Dear Stephen, The covariate relationship that you are trying seems unnatural to me. The interpretation of THETA(1) will be the clearance for an individual with SCR=0, and CL will increase as an exponential function of SCR?
I would suggest a parameterization with the covariates normalized to a typical value in the population (i.e. with SCR normalized to a typical SCR, TVSCR). A possible "power" parameterization for SCR: TVCL = THETA(1) * (SCR/TVSCR)**THETA(3) A linear effect of PCA could look something like this: TVCL = THETA(1) * (1 + THETA(4) * (PCA-TVPCA)) ; set boundaries for THETA(4) so that the expression between the brackets cant become negative With these two parameterizations the interpretation of THETA(1) will be CL for a typical individual (SCR=TVSCR and PCA=TVPCA). Furthermore it is from my recollection quite doubtful that serum creatinine by itself will be a good predictor of renal function in this population (Gordjani N. et al. Eur J Pediatr. 1988 Nov;148(2):143-5). Perhaps you should also look into some of the available algorithms to predict GFR in this population (modified Schwartz formula etc.). I hope that my small suggestions will help you resolve your problems. Best regards, Martin Bergstrand, MSc, PhD student ----------------------------------------------- Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University ----------------------------------------------- P.O. Box 591 SE-751 24 Uppsala Sweden ----------------------------------------------- [email protected] ----------------------------------------------- Work: +46 18 471 4639 Mobile: +46 709 994 396 Fax: +46 18 471 4003 -----Original Message----- From: [email protected] [mailto:[email protected]] On Behalf Of Stephen Maxwell Montgomery Sent: Thursday, August 05, 2010 2:23 PM To: [email protected] Subject: [NMusers] ETA1 tending to zero in a simple model Hi, I am currently model building with a neonatal PopPK dataset for a renally eliminated drug and have encountered the following problem: When I add serum creatinine level (SCR) or post-conceptual age (PCA) as a sole covariate, or almost any combination of two covariates, on the clearance model my ETA1 goes to 1.00E-04 as if I had over-parametrised, yet I only have one ETA term on the CL. This situation then triggers the failure of the covariance step due to a parameter estimate being to close to its boundary. What is the likely cause of this and what strategy can I pursue to avoid it? For completeness the relevant excerpts of a typical control file are given (using SCR as the sole covariate in this case): $SUBROUTINE ADVAN1,TRANS2 $PK TVCL=THETA(1)*EXP(THETA(3)*SCR) CL=TVCL*EXP(ETA(1)) TVV=THETA(2) V=TVV*EXP(ETA(2)) SC=V $ERROR Y=F+EPS(1) $EST PRINT=5 METHOD=1 $COVARIANCE Grateful for any help/suggestions/comments offered! All the best, -- Stephen Montgomery School of Pharmacy Queen's University Belfast 97 Lisburn Road Belfast BT9 7BL Tel: (028) 9097 2033=
