Dear all,
I am trying to model the parent and metabolite simultaneously with metabolite concentrations formed after oral dosing. The assumption from in vitro metabolism is that the metabolite is formed in the intestine (absorption compartment in WinNonlin). Can such scenarios can be modeled using phoenix.
The graphical model is attached for thoughts and modifications…
Best regards,
Rc
Parent_Metabolite_Absorption.docx (24.5 KB)
you can code whatever you want in graphical or in textual mode.
one think you should take care of is whether you want to split the amount that exit the depot to say FREL = X% ( formed into metabolite) and then 1-FREL = stayed as parent.
by clicking the abosportion compartmetn you can tick the bioavailibility and insert a bioavailbility parameter if you want to model it.
another consideration is whether you need a liver compartment:
http://dmd.aspetjournals.org/content/25/10/1215/F1.expansion.html
Hi Samer,
Thank you for the response…
Find the graphical model attached to model parent and metabolite simultaneously. the parent is dosed orally and plasma concentration of parent and metabolite measured over time. Parent alone modeling and metabolite alone modeling indicate that they follow 2 compartment kinetics. So, a peripheral compartment was included for both parent and metabolite in joint model.
The information about the parent is metabolized (95 %) and minor quantities excreted in urine.
Now how do i differentiate CLPar2Met and CL in the code below (indicated in bold) ? Can i exclude CL as it is negligible through other routes than metabolism?
Can i use a conversion factor such as fm (0.95), fraction metabolized to differentiate the clearances ?
Please suggest the changes in the code and provide if any example projects of Oral parent and metabolite modeled simultaneously.
test(){
deriv(A1 = (Aa * Ka)- (Cl2 * (C - C2))- (CLPar2Met * C)- (CL * C))
deriv(Aa = - (Aa * Ka))
deriv(A2 = (Cl2 * (C - C2)))
deriv(AMet = (CLPar2Met * C)- (CLMet * C3)- (CL3 * (C3 - C4)))
urinecpt(A0Met = (CLMet * C3))
urinecpt(A0Par = (CL * C))
deriv(A4 = (CL3 * (C3 - C4)))
C = A1 / V
dosepoint(Aa, idosevar = AaDose, infdosevar = AaInfDose, infratevar = AaInfRate)
C2 = A2 / V2
error(CEpspar = 0.310454)
observe(CObsPar = C * (1 + CEpspar))
C3 = AMet / VMet
error(CEpsmet = 0.292077)
observe(CObsMet = C3 * (1 + CEpsmet))
C4 = A4 / V4
stparm(V = tvV * exp(nV))
stparm(Ka = tvKa * exp(nKa))
stparm(V2 = tvV2 * exp(nV2))
stparm(Cl2 = tvCl2 * exp(nCl2))
stparm(VMet = tvVMet * exp(nVMet))
stparm(CLPar2Met = tvCLPar2Met * exp(nCLPar2Met))
stparm(CLMet = tvCLMet * exp(nCLMet))
stparm(CL = tvCL * exp(nCL))
stparm(V4 = tvV4 * exp(nV4))
stparm(CL3 = tvCL3 * exp(nCL3))
fixef(tvV = c(, 9176.52, ))
fixef(tvKa = c(, 1.34823, ))
fixef(tvV2 = c(, 8088.82, ))
fixef(tvCl2 = c(, 391.457, ))
fixef(tvVMet = c(, 132.041, ))
fixef(tvCLPar2Met = c(, 468.442, ))
fixef(tvCLMet = c(, 145.871, ))
fixef(tvCL = c(, 810.118, ))
fixef(tvV4 = c(, 3278.18, ))
fixef(tvCL3 = c(, 122.53, ))
ranef(diag(nV, nKa, nV2, nCl2, nVMet, nCLMet, nCLPar2Met, nCL, nCL3, nV4) = c(0.66270388, 1.1643188, 0.21073429, 1.6304378E-06, 0.091136102, 0.027918936, 0.082136817, 0.63107773, 1.3660761E-06, 6.6362677E-05))
Thanks in advance,
Rc
Hi Serge,
I am trying to model the parent and Metabolite data after oral administration. I have preliminary info that the drug is metabolized by 3A4 and is also metabolized in the gut compartment. Now i want to define the fraction of dose that is converted to metabolite in the gut and fraction remained as parent. Can anybody help writing the code with respect to splitting the dose ?
The dose is 5 mg and in the absorption compartment parent converted to metabolite (~ 90 %) due to metabolism (first pass. Both parent and metabolite are absorbed in to the central compartment and the parent may further metabolize in the liver before reaching the central compartment.
Can i use the below code for splitting the dose:
dosepoint(Aa,bioavail = (f AaF), idosevar = AaDose, infdosevar = AainfDose, infratevar = AainfRate, split)
dosepoint2(Aa,bioavail = (fAa1-F)
f =1; where f is fraction absorbed,
Regards,
RC
Dear Serge Guzy / Simon / Samer,
The following is the NONMEM code for sunitinib and its metabolite with presystemic metabolism and systemic metabolism
$DATA Data_input_file_PKsun.csv
$SUBROUTINE ADVAN6 TOL=4
$MODEL
NCOMP=4
COMP=(DEPOTD,DEFDOSE) ;Dosing compartment
COMP=(CENTRAL) ;Sunitinib central compartment
COMP=(PERIPH) ;Sunitinib peripheral compartment
COMP=(MET) ;SU12662 central compartment
;INITIAL VALUES
$THETA
(0,30) ; THCL - Clearance/F of sunitinib
(0,1500) ; THV1 - Central volume of distribution (Vd)/F of sunitinb
(0,200) ; THV2 - Peripheral Vd/F
(0,2.5) ; THQ - Intercompartmental clearance/F of sunitinib
(0.1,0.5) ; THKA - Absorption rate constant
(0.001,1.3) ; THMTT - Mean transit time
(0,1.3,5) ; THN - Number of transit compartments
(0,2.0) ; THRPS - Ratio of presystemic to systemic metabolism
(0.21 FIX) ; THFM - Fraction metabolized to SU12662
(1 FIX) ; THFABS - Fraction of dose absorbed
(0,14) ; THCLM - Clearance/FABS of SU12662
(0,1410) ; THVM1 - Vd/FABS of SU12662
(0,0.06) ; SD_PAR - Additive residual error sunitinib
(0,0.10) ; CV_PAR - Proportional residual error sunitinib
(0,0.06) ; SD_MET - Additive residual error SU12662
(0,0.10) ; CV_MET - Proportional residual error SU12662
$OMEGA BLOCK(4)
0.074 ; ETACL - Interindividual variability (IIV) of CL
0.0793 0.109 ; ETAV1 - IIV of V1
0.02 0.02 0.168 ; ETACLM - IIV of CLM
0.02 0.02 0.0185 0.205 ; ETAVM1 - IIV of VM1 (Covariances are the off-diagonal elements)
$OMEGA 0.1 ; ETAN - IIV of N
$OMEGA 0.05 ; ETAKA - IIV of KA
$OMEGA BLOCK(1) 0.95 ; KPMTT1 - Interoccasion variability in MTT
$OMEGA BLOCK(1) SAME ; KPMTT2
$OMEGA BLOCK(1) SAME ; KPMTT3
$OMEGA BLOCK(1) SAME ; KPMTT4
$OMEGA BLOCK(1) SAME ; KPMTT5
$SIGMA 1 FIX
$PK
;Increase maximum number of integrations of the differential equations
"FIRST
" COMMON /PRCOMG/ IDUM1,IDUM2,IMAX,IDUM4,IDUM5
" INTEGER IDUM1,IDUM2,IMAX,IDUM4,IDUM5
" IMAX=99000000
FM = THFM
RPS = THRPS
;The following function is needed for the calculation of FPRE and FSYSS
;under the condition that FM=FPRE+(1-FPRE)*FSYSS and RPS=FPRE/FSYSS and FM,FSYS,FPRE<1
SQ = SQRT(1+2RPS+RPS**2-4RPS*FM)
FPRE = 0.5+0.5RPS-0.5SQ
FSYS = FPRE/RPS
FABS = THFABS
FD = (1-FPRE)*FABS ;Bioavailability of sunitinib (FD=F)
KA = THKA*EXP(ETAKA)
CL = FDTHCLEXP(ETACL)
V1 = FDTHV1EXP(ETAV1)
V2 = FD*THV2
Q = FD*THQ
CLM = THCLM*EXP(ETACLM)
VM1 = THVM1*EXP(ETAVM1)
Please help me to write the code in phoenix, with emphasis on code that is indicated in bold. Is it possible graphically ?
Best regards,
Raghav
Dear Serge,
the graphical representation is attached here (sunitinib + metabolite ).
With best regards,
Raghav
Sunitinib_Parent_Metabolite_Model.docx (44.1 KB)
Dear Dr. Serge Guzy,
I am trying to model the parent and metabolite conc of drug administered orally, with parent being metabolized in the gut, (metabolite peaks before the parent). I have created a graphical model (by following a reference attached with NONMEM code) and tried to fit the data but in vain. Find the project attached.
Regards,
Raghav
M&S_070616.phxproj (652 KB)6250-Simultaneous Population Pharmacokinetic Modelling of Parent Compound and Metabolite in Plasma and Urine for a New Drug Candidate.pdf (440 KB)
Hi Serge,
Can you help me regarding the problem posted above
thanks in advance,
RC