Dear Xiaofeng,
Presumably the CL at the start and at SS are correlated. If you in the model assumed a lack of correlation, that may well be the cause of a variance driven to zero. I agree with Toufigh that starting simple is usually a good idea. Given your data sparsity, I would start very simple. Why not apply a one-compartment model without CL induction. You can then extend to a model that has 2 compartments and separately one that has a CL changing with time (or even better one that changes with concentration as was discussed recently on nmusers). If both are models better than your simple starting model, you can try combining the two. Best regards, Mats Mats Karlsson, PhD Professor of Pharmacometrics Dept of Pharmaceutical Biosciences Faculty of Pharmacy Uppsala University Box 591 75124 Uppsala Phone: +46 18 4714105 Fax + 46 18 4714003 From: owner-nmus...@globomaxnm.com [mailto:owner-nmus...@globomaxnm.com] On Behalf Of Toufigh Gordi Sent: 05 March 2012 22:45 To: Wang, Xiaofeng; 'nmusers@globomaxnm.com' Subject: Re: [NMusers] time-dependent clearance model Whenever I start a modeling process, my first objective is to get the structural model, i.e., your PK model in this case, well defined and in place. If you start from there and you are pretty confident that you have the right model, finding what parameters differ between subjects should not be difficult. In your case with the very low ETA on CL1, how confident are you about the model estimates, i.e., V3 or Q? Are they stay the same from days 1 to ss? I can't really give any specific advice since I haven't seen the results and know very little about the model and the fits. Toufigh On 3/5/12 1:30 PM, "Wang, Xiaofeng" <xiaofeng-w...@uiowa.edu> wrote: Hi Toufigh, Thank you for the suggestion. I tried the simplest model with 2 ETAs on the pre- and post-induction clearance. The result gave very small omega estimate for the pre-induction clearance (2.50e-005). But I don't believe that there is no between subject variability for the pre-induction clearance. Could you please give me some suggestion about this? Thank you. Best, Xiaofeng _____ From: Toufigh Gordi [tgo...@rosaandco.com] Sent: Monday, March 05, 2012 2:30 AM To: Wang, Xiaofeng; 'nmusers@globomaxnm.com' Subject: Re: [NMusers] time-dependent clearance model Xiaofeng, It always amazes me how many parameters we try to estimate based on the limited amount of data available. This is specially the case when a rather complex event is taking place, such as autoinduction in this case, and that based on sparse samples. In your case, there are a total of 15 parameters to be estimated, which, as Katya points out seems to be way too many. I would suggest that you start with the simplest model and then make it more complex once you have the structural (i.e., your PK) model in place. Since you have data only at pre- and post-induction, I think it is a good idea to estimate different CL values for the two occasions. This way, you can use the built-in library, with explicit solutions, which is normally faster than trying to solve the equations in the $DES. Why not start with this and 1-2 ETAs on the CLs on days 1 and 7? If this simple model works, you can always move ahead and add ETAs. Toufigh On 3/4/12 8:51 PM, "Wang, Xiaofeng" <xiaofeng-w...@uiowa.edu <UrlBlockedError.aspx> > wrote: Hi Katya, Thank you. I double checked the units. mcg for AMT, ng/mL for DV, and L for CL. I think there is no problem with the units. Since I am using log-transformed data, does that influence the units? I will try kicking in CLSS after day 1. For 6 observations per patients, what is the reasonable number of ETAs? Best, Xiaofeng _____ From: owner-nmus...@globomaxnm.com <UrlBlockedError.aspx> [owner-nmus...@globomaxnm.com <UrlBlockedError.aspx> ] on behalf of Ekaterina Gibiansky [egibian...@quantpharm.com <UrlBlockedError.aspx> ] Sent: Sunday, March 04, 2012 8:53 PM To: 'nmusers@globomaxnm.com <UrlBlockedError.aspx> ' Subject: Re: [NMusers] time-dependent clearance model Xiaofeng, Such a large difference suggests you may have a problem with units: check AMT, DV, and the parameter S2 for consistency. A couple of other points: - If the full induction is expected by day 7, and you only have data on day 1 and after day 7, you may not be able to estimate KIN. You may be better off with the model where there is CLI on day 1 and CLSS on days >1 (And you will not need $DES for that model). - You have 6 observations per subject and you have 7 ETAs, it is too many, your model should be overparameterized (Check whether relative standard errors are large). Regards, Katya Ekaterina Gibiansky, Ph.D. CEO&CSO, QuantPharm LLC Web: www.quantpharm.com <http://www.quantpharm.com> Email: EGibiansky at quantpharm.com On 3/4/2012 5:33 PM, Wang, Xiaofeng wrote: Dear nmusers, I have a drug with clearance autoinduction. I have sparse data(three observations on day 1, two between day 7 and 14, and one on day 28). I am trying to run a time-dependent clearance model. I tried FO and FOCEI, but I always got unreasonable estimate for the initial clearance (CLI) which is about 0.15 L/h (from knowledge of previous studies, the reasonable initial clearance should be around 20 L/h and maximum induction occurs around day 7). Could someone give me some advice about my model and my data? Thank you. Xiaofeng The CTL file: $PROB $INPUT C ID TIME AMT DV MDV EVID ADDL II CMT $DATA C:/ IGNORE=C $SUBROUTINES ADVAN6 TOL=6 $MODEL NCOMPARTMENTS=3 COMP=(DEPOT,DEFDOSE) COMP=(CENTRAL,DEFOBS) COMP=(PERIP) $PK CLI=THETA(1)*EXP(ETA(1)) CLSS=THETA(2)*EXP(ETA(2)) KIN=THETA(3)*EXP(ETA(3)) V2= THETA(4)*EXP(ETA(4)) Q= THETA(5)*EXP(ETA(5)) V3= THETA(6)*EXP(ETA(6)) KA= THETA(7)*EXP(ETA(7)) S2=V2 K23=Q/V2 K32=Q/V3 $DES CL=CLSS-(CLSS-CLI)*EXP(-KIN*T) K20=CL/V2 DADT(1)=-KA*A(1) DADT(2)=KA*A(1)+K32*A(3)-K23*A(2)-K20*A(2) DADT(3)=K23*A(2)-K32*A(3) $ERROR IPRE=LOG(1) IF(F.GT.0) IPRE=LOG(F) Y = IPRE+EPS(1) $EST METHOD=0 POSTHOC PRINT=10 MAX=9999 SIG=2 NOABORT MSFO=050.MSF $THETA (0, 20);[CLI] (0, 65);[CLSS] (0, 0.02) ;[KIN] (0, 45);[V2] (0, 5);[Q] (0, 58);[V3] (0, 0.2);[KA] $OMEGA .25 .25 .25 .25 .25 .25 .25 $SIGMA .2 $COV PRINT=E $TABLE ID TIME DV CLI CLSS KIN V2 Q V3 KA IPRE CWRES ONEHEADER NOPRINT FILE=050.TAB $TABLE ID TIME CLI CLSS KIN V2 Q V3 KA FIRSTONLY NOAPPEND NOPRINT FILE=050.PAR $TABLE ID ETA1 ETA2 ETA3 ETA4 ETA5 ETA6 ETA7 FIRSTONLY NOAPPEND NOPRINT FILE=050.ETA $TABLE ID TIME CLI CLSS KIN V2 Q V3 KA FIRSTONLY NOAPPEND NOPRINT FILE=PATAB050
