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Subject: Re: [NMusers] Problems with a physiologic model All the responses to Paul's email have been relevant. I would like to remark on few of his questions (the easy ones). The PARAM option of $MODEL describes the number of basic PK parameters, as defined by NM-TRAN. To NM-TRAN, a basic PK parameter is a variable that is defined in $PK and used in the $DES block. He has 6: CO, CLB, VI, VB, CLL, CTL. The PARAM option is not needed when the $PK and $DES blocks are present. NM-TRAN can count for itself. PARAM is only required when you write your own code, e.g., $SUBR ... DES=mydes My advice is to leave it out when the $PK and $DES block are present. Paul asks: When I set TOL=6, the execution of the model doesn't even begin interating (sat for > 24 hrs)   Why does it not even start when TOL=6, but it does when I lowered it to TOL=3? I would guess that, with TOL=6, an illegal floating point number (NaN) has been developed somewhere in PREDPP or NONMEM, and this has cause the code to go into an infinite loop. NONMEM is best compiled with options such that the run stops immediately when an illegal floating point operation has occured. As to why this problem is sensitive to the value of TOL, and the choice of ADVAN (6,8,9): something in the model is not well specified, so that it is very unstable and badly behaved numerically. In general: When using $DES, it is best to do as much of the arithmetic as possible in $PK rather than $DES. The $PK block is evaluated far less often. (Paul's cs specifies CALLFL=-2, as often as possible - this is not needed with a $PK block that calculates exactly same values for every event record, assuming that WGT is constant. Better to specify CALLFL=1, ONCE PER IR.) Either way, the $DES block is evaluated many times more often than the $PK block, and all those divisions in $DES are costly of run time. Leonid's suggestion to compute rate constants in $PK is an excellent one. It would be a good idea even if the D.E.'s were not linear in the compartment amounts A(i). (If the D.E.'s are non-linear in the A(i), then some arithmetic *must* be done in the D.E.s) But since, as Leonid points out, the D.E.s are linear, then Pual can try to use ADVAN7 (or ADVAN5 if ADVAN7 has a numerical problem.) ADVAN5 and 7 may well be faster and more stable than ADVAN6-8-9, although I do not have a lot of personal experience with this.