Hello. I’d like to fit single dose transdermal PK profile using Phoenix model. Basically, I used “Transdermal example of nicotine patch” text model with some modification test(){ deriv(A1 = Frate + Srate - Ke * A1 - K12 * A1 + K21 * A2) deriv(A2 = K12 * A1 - K21 * A2) Dose = 10000 Frate = (t <= Ftau ? ((Dose-SDose)/Ftau) : 0) Srate = (t <= Stau ? (SDose/Stau) : 0) C = A1 / V error(CEps = 1) observe(CObs = C * (1 + CEps)) stparm(Ftau = tvFtau * exp(nFtau)) stparm(Stau = tvStau * exp(nStau)) stparm(SDose = tvSDose * exp(nSDose)) stparm(V = tvV * exp(nV)) stparm(Ke = tvKe * exp(nKe)) stparm(K12 = tvK12 * exp(nK12)) stparm(K21 = tvK21 * exp(nK21)) stparm(Tlag = tvTlag * exp(nTlag)) fixef(tvV = c(0, 384, )) fixef(tvKe = c(0, 0.15, )) fixef(tvK12 = c(0, 0.01, )) fixef(tvK21 = c(0, 0.9, )) fixef(tvTlag = c(0, 0.75, )) fixef(tvFtau = c(8, 12, 16)) fixef(tvStau = c(16, 24, 28)) fixef(tvSDose = c(0, 8000, )) ranef(diag(nV, nKe, nK12, nK21, nTlag, nFtau, nStau, nSDose) = c(1, 1, 1, 1, 1, 1, 1, 1)) } But, Our PK profile has “Tlag” and I’d like to enter the Tlag as a parameter in above model. How can I put the “Tlag” in the model? Can you modify this model to Phoenix graphical model? and How can I simulate multiple dose profile (Tau = 24hr) using this model? Please give me advices Thanks [file name=TDS_modeling.phxproj size=365000]Certara | Drug Development Solutions (356 KB)
one way is to take advantage of the dosepoint satement and its argument tlag but then you need to map dosing information or you can code this into your equation Frate equation I prefer the dospoint style see below test(){ deriv(A1 = - Ke * A1 - K12 * A1 + K21 * A2) deriv(A2 = K12 * A1 - K21 * A2) dosepoint(A1,duration=tvFtau,tlag=tvTlag,bioavail=FREL) dosepoint2(A1,duration=tvStau,bioavail=1-FREL) # Dose = 10000 #Frate = (t <= Ftau ? ((Dose-SDose)/Ftau) : 0) #Srate = (t <= Stau ? (SDose/Stau) : 0) C = A1 / V error(CEps = 1) observe(CObs = C * (1 + CEps)) stparm(Ftau = tvFtau * exp(nFtau)) stparm(Stau = tvStau * exp(nStau)) stparm(V = tvV * exp(nV)) stparm(Ke = tvKe * exp(nKe)) stparm(K12 = tvK12 * exp(nK12)) stparm(K21 = tvK21 * exp(nK21)) stparm(Tlag = tvTlag * exp(nTlag)) fixef(tvV = c(0, 384, )) fixef(tvKe = c(0, 0.15, )) fixef(tvK12 = c(0, 0.01, )) fixef(tvK21 = c(0, 0.9, )) fixef(tvTlag = c(0, 0.75, )) fixef(tvFtau = c(8, 12, 16)) fixef(tvStau = c(16, 24, 28)) fixef(FREL = c(0, 0.8,1 )) ranef(diag(nV, nKe, nK12, nK21, nTlag, nFtau, nStau, nSDose) = c(1, 1, 1, 1, 1, 1, 1, 1)) }
Dear smouksassi I appreciate your kind reply. I have an another question about dosepoint. Follwing your advice, How can I map dosing information? (A1 1, A1 1 rate, A1 2, A1 2 rate, time) In case of total transdermal patch dose is 10 mg, How can I split the dose? I’ll be waiting for your reply. Best regards. shhong 
Dear Shong You can split the dose using this tyoe of code. I added a tlag to see the 2 splitted doses. best Serge test(){ deriv(A1 = - (Cl * C)) urinecpt(A0 = (Cl * C)) C = A1 / V dosepoint(A1, bioavail = (1-f), idosevar = A1Dose, infdosevar = A1InfDose, infratevar = A1InfRate) # first dose fraction 1-f dosepoint2(A1, tlag = (tlag), bioavail = (f)) # second dose fraction f after tlag error(CEps = 1) observe(CObs = C + CEps) stparm(V = tvV) stparm(Cl = tvCl) stparm(f = ilogit(tvf)) stparm(tlag = tvtlag * exp(ntlag)) fixef(tvV = c(, 50, )) fixef(tvCl = c(, 5, )) fixef(tvf = c(, 0, )) fixef(tvtlag = c(, 6, )) ranef(diag(ntlag) = c(0.0001)) }
as per the code Serge and I sent it is the FREL that is dividing the total dose of 10 000 to be split between the slow and fast rates. in the mapping you just input time =0 and A1 1 = total dose = 10 000 and A1 2 = 10 000 and you leave rates empty. now the total dose that will end up in the system = (10000 * F) + (10000 *(1- F) ) = 10 000
Thanks for your reply. I fitted our profile well. then, I’d like to simulate multiple dose profile (tau = 24) using ADDL input option. In case of split dose (infusion), How do I set the dosing option? I attached project file. Please give me advice again. Best regards [file name=TDS_modeling-20140922.phxproj size=729271]Certara | Drug Development Solutions (712 KB)
You got me on that one because both use the same dosepoint A1 and A11 and A12 are not dosepoints. The simplest way is just to write all the doses in the dosing tab A1 1 A1 1 Rate A1 2 A1 2 Rate Time 13300000 13300000 0 13300000 13300000 24 13300000 13300000 48 13300000 13300000 72 etc… This will work for sure. best Serge
I found a way to deal with ADDL if you just put extravascular input with infinite Ka, then it will work because the input dose is outside the central compartment. Look at the project and input options and let me know if it is clear. best Serge [file name=split_dose_2.phxproj size=98671]Certara | Drug Development Solutions (96.4 KB)
I am still working on it. I will come back after the holidays we have in Israel right now. What I sent you does not seem 100% correct but not sure yet. best Serge
Dear Shhong I made 3 versions of the model and all gave me the same simulation results. Please download the new Phoenix version that just came out. The project with the new version is attached. If you still need the previous version, let me know and I will make the translation to have it working on the previous version too. best Serge [file name=TDS_modeling_simulation_new_version.phxproj size=1479226]Certara | Drug Development Solutions (1.41 MB)
Dear Shhong I translated the 3 models to have them working on 1.3. It is attached. The only version we cannot make is the ADDL with split dose in the central compt. The 3 models are as follows: 1: ka infinite, 2 extravascular compts. ADDL works 2: split dose into central, all doses are explicitly shown in the data set. It works 3: Since the kinetic is linear, the principle of superposition applies and you can model the 2 input separately and add the two response to get the same profile as before. It works too. best Regards Serge [file name=split_dose_phoenix1point3.phxproj size=1104117]Certara | Drug Development Solutions
split_dose_phoenix1point3.phxproj (1.05 MB)
Dear Serge I’m very thankful for your kind answers. It was very helpful for me Best regards. Hong