From: majid.vakily@tap.com Subject: [NMusers] Cone shaped DV-PRED Date: Wed, April 20, 2005 4:58 pm I have been working on a drug with a complex absorption profile. I have used 2 compartment model with first order input and output (ADVAN4,TRANS1) and the estimated population parameters, individual estimates, and estimates of interindividual and residual variability values are reasonable. However, the population DVs often go as high as ~120 ng/L, population predictions never exceeds 35-45 ng/mL, resulting in a truncated, cone-shaped DV vs PRED plot. As I indicated the DV vs IPRED values appear to be fine. I have approximately 5 samples/patient (over 300 patients in the index set). Considering the complex nature of absorption for this drug with a slow early phase (0.25 to 0.5 hour postdose) and a rapid phase, I decided to use series of absorption compartments to mimic the shape of the plasma concentration-time curve during the absorption phase and capture the Cmax. However, the program is running very slow and I am not sure this is expected or I have a fundamental error in my codes. I appreciate input about this issue or any other suggestions which may improve the fit. $PROB RUN# 1 OUR TEXT $INPUT C STDY=DROP SOUD=DROP ID CMT=DROP DATE TIME AMT DV TYPE=DROP EVID SS II UT=DROP AGE=DROP BMI=DROP RACE=DROP ALC=DROP SMK=DROP HTEN=DROP DBET=DROP CAD=DROP DOSE=DROP ALB=DROP ALT=DROP BIL=DROP CRCL=DROP ACEI=DROP ACT=DROP ASA=DROP DRTC=DROP STER=DROP IRON=DROP NSDS=DROP PPI=DROP SSRI=DROP DCDT=DROP RSND=DROP COM1=DROP $DATA POPPKASO1.csv IGNORE=C $SUBROUTINES ADVAN6 TRANS1 TOL=3 $MODEL NCOMP=5 NPAR=14 COMP=(DEPOT DEFDOSE) ;GUT COMPARTMENT FOR PARENT DRUG COMP=(GUT NODOSE);GI COMPARTMENT 2 FOR PARENT DRUG COMP=(GUT NODOSE);GI COMPARTMENT 3 FOR PARENT DRUG COMP=(CENTRAL DEFOBS NODOSE);CENTRAL COMPARTMENT FOR PARENT DRUG COMP=(PERIPH NODOSE) ;PERIPHERAL COMPARTMENT FOR PARENT DRUG $PK TVCL=THETA(1) CL=TVCL*EXP(ETA(1)) TVV4=THETA(2) V4=TVV4*EXP(ETA(2)) TVKA=THETA(3) KA=TVKA*EXP(ETA(3)) TVV5=THETA(4) V5=TVV5*EXP(ETA(4)) TVQ=THETA(5) Q=TVQ*EXP(ETA(5)) TVMT=THETA(6) MT=TVMT*EXP(ETA(6)) Kel=CL/V4 K45=Q/V4 K54=Q/V5 KT=3/MT S4=V4/1000 $DES DADT(1)=-KT*A(1) DADT(2)=KT*A(1)-KT*A(2) DADT(3)=KT*A(2)-KA*A(3) DADT(4)=KA*A(3)+K54*A(5)-Kel*A(4)-K45*A(4) DADT(5)=K45*A(4)-K54*A(5) $ERROR Y=(A(4)/V4)*(1+ERR(1))+ERR(2) DEL=0 IF (F.EQ.0) DEL=1 IPRED=F W=IPRED+DEL IRES=DV-IPRED IWRES=IRES/W $THETA (15, 150, 1500) ;[CL] (3, 200, 2000) ;[V4] (0.1, 1, 100) ;[KA] (3, 800, 8000) ;[V5] (10, 100, 3000) ;[Q] (0.01, 0.25, 2.5) ;[MT] $OMEGA 0.5 ;[CL] 1 ;[V4] 0.5 ;[KA] 1 ;[V5] 1 ;[Q] 0.4 ;[MT] $SIGMA 0.4 ;[PROPORTIONAL] 4 ;[ADDITIVE] $EST MAXEVAL=9999 MSF=1.msf PRINT=5 NOABORT METHOD=0 POSTHOC $COVARIANCE $TABLE ID TIME IPRED CL V4 Q V5 KA MT AUC T50 NOPRINT ONEHEADER FILE=1.TAB Thanks, Majid Vakily, Ph.D. Senior Research Investigator Department of Drug Metabolism & Pharmacokinetics Phone: (847) 582-2198 Fax; (847) 582-2388 _______________________________________________________ From: bulitta@ibmp.osn.de Subject: Re: [NMusers] Cone shaped DV-PRED Date: Wed, April 20, 2005 9:48 pm Dear Dr Vakily, One proposal to model your data would be to dose a zero order input into the gut compartment with first order absorption from the gut into the central compartment. You might add more flexibility to the absorption process by adding a lag-time for the zero-order input. It is questionable, whether this model has a real mechanistic interpretation. However, you can use e.g. ADVAN 2 / 4 / 12, and thus it is very fast. I am not sure, if your data (5 points per profile) allow to estimate all the parameters and their between subject variability (BSV). From my experience, especially BSV on the duration (TK0) of the zero order input may become difficult. I usually do not include BSV on TK0, unless it really improves the predictive performance. I noticed a tendency that the predictive performance was better, with a BLOCK structure for the OMEGAs of the absorption parameters. After Nick showed me how to do this, I was happy to test this model and a series of others on about 10 drugs with complex absorption characteristics (solubility limit, active transporters, pH-dependent lipophilicity (Log D) etc.). Maybe it only worked, since I had at least 10 data points per profile. However, it might be worth to give it a try. I would recommend to start with a one-compartment disposition model to get reasonable estimates for the absorption parameters (and their variability) and then add more disposition compartments, if required. I got this model to work with three disposition compartments with convincing predictive performance. However, if the initials for the absorption parameters are really bad, there is a good chance that this model fails completely. If you still experience an insufficient predictive performance in the "Cmax region", I would try the "sequential independent zero and then first order absorption model" described in Nicks paper below. Please find two papers on complex absorption models and the control stream below. Hope this helps. Best wishes Juergen ---------------------------------------------------- Juergen Bulitta, M.Sc. Research Scientist IBMP - Institute for Biomedical and Pharmaceutical Research Paul-Ehrlich-Strasse 19 90562 Nurnberg - Heroldsberg Germany ---------------------------------------------------- Holford, N. H., R. J. Ambros, and K. Stoeckel. 1992. Models for describing absorption rate and estimating extent of bioavailability: application to cefetamet pivoxil. J Pharmacokinet Biopharm 20:421-42. Piotrovskij, V. K., G. Paintaud, G. Alvan, and T. Trnovec. 1994. Modeling of the saturable time-constrained amoxicillin absorption in humans. Pharm Res 11:1346-51. $PROBLEM Zero order input into the gut compartment $INPUT ID TIME AMT RATE CMT EVID DVID DV $DATA ../Data/Raw_data.csv IGNORE=# $ESTIM MAXEVAL=9999 NOABORT PRINT=1 METHOD=COND INTERACTION SLOW SIG=5 $COV $SUB ADVAN4 TRANS4 $THETA (0,10) ;POP_CLT unit L/h total body clearance $THETA (0,20) ;POP_V1 unit L volume of central compartment $THETA (0,100) ;POP_V2 unit L volume of peripheral compartment $THETA (0,10) ;POP_CLD2 unit L/h intercompartmental clearance $THETA (0,15) ;POP_TABS unit min half-life of absorption from gut into central compartment $THETA (0,36) ;POP_TK0 unit min duration of zero order input into the gut compartment $THETA (0,12) ;POP_TLAG unit min lag time for the zero order input into the gut $OMEGA 0.05 ; BSVCLT $OMEGA 0.08 ; BSVVSS $OMEGA BLOCK(3) 0.2 ; BSVTK0 0.01 0.01 ; BSVTABS 0.01 0.01 0.3 ; BSVLAG $SIGMA 0.01 ;cvcp $SIGMA 0.001 ;sdcp $PK CL = POP_CLT*EXP(BSVCLT) V2 = POP_V1*EXP(BSVVSS) V3 = POP_V2*EXP(BSVVSS) Q = POP_CLD2 TABS = POP_TABS*EXP(BSVTABS) KA = LOG(2)/(TABS/60) S2 = V2 Tk0 = POP_Tk0*EXP(BSVTK0) D1 = TK0/60 TLAG = POP_TLAG*EXP(BSVLAG) ALAG1 = TLAG/60 $ERROR CP=F Y=CP*(1+CVCP)+SDCP $TABLE ID TIME AMT CMT EVID DVID CL V2 V3 KA TK0 Y ONEHEADER NOPRINT FILE=Zero_order_input_into_gut.fit ######################### raw_data.csv example #ID,TIME,AMT,RATE,CMT,EVID,DVID,DV 1,0,800,-2,1,1,0,. 1,0,.,.,.,2,1,. 1,0.167,.,.,.,2,1,. 1,0.333,.,.,.,0,1,0.12 1,0.5,.,.,.,0,1,0.95 1,0.75,.,.,.,0,1,1.5 1,1,.,.,.,0,1,2.6 1,2,.,.,.,0,1,7.2 1,3,.,.,.,0,1,13.5 1,4,.,.,.,0,1,12.2 1,6,.,.,.,0,1,11.2 1,8,.,.,.,0,1,10.3 1,12,.,.,.,0,1,7.92 1,16,.,.,.,0,1,5.51 1,24,.,.,.,0,1,2.98 1,36,.,.,.,0,1,0.82 1,48,.,.,.,0,1,0.25 ################################ _______________________________________________________