Dear Serge, I am trying to fit one PD data using IDR4 and Pk was fitted with TMDD model. I could able to fit the data using gamma =0.1, but I am estimating gamma also which is giving negative value. 1. I also tried to fixe gamma …doesn’t work 2. also kept value as zeo…not working. Without gamma fit is very poor. Below is the equation test (){ deriv(TotDrugconc1 = - (ke+k12)Drugconc1 -kmComp1+k21Peri1/V) deriv(Target1 = kin-koutTarget1 -konDrugconc1Target1 +koffComp1) deriv (TotTarget1= kin-koutTarget1 -kmComp1) deriv(Peri1 = k12Drugconc1V-k21Peri1) deriv(BM1 = kinm-koutm*(1+(EmaxTarget1g/(EC50g+Target1**g)))BM1) Drugconc1=TotDrugconc1-TotTarget1+Target1 Comp1=TotTarget1-Target1 Dose1=416.67 C1=TotDrugconc1 sequence {Target1=BSL;TotTarget1=BSL;BM1=BSLm; TotDrugconc1=Dose1/V} error(C1Eps = 1) error(Target1Eps = 1) error(TotTarget1Eps = 1) error(BM1Eps = 1) observe(C1Obs = C1(1+ C1Eps)) observe(Target1Obs = Target1(1+ Target1Eps)) observe(TotTarget1Obs = TotTarget1*(1+TotTarget1Eps)) observe(BM1Obs = BM1*(1+BM1Eps)) kon=2.01 kin=koutBSL BSL=4.0 ke=0.81 k12=0.65 k21=0.28 km=0.11 kout=0.8 koff=38 V=0.03 kinm=koutmBSLm BSLm=100 stparm(koutm = (tvkoutm)) stparm(Emax = (tvEmax)) stparm(EC50 = (tvEC50)) stparm(g = (tvg)) fixef(tvkoutm = c(,1.76, )) fixef(tvEmax = c(,62, )) fixef(tvEC50 = c(,350, )) fixef(tvg = c(,0.1, )) }
Dear Raja I made some corrections to your code. First of all, there were 3 equations that used variables that were not defined at the time. I had to first define these variables and then put the equations. In the pml, if you are using a mathematical formula like for example BSL=4, then any equation that sues BSL must show up after the equation for BSL. IT APPLIES ONLY TO EQUAITONS AND SEQUENCE statements BUT NOT TO derive, stparm and any other statements. Your differential equations are very stiff especially because you are using different time scale for the rate constants (kon, koff and regular microconstants). I changed the differential equation setting to stiff instead of the default one. I then simulate data just to see that it is working and ti worked. Now you have only fixed effects and I wonder if this model is identifiable without relying on a population approach. Let us go step, try this one attached and put 0 as lower bound (in fixed effects) for g. Use FOCE ELS as engine, max 100 iterations as a fist shot and let me know how it goes SERGE PS: IF YOU FIT, THEN CHANGE IN RUN OPTIONS FROM SIMULATION TO SIMPLE [file name=idr4_raja_serge_corrected_official.phxproj size=448960]Certara | Drug Development Solutions (438 KB)
Thank you very much Dr Serge…I am not able to open the file, moreover it is password protected. Kindly upload the text file if you can. Thanks Raj
Dear Raj Here is the code. please choose for the integrator stiff as your diff eq are stiff. best Serge The link to the project is Box In case it still does not work, here is the code. test (){ deriv(TotDrugconc1 = - (ke+k12)Drugconc1 -kmComp1+k21Peri1/V) deriv(Target1 = kin-koutTarget1 -konDrugconc1Target1 +koffComp1) deriv (TotTarget1= kin-koutTarget1 -kmComp1) deriv(Peri1 = k12Drugconc1V-k21Peri1) deriv(BM1 = kinm-koutm*(1+(EmaxTarget1g/(EC50g+Target1**g)))BM1) Drugconc1=TotDrugconc1-TotTarget1+Target1 Comp1=TotTarget1-Target1 Dose1=416.67 C1=TotDrugconc1 sequence {Target1=BSL;TotTarget1=BSL;BM1=BSLm; TotDrugconc1=Dose1/V} error(C1Eps = 1) error(Target1Eps = 1) error(TotTarget1Eps = 1) error(BM1Eps = 1) observe(C1Obs = C1(1+ C1Eps)) observe(Target1Obs = Target1(1+ Target1Eps)) observe(TotTarget1Obs = TotTarget1*(1+TotTarget1Eps)) observe(BM1Obs = BM1*(1+BM1Eps)) BSL=4.0 kon=2.01 kout=0.8 kin=koutBSL #BSL=4.0 ke=0.81 k12=0.65 k21=0.28 km=0.11 #kout=0.8 koff=38 V=0.03 BSLm=100 kinm=koutmBSLm #BSLm=100 stparm(koutm = (tvkoutm)) stparm(Emax = (tvEmax)) stparm(EC50 = (tvEC50)) stparm(g = (tvg)) fixef(tvkoutm = c(,1.76, )) fixef(tvEmax = c(,62, )) fixef(tvEC50 = c(,350, )) fixef(tvg = c(,0.1, )) }
Raj, if you’re using IE in particular as your browser it “helpfully” renames the PHXPROJ file to Zip (since it is in fact a compressed file). Just download the file then rename the extension back to xxx.PHXPROJ, there is no password protection on Serge’s file when opened in Phoenix.
Thanks much Dr Serge and Simon. It is really helping me. Thanks Raj