Re: Steady state dose

On Tuesday, October 18, 2011 9:42 AM, "Nick Holford" <[email protected]> wrote: > Joanna, > > I don't know of any way to request a positive SS solution. However I > wonder if the problem is related to the way you use the SS data item in > the code. > > HIV = SS*THETA(9)*EXP(ETA(9)) > > Usually there is just one record with SS=1 at the start of each > subject's records. If this is the case then the value of HIV will be > zero at all times after the SS=1 record. Does this make sense for your > model? > > I am not even sure that SS would have the value of 1 during the > calculation of the steady state solution -- although that would be a > reasonable assumption that could be confirmed by someone such as Alison > Boeckmann. > > Nick > > PS NONMEM calculates steady state amounts in compartments -- it does not > calculate steady state doses. > > On 15/10/2011 3:07 a.m., Joanna Lewis wrote: > > Dear NONMEM users, > > > > I have a question about NONMEM's calculation of steady-state doses. > > > > I am trying to model a system with two compartments. I want my t=0 > > boundary condition to be that the system is at steady-state, with a > > rate of cell death/clearance from one of the compartments which is > > higher than for all t>0. Unfortunately, I don't think there is an > > analytic solution for this steady state (see code copied below). > > > > From an old NMusers thread > > ( http://www.mail-archive.com/[email protected]/msg00584.html), I > > found out that NONMEM will find the steady state if you give it SS=1, > > RATE=0, AMT=0 in a t=0 record in the data file. When I tried this > > though, NONMEM found the wrong root of the steady-state equation (a > > negative one). Do you know if there is a way of making sure the steady > > state it finds is the positive one? For the moment, I have been > > initialising the compartments near to the steady state and at t=-(a > > lot), and letting them equilibrate, but I think this is slowing down > > my runs and would prefer to use another method. > > > > Thank you very much in advance for any advice you can offer. > > Joanna Lewis > > > > PhD student > > UCL Institute for Child Health > > 30 Guilford Street, London WC1N 1EH > > > > $PROBLEM hapuarachchi0_15sep_1 > > $INPUT ID BAGE AGE WEEK TIME CD DV AMT RATE SS TYPE CMT IG > > $DATA data.csv IGNORE=@ > > > > $SUBROUTINE ADVAN6 TOL=5 > > > > $MODEL > > COMP=(X) > > COMP=(Y) > > > > $PK > > ANO = THETA(1)*EXP(ETA(1)) > > EP = THETA(2)*EXP(ETA(2)) > > DEO = THETA(3)*EXP(ETA(3)) > > SIG = THETA(4)*EXP(ETA(4)) > > SCA = THETA(5)*EXP(ETA(5)) > > Q = THETA(6)*EXP(ETA(6)) > > > > THE = THETA(7)*EXP(ETA(7)) > > RHO = THETA(8)*EXP(ETA(8)) > > > > HIV = SS*THETA(9)*EXP(ETA(9)) > > > > $DES > > > > ALP = ANO*EXP(-EP*SCA*A(1)) > > DEL = DEO*EXP(SIG*SCA*A(1)) > > MU = Q*A(2) + HIV > > > > DADT(1) = THE + 2*RHO*A(2) - ALP*A(1) - DEL*A(1) > > DADT(2) = ALP*A(1) - RHO*A(2) - MU*A(2) > > > > $ERROR > > IPCD = A(1)+A(2) > > > > Y = IPCD + IPCD*EPS(1) > > > > $THETA > > > > ...etc.. > > > > $OMEGA > > > > ...etc... > > > > $SIGMA > > > > ...etc... > > > > $ESTIMATION MAXEVAL=0 METHOD=1 INTER SIGDIG=1 PRINT=1 > > > > $TABLE > > > > ...etc... > > -- > Nick Holford, Professor Clinical Pharmacology > Dept Pharmacology& Clinical Pharmacology > University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand > tel:+64(9)923-6730 fax:+64(9)373-7090 mobile:+64(21)46 23 53 > email: [email protected] > http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford > > -- Alison Boeckmann [email protected] Joanna Lewis is correct in that it is possible to compute a steady-state based on endogenous dose, using a record with SS=1 and AMT=0 and RATE=0. The DES routine may use any values from the SS dose record, including the SS data item (which will indeed be 1, as Nick suggests). But, as Nick also points out, this term is a little strange: HIV = SS*THETA(9)*EXP(ETA(9)) Joanna writes: I want my t=0 boundary condition to be that the system is at steady-state, with a rate of cell death/clearance from one of the compartments which is higher than for all t>0. I am not familiar with such a model, and don't understand how steady state can be reached by letting the model run for a while and then equilibrate. Presumably this would be done with SS=0 and HIV=0, so I don't understand how it could reach the same Steady state computed with SS=1 and HIV=THETA(9)*EXP(ETA(9)) As for the negative root: I am not sure what is meant by this. However, I can suggest a general way to avoid inappropriate solutions (e.g., false minima) of a PK/PD system using the EXIT statement. E.g., IF (condition) EXIT 1 1 This tells NONMEM to avoid the values of THETA and ETA that led to this exit. (In effect, it puts a spike in the objective function at these values of THETA/ETA.) E.g., $ERROR IF (A(1) < A(2)) EXIT 1 1 One needs to use NOABORT on the $ESTIMATION record. I am a little hesitant to suggest this because I am sure it is much better to define the model and bound the parameters in such away as to avoid false minima, but it may be that sometimes this is the only way. I have no actual experience with using the EXIT statement this way.. I don't think it would help in Joanna's case if the EXIT occurs with the initial values of theta and eta.