Covariate Models Using Weight

From: Rebecca Wrishko <wrishko@unixg.ubc.ca> Subject: Covariate Models Using Weight Date: Wed, 17 Nov 1999 11:54:08 -0800 Further to the discussion and suggestions forwarded by Vladimir Piotrovskij and Nick Holford with respect to implementation of a parameter centered by some median/mean weight, does the distribution of the population weights have to be fairly narrow, that is is a narrow range, to use TVCL=Theta(1)+Theta(2)*(wt-70)? I attempted to implement this suggestion for a small (6) pediatric population with a mean weight of 20kg (11.2, 17, 18.7, 22.2, 25, 33) with an ADVAN3 TRANS3 subroutine under default (Method 0) estimation and was unable to obtain a successful execution due to a negative V value. However, if the mean weight was changed to 12 and the NM-TRAN control stream (below) was executed final parameter estimates were obtained. Does the centering for mean weight strategy require a robust population? Also I believe that the estimates of theta(1)-1.09L/hr, theta(3)-4.09L, theta(5)-3.17L are in the units of /12kg . However, when one wishes to translate to TVCL (with units of /kg) must the theta(1) and theta(2) values be added and then divided by weight given in the parenthetical term or mean weight (ie. 1.09+0.145/12 or 1.09+0.145/20)? $SUBROUTINES ADVAN3 TRANS3; Two Compartment Linear Model of entire population $PK TVCL=THETA(1)+THETA(2)*(WT-12) ; typical clearance normalized for wt CL=TVCL*(1+ETA(1)) ; mean clearance TVV=THETA(3)+THETA(4)*(WT-12) ; typical central volume normalized for wt V=TVV*(1+ETA(2)) ; mean central volume TVVSS=V+THETA(5)+THETA(6)*(WT-12) ; typical vss normalized for wt VSS=TVVSS*(1+ETA(3)) ; mean theta 3 Q=THETA(7) K=CL/V; reparameterization lines K12=Q/V K21=Q/(VSS-V) S1=V $THETA (0,0.5) (0,0.01) (0,0.5) (0,0.01) (0,1) (0,0.01) (0,3) $OMEGA .25 .25 .25 ; fifty percent cv $SIGMA .04 ; twenty percent cv $ERROR Y=F*(1+EPS(1)) ; proportional error term $ESTIMATION MAXEVAL=850 SIGDIGITS=4 $COVARIANCE Thank you for your assistance Rebecca >Rebecca Wrishko >Division of Clinical Pharmacy >Faculty of Pharmaceutical Sciences >University of British Columbia >Vancouver, British Columbia, Canada >Email: wrishko@unixg.ubc.ca