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- [NMusers] Nonmem install problem

tar But the test fails for CONTROL5 I tried the same on a linux machine and get the same error I m in the C shell and have had succesful installs on similar systems in the past I m not quite sure where to go with these errors but if anyone has any suggestions they d be much appreciated The errors look as follows perin mybic run nmfe5 CONTROL5 rep5 AN ERROR WAS FOUND IN THE CONTROL STATEMENTS 36 ERROR HAS OCCURRED WHILE CREATING REQUIRED FILE FCON STOP 4 statement executed After SUDO ing perin mybic run sudo nmfe5 CONTROL5 rep5 nmfe5 line 27 syntax error near unexpected token exit nmfe5 line 27 if e FREPORT exit Juan Perin Children s Hospital of Philadelphia From Darin Perusich Darin Perusich cognigencorp com Subject Re NMusers Nonmem install problem Date Mon 31 Oct 2005 15 17 30 0500 The errors look as follows perin mybic run nmfe5 CONTROL5 rep5 AN ERROR WAS FOUND IN THE CONTROL STATEMENTS 36 ERROR HAS OCCURRED WHILE CREATING REQUIRED FILE FCON STOP 4 statement executed what do the permissions on the run directory look like does CONTROL3 run After SUDO ing perin mybic run sudo nmfe5 CONTROL5

Original URL path: http://nonmem.org/nonmem/nm/99oct312005.html (2016-04-25)

Open archived version from archive - [NMusers] target-mediated model - steady state - unstable system?

KET A 2 KON A 2 A 3 KOFF A 4 Tin DADT 3 KEV A 3 KON A 2 A 3 KOFF A 4 Vin DADT 4 KETV A 4 KON A 2 A 3 KOFF A 4 There is one thing I do not fully understand If I assume that patients get infinite infusion Tin is the infusuin rate then concentrations can achieve steady state The system of differential equatuions transformes into system of 3 algebraic equations because in steady state all derivavtives are equal to zero I tried to get A3 hormone which we try to eliminate but cannot measure as a function of Tin I had to solve a simple quadratic equation to get function A3 A3 Tin Ket Kev Ketv Kon Koff Surprisingly when Tin is large enough disctiminant is negative Possibly this means that the steady state does not exist i e concentration of A4 A4 is complex A2 bound to A3 grows infinitely When I studied control systems we called it unstable system Does it sound familiar to you Is there anyone who is familiar with properties of this model Can this system get unstable Thanks Pavel From Leonid Gibiansky leonidg metrumrg com

Original URL path: http://nonmem.org/nonmem/nm/99oct272005.html (2016-04-25)

Open archived version from archive - [NMusers] Setting up CPU Affinity on Linux

know how to set up the CPU affinity for NONMEM on Linux Terri Fisher CLINapps Inc 910 Hampshire Road Suite G Westlake Village CA 91361 USA Phone 805 494 1777 Ext 15 Fax 805 494 1702 tjfisher clinapps com www clinapps com From PMDI Paul Matthias Diderichsen pmdi novonordisk com Subject RE NMusers Setting up CPU Affinity on Linux Date Fri 21 Oct 2005 10 25 21 0200 Are you

Original URL path: http://nonmem.org/nonmem/nm/99oct202005.html (2016-04-25)

Open archived version from archive - [NMusers] Inclusion of covariates and model improvement

correlation between the two and that s why I used the simpler coding Am I correct in my guess that part of your proposed model is due to allometric scaling and other is a general median weight being 70 Toufigh From Leonid Gibiansky leonidg metrumrg com Subject Re NMusers Inclusion of covariates and model improvement Date Thu 20 Oct 2005 00 47 27 0400 Hi Toufigh This is the black magic that I practice when I have time Actually this is the standard way to include weight into the model with the exception of strict allometric scaling approach that assumes that THETA 2 should always be equal to 1 This model allows for not so steep increase of VC with weight 70 is the mean median value normalization should not change the model but simplifies the interpretation THETA 1 is the VC of a typical 70 kg patient I am not 100 sure but normalization may also influence the precision of estimation Leonid From Nick Holford n holford auckland ac nz Subject Re NMusers Inclusion of covariates and model improvement Date Thu 20 Oct 2005 18 03 18 1300 Toufigh The model proposed by Leonid is an empirical allometric model However there is a substantial amount of theory and evidence to believe that the allometric exponent is 1 for volume and 0 75 for clearance I would recommend using theory rather than empiricism if you intend to use your model for prediction or simulation extrapolation A more coherent approach would be to apply allometric scaling to all PK parameters that are known to vary with size e g CL Q V1 V2 I can think of no sensible reason to believe that these parameters should be modelled as if they did not vary with size Centering of the parameter e g on a weight of 70 kg is always a good idea Primarily because it means that the population parameter estimate refers to a general individual of standard and clearly specified size or age or Clcr etc There may also be some statistical advantages in producing more robust parameter estimates lower imprecision but this is not very sensitive in my experience to any plausible value e g there is no appreciable difference in the predictions if one centers on 70kg or on 10 kg when doing analyses of children with a median weight around 10 kg Nick Nick Holford Dept Pharmacology Clinical Pharmacology University of Auckland 85 Park Rd Private Bag 92019 Auckland New Zealand email n holford auckland ac nz tel 64 9 373 7599x86730 fax 373 7556 http www health auckland ac nz pharmacology staff nholford From Stephen Duffull steveduffull yahoo com au Subject Re NMusers Inclusion of covariates and model improvement Date Thu 20 Oct 2005 17 38 14 1000 EST Toufigh I think there are 2 issues here that can be considered 1 What did you write in your analysis plan If you wrote that the OBJF and BSV IIV in your notation should decrease when

Original URL path: http://nonmem.org/nonmem/nm/99oct192005.html (2016-04-25)

Open archived version from archive - [NMusers] 3 questions

are simple functions of parameters in the model Is that possible to specify initial conditions in NONMEM when they are functions of both dose and parameters in the model Example A 1 T 0 f dose Ke Protein production Vd 2 Can NONMEM change diffetential equations during integration process between events For example if we have A2 A 2 A3 A 3 IF A2 LT A3 THEN DADT 2 DADT

Original URL path: http://nonmem.org/nonmem/nm/99oct172005.html (2016-04-25)

Open archived version from archive - [NMusers] difficulty with FOCE

it runs with first order conditional estimation FOCE convergence becomes almost impossible Iteration becomes extremely slow and after several iterations there is always an error message like Occurs during search for ETA at a nonzero value of ETA Numerical difficulties with integration routine Maximum No of evaluaitons of differential equations exceeded 100000 Does anyone have some good ideas to solve this problem I appreciate Also is it acceptable to report parameters produced by FO I am wondering if there are some guidelines or references for the choice of FO and FOCE Thanks you in advance for any help Sincerely Jing From Justin Wilkins justin wilkins farmbio uu se Subject Re NMusers difficulty with FOCE Date Thu 13 Oct 2005 17 48 30 0200 Hi Jing Without seeing your model it s hard to narrow down the specific cause of your problem but a typical rule of thumb to follow when this sort of thing happens is to make sure that your model is not overparameterized FOCE is much more sensitive to unneeded model parameters than FO I would test each of your parameters starting with ETAs and the ones with the largest RSE to make sure it belongs in the model If the 95 CI of a parameter calculated from the standard error overlaps zero it s probably not needed Check your FOCE output file for zero gradients or very low gradient values in any of the parameters as another clue as to which to start investigating first If any of the FOCE parameter estimates look odd or very low remove them and try again If you re using ADVAN6 you might try using ADVAN8 instead especially if your system is stiff if there are large differences in the quantities used in your differential equations It would be very helpful

Original URL path: http://nonmem.org/nonmem/nm/99oct132005.html (2016-04-25)

Open archived version from archive - [NMusers] non-linear PK

2005 12 29 45 0400 Hi At a quick glance and without knowing more about your specific PK model one of the things that I noticed in your control stream is that the differential equation for compartment 2 Dadt 2 you include a term K21 A 2 but a corresponding term K21 A 2 is not included in the Dadt 1 differential equation This may contribute to the difficulties that you are seeing Regards Brenda From Perez Ruixo Juan Jose PRDBE JPEREZRU PRDBE jnj com Subject Re NMusers non linear PK Date Thu 6 Oct 2005 18 51 56 0200 Dear Jing The input from the second compartment to the first compartment is missing Probably what you want to fit is a system of DE as follows DADT 1 K12 A 1 K21 A 2 A 1 VM KM C1 DADT 2 K12 A 1 K21 A 2 K23 A 2 K32 A 3 DADT 3 K23 A 2 K32 A 3 However I m not sure you want to start with a catenary model instead of a mamillary model If you like to test a mamillary model it should be as follows DADT 1 K12 A 1 K21 A 2 K13 A 1 K31 A 3 A 1 VM KM C1 DADT 2 K12 A 1 K21 A 2 DADT 3 K13 A 1 K31 A 3 Regards Juan Jose Perez Ruixo PhD Principal Scientist Advanced PK PD Modelling Simulation Global Clinical Pharmacokinetic and Clinical Pharmacology Johnson Johnson Pharmaceutical Research Development a Division of Janssen Pharmaceutica NV Email jperezru prdbe jnj com From Kowalski Ken Ken Kowalski pfizer com Subject Re NMusers non linear PK Date Thu 6 Oct 2005 13 05 35 0400 Leonid I think W is correctly specified in Jing s control stream below As she has coded it W is the residual standard deviation given the ETAs for the combined proportional and additive error model That is Var Y ETAs W2 Var ERR 1 W2 THETA 8 2 THETA 9 2 F F where THETA 8 is the residual SD for the additive component and THETA 9 is the residual CV for the proportional component Ken From Leonid Gibiansky leonidg metrumrg com Subject Re NMusers non linear PK Date Thu 06 Oct 2005 13 20 13 0400 Ken Note that data are log transformed See http www cognigencorp com nonmem nm 99apr232002 html for Mats Karlsson explanation how to apply combined error in the log transformed case cut here To get the same error structure for log transformed data as the additive proportional on the normal scale I use Y LOG F SQRT THETA x 2 THETA y 2 F 2 EPS 1 with SIGMA 1 FIX THETA x and THETA y will have the same meaning as on the untransformed scale with Y F SQRT THETA y 2 THETA x 2 F 2 EPS 1 with SIGMA 1 FIX cut here Leonid From Paul Hutson prhutson pharmacy wisc edu Subject Re NMusers non linear

Original URL path: http://nonmem.org/nonmem/nm/99oct062005.html (2016-04-25)

Open archived version from archive - [NMusers] associatin/dissociation model

AUC AUC A 5 IF EVID EQ 4 AUC 0 A1 A 1 A2 A 2 A3 A 3 A4 A 4 THETA 1 80 300 VD VOLUME OF DISTRIBUTION 0 1 3 30 KA ABSORBTION COEFFICIENT 0 1 10 1000 KON ASSOCIATION RATE CONSTANT 0 1 1 1000 KOFF DISSOCIATION RATE CONSTANT 0 002 0 04 0 1 RIN PRODUCTION RATE OF V 0 05 5 30 CLV CLEARANCE 0 05 0 3 5 CLT CLEARANCE 0 05 0 3 5 CLTV CLEARANCE ERROR CONC F Y CONC ERR 1 Y CONC EXP ERR 1 ERR 2 CONCENTRATION ERROR IF CMT EQ 2 Y CONC EXP ERR 1 ERR 2 CONCENTRATION ERROR IF CMT EQ 4 Y CONC EXP ERR 1 ERR 3 CONCENTRATION ERROR IPRE CONC individual specific prediction IRES DV IPRE individual specific residual IWRE IRES CONC individual specific weighted residual OMEGA DIAGONAL 3 50 0 6 0 3 VARIANCE OF THETA SIGMA 50 0 5 VARIANCE OF EPS From Perez Ruixo Juan Jose PRDBE JPEREZRU PRDBE jnj com Subject RE NMusers associatin dissociation model Date Thu 6 Oct 2005 14 09 32 0200 Dear The model you described has been also called target mediated drug disposition model From the information you provide it s very difficult to provide you with a clear answer In fact I ve more questions than clarifications Hope you don t mind In my experience it s very difficult to have enough information in the data to estimate independently Kon Koff KETV and the turnover parameters of the target or receptor Did you perform a sensitivity analysis to evaluate what are the parameters of your model that can be identified given the information you have I would suggest you to include IV data if available Just SC data might not be good enough to fully characterize this complex model Also I assume the bioassays used allow you to quantify the free drug Do you have observations from the A 4 If that s the case it should be incorporated in the database and fit together with the free drug concentrations This information is critical to estimate the receptor turnover Do you have prior information about the target receptor binding and elimination of the drug receptor complex If you have it you could try to fix Koff and or KETV to the values obtain from previous in vitro experiments However I m not a big fan of that approach I personally prefer the quasi equilibrium approach that has been recently published Mager DE Krzyzanski W Quasi equilibrium pharmacokinetic model for drugs exhibiting target mediated drug disposition Pharm Res 2005 Oct 22 10 1589 96 With that approach NONMEM runs are faster and the difference in parameter estimates and model predictions between the full model and the quasi equilibrium model are acceptable in most of the cases Hope it helps Juan Jose Perez Ruixo PhD Principal Scientist Advanced PK PD Modelling Simulation Global Clinical Pharmacokinetic and Clinical Pharmacology Johnson Johnson Pharmaceutical Research Development a

Original URL path: http://nonmem.org/nonmem/nm/99oct052005.html (2016-04-25)

Open archived version from archive