying attention to the warning msg from

Original URL path: http://nonmem.org/nonmem/nm/99feb092005.html (2016-04-25)

Open archived version from archive - [NMusers] Simulated PD value at time zero

BAV F5 BASE DES CONC A 2 VC HIT IEFF CONC IC50 CONC DADT 5 KIN 1 HIT A 5 KOUT What seems strange to me is that the simulated value for compartment 5 the effect is equal to 0 and not BASE at time 0 dose given at time 0 001 I have tried simulation data files with and without a value of 1 as dose for compartment 5 but the results are the same Sufficient time after dose the PD value returns and stays at the BASE value Also in the actual NONMEM run the initial value is equal to BASE Any suggestions why the 0 time values for the PD are predicted to 0 and not BASE Toufigh Gordi From AbuTarif Malaz malaz abutarif spcorp com Subject RE NMusers Simulated PD value at time zero Date Tue February 1 2005 3 55 pm Dear I think this is similar to what Max was asking earlier in the week NMusers Indirect response PD model Without the drug baseline PD is basically a steady state situation NonMem does not know that So the solution to your problem is exactly the solution to Max s problem I think Initialize the

Original URL path: http://nonmem.org/nonmem/nm/99feb012005.html (2016-04-25)

Open archived version from archive - [NMusers] Indirect response PD model

2 666667 4 104 2 2 2 4 104 4 1 6 4 104 6 1 4 4 104 8 1 4 4 104 12 2 4 104 24 2 3 4 Max Tsai Ph D Senior Scientist DM PK Schering Plough Corporation 2015 Galloping Hill Road K 15 2 2650 Kenilworth NJ 07033 0530 908 740 3911 Ê 908 740 2916 max tsai spcorp com From Sam Liao sliao pharmaxresearch com Subject Re NMusers Indirect response PD model Date Fri January 28 2005 6 30 pm Hi Max You need to set up the initial condition for CMT 4 WinNonMix set it up for you But in nmv you need to do it in the data and control file Please see the nmv usernet archiev for detailed discussion http www cognigencorp com nonmem nm 99oct052000 html Subject PD initialization Posting October 5 2000 Best regards Sam Liao Pharmax Research From mathangi mathangi msn com Subject Re NMusers Indirect response PD model Date Fri January 28 2005 7 11 pm Hello Max The indirect model you have used requires initialization of baseline response It could be done the following way in the data set and control file CONTROL FILE PD MODEL TVKIN THETA 1 TVKOUT THETA 2 TVIC50 THETA 3 KIN TVKIN EXP ETA 1 KOUT TVKOUT EXP ETA 2 IC50 TVIC50 EXP ETA 3 F4 KIN KOUT Initializing to baseline R0 kin kout DATA SET 101 10 0 1 101 1 0 0 4 101 0 6 4 4 101 2 5 7 4 101 4 4 9 4 101 6 3 8 4 101 8 3 5 4 101 12 2 2 4 101 24 2 4 4 The modified model runs successfully Hope this is helpful Just a suggestion Parametrizing in terms of CL and V would lead to meaningful interpretation of the model Thanks Mathangi From Tsai Max max tsai spcorp com Subject RE NMusers Indirect response PD model Date Mon January 31 2005 8 34 am Thanks to Sam and Mathangi for the helpful advice It appears that was all that was needed Is this initialization required only when working with differential equations for PK PD modeling Max From Sam Liao sliao pharmaxresearch com Subject Re NMusers Indirect response PD model Date Mon January 31 2005 10 26 am Hi Max It is needed only when the initial condition is not zero In this case the initial condition is set to be the steady state value Also you may want to use an integral function for the drug concentrations in stead of solving it in three DE to cut down your run time Best regards Sam Liao Pharmax Research From MANOJ KHURANA manoj2570 yahoo com Subject Re NMusers Indirect response PD model Date Mon January 31 2005 11 36 am Hi Sam This is pretty new to me but could you please elaborate on your suggestion Also you may want to use an integral function for the drug concentrations in stead of solving it in

Original URL path: http://nonmem.org/nonmem/nm/99jan282005.html (2016-04-25)

Open archived version from archive - [NMusers] questions on ODE solver errors

EXIT CODE MESSAGES FROM THE ESTIMATION STEP But NONMEM continues to plod along Does anyone know what NONMEM does instead I assume that the OBJ contribution for that subject cannot be calculated so the gradient for the dimension s requiring that OBJ cannot be calculated Seems like an error to simply ignore the OBJ contribution from that person resulting in a lower OBJ for that function evaluation and a bad

Original URL path: http://nonmem.org/nonmem/nm/98jan262005.html (2016-04-25)

Open archived version from archive - [NMusers] Missing data, MDV and PCMT

to log transformed values of two PK variables monitored in plasma and urine My remaining problem despite the above measures NONMEM occasionally avoids to predict some values where no observation were available I would appreciate any suggestion on how to solve this problem Kind regards Johan Rosenborg AstraZeneca R D Lund Experimental Medicine S 221 87 Lund Sweden Tel 46 46 33 65 99 Fax 46 46 33 71 91

Original URL path: http://nonmem.org/nonmem/nm/99jan262005.html (2016-04-25)

Open archived version from archive