Predicted Concetration derivations

From: Rebecca Wrishko <wrishko@unixg.ubc.ca> Subject: Predicted Concetration derivations Date: Wed, 17 Nov 1999 11:54:12 -0800 The assistance of the group would be greatly appreciated in solving the following question, how does NONMEM generate the predicted serum concentrations at the times for which there is a corresponding event record? Implementing Advan1 Trans2 (NMTRAN control stream below) and Advan3 Trans3 (NMTRAN control stream below) subroutines for the pk modeling of vancomycin in a small pediatric population, I was able to obtain final parameter estimates of CL, V and etas (One-Compartment) and Cl, V, Vss, and etas (Two-Compartment). I have attempted using the final PK parameter one- and two-compartment estimates of CL and Vss, obtained from the modeling routines to calculate expected drug concentrations and do not derive the same values as those generated from the NONMEM execution. How are the fixed (theta) and random (eta) parameters incorporated into the formulae for calculating the predicted serum concentrations? Thank you Rebecca NM-TRAN 1: $SUBROUTINES ADVAN1 TRANS2; One Compartment Linear Model $PK CL=THETA(1)*EXP(ETA(1)) ; mean clearance V=THETA(2)*EXP(ETA(2)) ; mean central volume K=CL/V ;reparameterization required S1=V $THETA (0,4.) ; clearance estimate (0,10.) ; volume estimate $OMEGA .04 .04 ; twenty percent cv $SIGMA .02 ; ten percent cv $ERROR Y=F+ERR(1) $ESTIMATION MAXEVAL=450 SIGDIGITS=4 $COVARIANCE NM-TRAN 2: $SUBROUTINES ADVAN3 TRANS3; Two Compartment Linear Model $PK CL=THETA(1)*EXP(ETA(1)) ; mean clearance V=THETA(2)*EXP(ETA(2)) ; mean central volume VSS=V+THETA(3)*EXP(ETA(3)) Q=THETA(4) K=CL/V; reparameterization lines K12=Q/V K21=Q/(VSS-V) S1=V $THETA (0,3) (0,5) (0,10) (0,3) $OMEGA .25 .25 .25 ; fifty percent cv $SIGMA .04 ; twenty percent cv $ERROR Y=F+ERR(1) $ESTIMATION MAXEVAL=450 SIGDIGITS=4 $COVARIANCE Rebecca Wrishko Division of Clinical Pharmacy Faculty of Pharmaceutical Sciences University of British Columbia Vancouver, British Columbia, Canada Email: wrishko@unixg.ubc.ca