Dear Experts, I am trying to fit a larget molecule data using TMDD fitting. I am facing some problem with dose points. How to put dose point in phoenix if you write all the diff equation in conc term. Dose we are giving in nmole/kg in raw data worksheet. Pls find below equation for the TMDD model I am using. test(){ deriv(TotDrug= - keDrug/V-kmComp-k12Drug/V+k21Peri/V) deriv(Target= kin-koutTarget -kon(Drug/V)Target +koffComp) deriv(TotTarget= kin-koutTarget -kmComp) deriv(Peri = k12Drug/V-k21Peri) Drug/V=TotDrug-TotTarget+Target Comp=TotTarget-Target dosepoint(TotDrug) C=TotDrug sequence {Target=BSL;TotTarget=BSL} error(CEps = 1) error(TargetEps = 1) error(TotTargetEps = 1) observe(CObs = C*(1+ CEps)) observe(TargetObs = Target*(+TargetEps)) observe(TotTargetObs = TotTarget+TotTargetEps) kon=2.01 kin=kout*BSL BSL=4.0 stparm(V = (tvV)) stparm(ke = (tvke)) stparm(koff = (tvkoff)) stparm(kout = (tvkout)) stparm(k12 = (tvk12)) stparm(k21 = (tvk21)) stparm(km = (tvkm)) fixef(tvV = c(, 0.06, )) fixef(tvke = c(, 0.31, )) fixef(tvkoff = c(,101.0, )) fixef(tvkout = c(, 2.2, )) fixef(tvk12 = c(, 0.29, )) fixef(tvk21 = c(, 0.34, )) fixef(tvkm = c(,0.05, )) } Thanks you in adavnce for you input Best Regards Raj
Hi Raj, I asked a colleague at Pharsight to take a look at your posting and he provided the following input that I hope you find useful: 1. If you want to have differential equations in concentration like this: deriv( C = - Cl * C ) but you want to dose to that compartment, you can do it like this: C = A / V deriv( A = -Cl * C * V ) dosepoint( A ) In other words, instead of a differential equation for C, you have one for A, and just make sure you convert to amount by multiplying by V on the right-hand-side. 2. I found this TMDD model confusing, because of working in terms of the “Totals”, rather than the individual compartments. So here’s how I would proceed: First, the units. In this code, the units of “amount” are in nanomoles per kilogram of body weight, but that doesn’t matter. Let’s just call it “amount”. Koff is simple. It is in units of 1/time. Kon is tricky. It’s units are 1/(time * concentration). I made the variable names really wordy to eliminate misunderstanding, and the basic statements would be: deriv( UnboundDrugAmount = - UnboundDrugConcRate * V ) dosepoint( UnboundDrugAmount ) UnboundDrugConc = UnboundDrugAmount / V unbindingRate = BoundComplexConc * Koff bindingRate = Kon * UnboundDrugConc * UnboundTargetConc PeripheralDrugConcRate = - UnboundDrugConc * K12 - PeripheralConc * K21 UnboundDrugConcRate = - PeripheralDrugConcRate - bindingRate + unbindingRate deriv( PeripheralConc = PeripheralDrugConcRate ) UnboundTargetConcRate = Kin - Kout*TargetConc - bindingRate + unbindingRate BoundComplexConcRate = bindRate - unbindingRate - BoundComplexConc * Km deriv( BoundComplexConc = BoundComplexConcRate ) deriv( UnboundTargetConc = UnboundTargetConcRate ) sequence{ UnboundTargetConc = Kin / Kout } TotalDrugConc = UnboundDrugConc + BoundComplexConc TotalTargetConc = UnboundTargetConc + BoundComplexConc and the rest should be straightforward…