From: "Tsai, Max" max.tsai@spcorp.com Subject: [NMusers] Indirect response PD model Date: Fri, January 28, 2005 4:38 pm Hello. I am rather new at modeling with NONMEM. As a learning opportunity, I'm trying to verify the results of a model that I ran successfully using WinNonMix. I have a set of PD data (shown below). The PK data has already been modeled and the PK parameters are fixed in the control stream (shown below). The PD model is an indirect response model with inhibition of production. When I run the model, it goes through many, many iterations before it fails. I have tried many different things such as changing initial estimates and altering error structures, but I come across the same errors: either there are rounding errors or r matrix is algorithmically singular and non-positive definite. I'm sure that the model can fit the data unless the algorithms for the two programs are that different (has anyone ever seen one program converge, but not the other?) If anyone could shed some light on this issue, it would be much appreciated. -Max $PROB PK-PD DATA $INPUT ID AMT TIME DV CMT $DATA CXCRPD.csv $SUBROUTINE ADVAN6 TOL=3 $MODEL NCOMP = 4 COMP = (GUT) COMP = (CENTRAL) COMP = (PERIPH) COMP = (EFFECT) $PK ;PK MODEL V = 216 KA = 2.35 K20 = 0.55 K23 = 0.17 K32 = 0.074 S2 = V/1000 ;PD MODEL TVKIN = THETA(1) TVKOUT = THETA(2) TVIC50 = THETA(3) KIN = TVKIN * EXP(ETA(1)) KOUT = TVKOUT * EXP(ETA(2)) IC50 = TVIC50 * EXP(ETA(3)) $DES DADT(1) = -KA * A(1) DADT(2) = (KA * A(1)) - ((K20 + K23) * A(2)) + (K32 * A(3)) DADT(3) = K23 * A(2) - K32 * A(3) CP = A(2)/S2 COEF = 1 - (CP / (IC50 + CP)) DADT(4) = KIN * COEF - KOUT * A(4) $THETA (0, 15); KIN (0, 0.15); KOUT (0, 5); IC50 $OMEGA 0.1; KIN 0.1; KOUT 0.1; IC50 $ERROR Y = F + EPS(1) $SIGMA 0.1 $EST MAXEVAL=5000 PRINT=1 $COV $SCAT (RES WRES) VS TIME Partial data set ID AMT TIME DV CMT 101 10 0 . 1 101 . 0 6.4 4 101 . 2 5.7 4 101 . 4 4.9 4 101 . 6 3.8 4 101 . 8 3.5 4 101 . 12 2.2 4 101 . 24 2.4 4 102 10 0 . 1 102 . 0 3.566667 4 102 . 2 3 4 102 . 4 2.4 4 102 . 6 1.6 4 102 . 8 1.8 4 102 . 12 2.4 4 102 . 24 2.9 4 104 10 0 . 1 104 . 0 2.666667 4 104 . 2 2.2 4 104 . 4 1.6 4 104 . 6 1.4 4 104 . 8 1.4 4 104 . 12 2 4 104 . 24 2.3 4 Max Tsai, Ph.D. Senior Scientist (DM/PK) Schering-Plough Corporation 2015 Galloping Hill Road K-15-2-2650 Kenilworth, NJ 07033-0530 (: (908) 740-3911 Ê: (908) 740-2916 *: max.tsai@spcorp.com _______________________________________________________ From: "Sam Liao" sliao@pharmaxresearch.com Subject: Re: [NMusers] Indirect response PD model Date: Fri, January 28, 2005 6:30 pm Hi Max: You need to set up the initial condition for CMT 4. WinNonMix set it up for you. But in nmv, you need to do it in the data and control file. Please see the nmv usernet archiev for detailed discussion. http://www.cognigencorp.com/nonmem/nm/99oct052000.html *Subject: * PD initialization *Posting: * October 5, 2000 Best regards, Sam Liao Pharmax Research _______________________________________________________ From: "mathangi" mathangi@msn.com Subject: Re: [NMusers] Indirect response PD model Date: Fri, January 28, 2005 7:11 pm Hello Max, The indirect model you have used requires initialization of baseline response. It could be done the following way in the data set and control file. CONTROL FILE ;PD MODEL TVKIN = THETA(1) TVKOUT = THETA(2) TVIC50 = THETA(3) KIN = TVKIN * EXP(ETA(1)) KOUT = TVKOUT * EXP(ETA(2)) IC50 = TVIC50 * EXP(ETA(3)) F4 = KIN/KOUT ;Initializing to baseline; R0 = kin/kout DATA SET 101 10 0 . 1 101 1 0 0 4 101 . 0 6.4 4 101 . 2 5.7 4 101 . 4 4.9 4 101 . 6 3.8 4 101 . 8 3.5 4 101 . 12 2.2 4 101 . 24 2.4 4 The modified model runs successfully. Hope this is helpful. Just a suggestion. Parametrizing in terms of CL and V would lead to meaningful interpretation of the model. Thanks Mathangi _______________________________________________________ From: "Tsai, Max" max.tsai@spcorp.com Subject: RE: [NMusers] Indirect response PD model Date: Mon, January 31, 2005 8:34 am Thanks to Sam and Mathangi for the helpful advice. It appears that was all that was needed. Is this initialization required only when working with differential equations for PK-PD modeling? -Max _______________________________________________________ From: "Sam Liao" sliao@pharmaxresearch.com Subject: Re: [NMusers] Indirect response PD model Date: Mon, January 31, 2005 10:26 am Hi Max: It is needed only when the initial condition is not zero. In this case, the initial condition is set to be the steady-state value. Also, you may want to use an integral function for the drug concentrations in stead of solving it in three DE to cut down your run time. Best regards, Sam Liao Pharmax Research _______________________________________________________ From: "MANOJ KHURANA" manoj2570@yahoo.com Subject: Re: [NMusers] Indirect response PD model Date: Mon, January 31, 2005 11:36 am Hi Sam, This is pretty new to me but could you please elaborate on your suggestion "Also, you may want to use an integral function for the drug concentrations in stead of solving it in three DE to cut down your run time." in terms of how it is done in NONMEM and would be nice if you can show some examples how those equations are written and also explain how would they cut down the run time. Thanks Manoj _______________________________________________________ From: "Sam Liao" sliao@pharmaxresearch.com Subject: Re: [NMusers] Indirect response PD model Date: Mon, January 31, 2005 12:14 pm Hi MANOJ: Please see the nmv usernet archieve below for an example, http://www.cognigencorp.com/nonmem/nm/99jan311996.html *Subject: *PK/PD analysis *Posting: * January 31, 1996 Max may be able to tell you later how much nmv run time can be saved using the integral equation for Cp. Best regards, Sam Liao Pharmax Research _______________________________________________________ From: "Tendolkar, Amol" amol.tendolkar@spcorp.com Subject: RE: [NMusers] Indirect response PD model Date: Tue, February 1, 2005 5:29 am Hi Max, Before you apply a programmatic solution to this problem, I would like to point out that the Indirect Pharmacologic Response model could be set up as a Direct or Indirect link model. It appears from your model setup, that you have an effect compartment, however, you have not linked it to either peripheral or central compartment with 'keo'. I also noticed that you are not simultaneously fitting pk and pd models. Therefore, you do not need a 4 compartment setup. A 1 compartment model (just for the response variable) should be adequate. Amol _______________________________________________________ From: "Tsai, Max" max.tsai@spcorp.com Subject: RE: [NMusers] Indirect response PD model Date: Tue, February 1, 2005 12:59 pm I agree that the 4 compartment setup is not necessary if the plasma concentrations from the PK model are entered into the dataset and the control stream is coded properly. However, I thought that since there is no mass actually being transferred to the effect compartment in the indirect response model, there is no need for a rate constant such as k1e to link the effect compartment and the central compartment, in my case. If anyone else in the users group would like to comment on this issue, please feel free. -Max _______________________________________________________ From: "Sam Liao" sliao@pharmaxresearch.com Subject: Re: [NMusers] Indirect response PD model Date: Tue, February 1, 2005 2:45 pm Hi Max: If you used the plasma conc (Cp) in the data set to run this model, you need to do some sort of interpolation of the Cp within the $DES block. Otherwise, the solution of the PD effect compartment will not be correct because the ODE solver will use a step function instead of a continuous curve of Cp. Best regards, Sam Liao Pharmax Research _______________________________________________________