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Hi I am trying to build a structural model for an oral drug. I am getting extremely large and unreasonable values for vd, eg a billion L, putting an upper limit on theta will give a near boundary warning. Does anyone have an idea why this might occur and how to solve it. This is part of the input file: $SUBROUTINE ADVAN2 TRANS2 $PK TVCL = THETA(1) CL = TVCL*EXP(ETA(1)) V = THETA(2) KA = THETA(3) S2 = V $THETA (0,10) $THETA (0,20) $THETA 2 FIXED Best regards Susan

Dear Susan I am a beginner in NONMEM here is my input from one of my online resources. I appreciate if you others comment on this. Go through individual profiles one by one, perform NCA analysis in WINONLIN for initial estimates (for further information go through Chapter 10 of ENE ETTE BOOK) 1.Try different starting estimates. Sometimes NONMEM is very sensitive to the starting estimates of the parameters. For variability parameters, NONMEM tends to perform better if the initial estimates are too high, rather than too low. 2. Reduce the number of THETAs in the model. If a model is over-specified, then NONMEM can thrash trying to find the correct value for THETA. Reduce a 3 compartment model to a 2 compartment model. Eliminate covariate effects. The fewer parameters NONMEM tries to estimate, the more likely it is to successfully estimate the value of the parameters. 3. Reduce the number of variance parameters. Variance parameters can be particularly troublesome. Try having only 1 ETA and 1 EPS in the model. 4. Fix the values of ETA at 0. This is the naïve pooled data (NPD) approach, and it works surprisingly well. NONMEM sometimes has real problems estimating the structural model and the variance model at the same time. When this is the case, you may be able to get NONMEM to run by fixing every ETA value at 0 (e.g., $OMEGA 0 FIX 0 FIX 0 FIX ) and so on. With the ETA estimates fixed at 0, estimate the values of THETA. Then, fix the THETA values at those estimated, and now estimate the OMEGA matrix (i.e. ETA) for the fixed values of THETA. This way NONMEM isn’t trying to estimate both THETA and OMEGA at the same time. For further detailed information you should go through NONMEM manual 5 and this chapter helps you well in NONMEM 5 (Chapter 9 - Additional NM-TRAN Records) All the best.

1) Likely your data units are off by a few orders of magnitude. (maybe concentrations are shown in ng/mL or maybe in ug/mL or pg/mL) 2) perhaps your bioavailability is also small 3) perhaps your drug units are in ug instead of mg? 4) Try scaling S2=V/1000000 to compensate 5)Don't put upperbounds on your volume till you know the right scale and order of magnitude Good luck! - Joseph Joseph Kahn, Ph.D. Novartis Pharmaceuticals Corporation Novartis Pharmaceuticals Corporation One Health Plaza East Hanover, NJ 07936-1080 USA Phone: +1 862 7783939 Email : [email protected] Susan Al taher <[email protected]> Sent by: [email protected] 03/05/2011 12:34 PM To <[email protected]> cc Subject Hi I am trying to build a structural model for an oral drug. I am getting extremely large and unreasonable values for vd, eg a billion L, putting an upper limit on theta will give a near boundary warning. Does anyone have an idea why this might occur and how to solve it. This is part of the input file: $SUBROUTINE ADVAN2 TRANS2 $PK TVCL = THETA(1) CL = TVCL*EXP(ETA(1)) V = THETA(2) KA = THETA(3) S2 = V $THETA (0,10) $THETA (0,20) $THETA 2 FIXED Best regards Susan

It might be helpful if you could show some of the data records. I am guessing it has something to do with the units of conc and dose. You can also simulate PK with your initial guesses and overlay on your data to see if these guesses are even reasonable to begin with or not ? Best Jeet Sent from my iPhone

Susan, In my experience very large estimates for volume of distribution are almost always a results of inaccuracies with units between concentration observations (DV), dosing amounts (AMT), and the scale parameter (S). I believe you can correct your issue by adjusting the S2=V code in your control stream. Please see my blog (blog.learnpkpd.com) for a complete description. The specific post on the scale parameter is located here: http://wp.me/p1fZzZ-4O Best of luck! Nathan _____________________________ Nathan Teuscher Founder PK/PD Associates [email protected] www.learnpkpd.com blog.learnpkpd.com www.youtube.com/learnpkpd www.twitter.com/learnpkpd