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- [NMusers] "First-pass" 3-compartment model

unsure of how to write the proper routine Any help is greatly appreciated Martin From Luann Phillips luann phillips cognigencorp com Subject RE NMusers First pass 3 compartment model Date Wed August 11 2004 6 47 pm Martin There is not a standard ADVAN for this type model If the system is linear you could implement it with ADVAN5 If you have any nonlinearity then you would need to use ADVAN6 Example Oral Drug dose to depot with first order absorption to the central compartment and elimination from the peripheral cmt PROB 3 cmt model with elim from peri INPUT DATA SUBROUTINES ADVAN5 MODEL COMP DEPOT INITIALOFF DEFDOSE cmt 1 COMP CENTRAL cmt 2 COMP PERI cmt 3 PK KA THETA 1 EXP ETA 1 CL THETA 2 EXP ETA 2 Q THETA 3 EXP ETA 3 VC THETA 4 EXP ETA 4 VP THETA 5 EXP ETA 5 S2 v2 1000 ADVAN5 expects Kij parameters where i cmt number where flow originates j cmt number where flow stops and 0 outside the system Note the following equations are just to demonstrate that you can still model macro parameters in ADVAN5 as long as you provide the equations for the

Original URL path: http://nonmem.org/nonmem/nm/98aug102004.html (2016-04-25)

Open archived version from archive - [NMusers] Changing Clearance over time : Enzyme auto-induction

59 am Dear Partha Leonid et al Interesting discussion May I propose a first order induction function since often enzyme reactions can be approximated to that as an alternative to the previously proposed models Namely CL CLinduced CLinduced CLpre exp kout t Tlag where kout corresponds to the fractional turnover rate of the induced enzyme CLpre the pre induction clearance your CL0 I suppose CLinduced the clearance at steady state post induction and Tlag the lag time for induction to occur I suppose your NewT parameter I have personally applied this relationship taken from the textbook of Gibaldi and Perrier 1982 pgs 304 305 at several occassions The nice thing about the model is that it gives you some info about the apparent fractional turnover rate and turnover time of the inducing enzyme provided the rate limiting step is the change of the amount of enzyme rather than the half life of the drug T1 2kout T1 2K drug and that the turnover rate production rather than the fractional turnover rate loss of enzyme is affected I have some documented practical examples of simultaneous pre peri and post induction modelling after repeated dosing p o and i v that I ll be happy to share if you are interested Johan From Mats Karlsson Subject RE NMusers Changing Clearance over time Enzyme auto induction Date Mon August 9 2004 3 23 am Dear Partha I agree with Johan that a more physiological model is often preferable Taking it one step further is to make the magnitude of induction graded It may be reasonable to make it dependent on the plasma drug concentration Code for such a model is given below Also there may be both inducible and uninducible pathways of elimination for a drug If you have metabolite data you need to take this into account We used such a model in Hassan M et al A mechanism based pharmacokinetic enzyme model for cyclophosphamide autoinduction in breast cancer patients Br J Clin Pharmacol 1999 Nov 48 5 669 77 With this model you don t need to make any assumption about relative rates of drug and enzyme turn over If it takes some time before the induction is becoming apparent it can be modeled with a lagtime but on the other hand a lagtime is not particularly physiological One solution that Toufigh Gordi and I have used is to include a precursor into the chain of events ie drug induces production of precursor which in turn increases the rate of enzyme production the turn over of the precursor will determine the delay in appearance of observable induction Best regards Mats PROBLEM Cyklophosfamid induction drug metabolite INPUT DROP ID TIME DV NEWA AMT RATE CMT FLAG DURA DATA cp11 dta IGNORE SUBROUTINES ADVAN9 TOL 6 MODEL COMP CENTRAL COMP PERI COMP 4OH COMP ENZ PK CLUI THETA 1 EXP ETA 1 CLI THETA 2 V1 THETA 3 EXP ETA 2 Q THETA 4 EXP ETA 3 V2 THETA 5 EXP ETA 4

Original URL path: http://nonmem.org/nonmem/nm/99aug062004.html (2016-04-25)

Open archived version from archive - [NMusers] Simultaneous model of plasma and whole blood data

indicating a significant uptake of the drug by blood cells Separately plasma and whole blood concentrations are both well fitted using a three compartmental mode while we were expecting to need one additional compartment for plasma related to blood cells Many thanks in advance for any suggestion in the interpretation of this situation Fabrice Nollevaux SGS Biopharma Wavre Belgium www sgsbiopharma com From Bhattaram Atul BhattaramA cder fda gov Subject

Original URL path: http://nonmem.org/nonmem/nm/97aug062004.html (2016-04-25)

Open archived version from archive - [NMusers] ADVAN12

Johnson pfizer com Subject NMusers ADVAN12 Date Fri August 6 2004 9 42 am Dear All Would someone please point me in the right direction to find the underlying parameterisation

Original URL path: http://nonmem.org/nonmem/nm/98aug062004.html (2016-04-25)

Open archived version from archive