Use of NONMEM With The Standard Two-Stage Estimation Method

In a memo dated December 12 1994, Stuart Beal and Steve Shafer describe how a NONMEM run may be constructed to quickly and conveniently obtain the first-stage PK estimates used with the standard two stage estimation method. These estimates are output in a NONMEM table. This memo describes the same thing, only it goes a little further. It describes how to produce the table so that it in turn can be used as the data set for subsequent NONMEM runs which can obtain the second-stage estimates. Mimicking the earlier discussion about obtaining first-stage estimates: Using (for the sake of illustration) a simple one-compartment model with constant cv residual error, the control stream for obtaining first-stage estimates should include the following: $SUBROUTINE ADVAN1 TRANS2 $PK CL=THETA(1)*EXP(ETA(1)) V =THETA(2)*EXP(ETA(2)) M=0 IF (NEWIND.EQ.2) M=1 ;M is an MDV value for the subsequent runs $ERROR Y=F+F*EXP(ETA(3))*ERR(1) $THETA 5 50 ;these are rough typical population values $OMEGA 100 100 100 $SIGMA 1 FIXED $ESTIMATION MAXEVAL=0 POSTHOC FOCE INTERACTION $TABLE CL V M COV FILE=firststage ; COV is a covariate MAXEVALS=0 means that no population estimation will occur POSTHOC means that individual conditional estimates of CL and V will be obtained. The Bayesian influence is nill, since OMEGA is purposely chosen to be very large. What results then, are simple extended least squares estimates. FOCE needed only because without it, INTERACTION cannot also be used. INTERACTION means that individual estimates of ETA(3) are also obtained. EXP(ETA(3)) is in effect, the standard deviation of ERR(1) since SIGMA is fixed to 1. Were SIGMA not fixed to 1, and were EXP(ETA(3)) absent, then all residual errors, for all