Re: [NMusers] Help with a PK code
Dears Leonid and Saeheum, First of all, thank you for your suggestions, they are very useful and cleared up some queries I had. Leonid, regarding your question about measurement of free or total ligand concentration, in this study we only measured the free ligand concentration. Thank so much, Regards, Niurys 2019-04-23 12:00 GMT-05:00, Leonid Gibiansky : > The code will work as written (if you add ENDIF after TVVM = THETA (6), > and define all parameters CL, V1, Q, V2, KINT, ...) but mechanistically, > this is not a good idea to have two models for two dose levels. You may > want to try QSS model with non-constant Rtot (MM model is usually good > when Rtot is low, while QSS is good when Rtot has accumulation, so may > be this is why you see MM model at low doses and QSS at high doses). > > Also, what is measured, is it free or total concentration? This part of > the code was not shown, and it depends on the assay (for QSS part of the > model). > > Thanks > Leonid > > > On 4/23/2019 8:34 AM, Niurys.CS wrote: >> Dear All, >> >> I'm working on the population pharmacokinetics of a mAb, in this study >> 4 dose levels (50, 100, 200 and 400 mg) were evaluated. I tested >> different models, but none of them fit well; that's why I decided to >> find for each dose level the best model. I found the two lower dose >> levels fitted to Michaelis Menten + CL linear model and the two higher >> dose levels fitted to QSS Rtot model. >> I think if I use this code, I'll find the best model for my data, so I >> appreaciate your suggestions: >> >> $PK >> >> TVCL= THETA(1) >> TVV1= THETA(2) >> TVQ = THETA(3) >> TVV2 = THETA (4) >> >> TVKM = 0 >> TVVM = 0 >> >> IF(DOS.LT.200) THEN >> TVKM = THETA (5) >> TVVM = THETA (6) >> >> TVKSS = 0 >> TVKINT = 0 >> TVKDEG = 0 >> TVRMAX = 0 >> >> IF(DOS.GT.100) THEN >> >> TVKSS = THETA (7) >> TVKKINT = THETA(8) >> TVRMAX = THETA(9) >> >> ENDIF >> >> >> K = CL/V1 >> K12 = Q/V1 >> K21 = Q/V2 >> S1 = V1 >> >> ;-- >> $DES >> >> CONC=0.5*(A(1)/V1-RMAX-KSS)+0.5*SQRT((A(1)/V1-RMAX-KSS)**2+4*KSS*A(1)/V1) >> >> DADT(1) = >> -(K+K12)*CONC*V1+K21*A(2)-KINT*RMAX*CONC*V1/(KSS+CONC)-VM*CONC*V1/(KM+CONC) >> DADT(2) = K12*CONC*V1-K21*A(2) >> >> >> Thank you, >> >> Regards, >> Niurys de Castro >> > -- MSc Niurys de Castro Suárez Profesor Asistente Farmacometría Investigador Agregado Departamento Farmacia Instituto de Farmacia y Alimentos, Universidad de La Habana Cuba "Una estrella brilla en la hora de nuestro encuentro"
Re: [NMusers] Help with a PK code
The code will work as written (if you add ENDIF after TVVM = THETA (6), and define all parameters CL, V1, Q, V2, KINT, ...) but mechanistically, this is not a good idea to have two models for two dose levels. You may want to try QSS model with non-constant Rtot (MM model is usually good when Rtot is low, while QSS is good when Rtot has accumulation, so may be this is why you see MM model at low doses and QSS at high doses). Also, what is measured, is it free or total concentration? This part of the code was not shown, and it depends on the assay (for QSS part of the model). Thanks Leonid On 4/23/2019 8:34 AM, Niurys.CS wrote: Dear All, I'm working on the population pharmacokinetics of a mAb, in this study 4 dose levels (50, 100, 200 and 400 mg) were evaluated. I tested different models, but none of them fit well; that's why I decided to find for each dose level the best model. I found the two lower dose levels fitted to Michaelis Menten + CL linear model and the two higher dose levels fitted to QSS Rtot model. I think if I use this code, I'll find the best model for my data, so I appreaciate your suggestions: $PK TVCL= THETA(1) TVV1= THETA(2) TVQ = THETA(3) TVV2 = THETA (4) TVKM = 0 TVVM = 0 IF(DOS.LT.200) THEN TVKM = THETA (5) TVVM = THETA (6) TVKSS = 0 TVKINT = 0 TVKDEG = 0 TVRMAX = 0 IF(DOS.GT.100) THEN TVKSS = THETA (7) TVKKINT = THETA(8) TVRMAX = THETA(9) ENDIF K = CL/V1 K12 = Q/V1 K21 = Q/V2 S1 = V1 ;-- $DES CONC=0.5*(A(1)/V1-RMAX-KSS)+0.5*SQRT((A(1)/V1-RMAX-KSS)**2+4*KSS*A(1)/V1) DADT(1) = -(K+K12)*CONC*V1+K21*A(2)-KINT*RMAX*CONC*V1/(KSS+CONC)-VM*CONC*V1/(KM+CONC) DADT(2) = K12*CONC*V1-K21*A(2) Thank you, Regards, Niurys de Castro
Re: [NMusers] Help with a PK code
Generally speaking, the portion which undergoes saturatable clearance due to ligand or receptor engagement will be negligible at high concentrations. Therefore, it is recommend to use one saturable equation without needs of dose dependent “IF .. THEN … ENDIF “ Statement The followings are some programming comments in NONMEM coding. IF(DOS.LT.200) THEN;; This assumes DOSE below 50 and 100 not 200 ;;; LT = less than ;;; LE = less than or Equal to TVKM = THETA (5) TVVM = THETA (6) ;; THIS needs to be end in order to next if Then statement effective *ENDIF;;* ;;; TVKSS = 0 TVKINT = 0 TVKDEG = 0 TVRMAX = 0 IF(DOS.GT.100) THEN;;; This assumes that DOS 200 and 400 ;;; GT = Greater than ;;; GE = Great or Equal to TVKSS = THETA (7) TVKKINT = THETA(8) TVRMAX = THETA(9) ENDIF $DES CONC=0.5*(A(1)/V1-RMAX-KSS)+0.5*SQRT((A(1)/V1-RMAX-KSS)**2+4*KSS*A(1)/V1) ;; CONC is simply A(1)/V1 and RMAX and KSS are undefined variables. Hope it helps. On Tue, Apr 23, 2019 at 8:49 AM Niurys.CS wrote: > Dear All, > > I'm working on the population pharmacokinetics of a mAb, in this study > 4 dose levels (50, 100, 200 and 400 mg) were evaluated. I tested > different models, but none of them fit well; that's why I decided to > find for each dose level the best model. I found the two lower dose > levels fitted to Michaelis Menten + CL linear model and the two higher > dose levels fitted to QSS Rtot model. > I think if I use this code, I'll find the best model for my data, so I > appreaciate your suggestions: > > $PK > > TVCL= THETA(1) > TVV1= THETA(2) > TVQ = THETA(3) > TVV2 = THETA (4) > > TVKM = 0 > TVVM = 0 > > IF(DOS.LT.200) THEN > TVKM = THETA (5) > TVVM = THETA (6) > > TVKSS = 0 > TVKINT = 0 > TVKDEG = 0 > TVRMAX = 0 > > IF(DOS.GT.100) THEN > > TVKSS = THETA (7) > TVKKINT = THETA(8) > TVRMAX = THETA(9) > > ENDIF > > > K = CL/V1 > K12 = Q/V1 > K21 = Q/V2 > S1 = V1 > > ;-- > $DES > > CONC=0.5*(A(1)/V1-RMAX-KSS)+0.5*SQRT((A(1)/V1-RMAX-KSS)**2+4*KSS*A(1)/V1) > > DADT(1) = > -(K+K12)*CONC*V1+K21*A(2)-KINT*RMAX*CONC*V1/(KSS+CONC)-VM*CONC*V1/(KM+CONC) > DADT(2) = K12*CONC*V1-K21*A(2) > > > Thank you, > > Regards, > Niurys de Castro > > -- > > MSc Niurys de Castro Suárez > Profesor Asistente Farmacometría > Investigador Agregado > Departamento Farmacia > Instituto de Farmacia y Alimentos, Universidad de La Habana > Cuba > >
[NMusers] Help with a PK code
Dear All, I'm working on the population pharmacokinetics of a mAb, in this study 4 dose levels (50, 100, 200 and 400 mg) were evaluated. I tested different models, but none of them fit well; that's why I decided to find for each dose level the best model. I found the two lower dose levels fitted to Michaelis Menten + CL linear model and the two higher dose levels fitted to QSS Rtot model. I think if I use this code, I'll find the best model for my data, so I appreaciate your suggestions: $PK TVCL= THETA(1) TVV1= THETA(2) TVQ = THETA(3) TVV2 = THETA (4) TVKM = 0 TVVM = 0 IF(DOS.LT.200) THEN TVKM = THETA (5) TVVM = THETA (6) TVKSS = 0 TVKINT = 0 TVKDEG = 0 TVRMAX = 0 IF(DOS.GT.100) THEN TVKSS = THETA (7) TVKKINT = THETA(8) TVRMAX = THETA(9) ENDIF K = CL/V1 K12 = Q/V1 K21 = Q/V2 S1 = V1 ;-- $DES CONC=0.5*(A(1)/V1-RMAX-KSS)+0.5*SQRT((A(1)/V1-RMAX-KSS)**2+4*KSS*A(1)/V1) DADT(1) = -(K+K12)*CONC*V1+K21*A(2)-KINT*RMAX*CONC*V1/(KSS+CONC)-VM*CONC*V1/(KM+CONC) DADT(2) = K12*CONC*V1-K21*A(2) Thank you, Regards, Niurys de Castro -- MSc Niurys de Castro Suárez Profesor Asistente Farmacometría Investigador Agregado Departamento Farmacia Instituto de Farmacia y Alimentos, Universidad de La Habana Cuba
