Dear European NMusers, I am trying to get to the registration page for PAGE 2010 in Berlin. I cannot access due to....?
This happened only 15 min after registration opened. Can somebody sort this out? Joachim Grevel Senior Pharmacometrician _____________________________________________________________________ AstraZeneca R&D Charnwood Clinical Pharmacology & DMPK, Charnwood Bakewell Road, Loughborough, Leics., LE11 5RH, England Tel +44 (0) 1509 644035 Fax +44 (0) 1509 645576 Mobile +44 (0) 7920 285905 [email protected] P Please consider the environment before printing this e-mail From: [email protected] [mailto:[email protected]] On Behalf Of M Jamei Sent: 17 December 2009 03:12 To: [email protected]; [email protected]; [email protected] Subject: RE: [NMusers] Duration of Absorption Time From Depot (Gut) as Covariate Hi Paul In your first email you mentioned: ... data that suggest a dependence of AUC and Cmax upon transit time in the gut. The elimination rates for the one compartment model are quite similar, suggesting that the variability lies in bioavailability. Preliminary data suggest that the absorption of this drug from the gut is transporter-limited, and may be dependent upon the duration of time that the drug is exposed to a specific portion of the duodenum or jejunum. Based on these indications, if you manage to obtain reliable predictions for the Weibull distribution function and the time mapping parameter [THETA(IVIVC)] these parameters embody a mixture of dissolution transformation (in vitro to in vivo), interplay of transporters and gut enzymes, drug permeability in different segments of the gut and the gut physiology and anatomy e.g. small intestine transit time, duodenum length, etc. Also the related inter-individual variability values and covariates may not provide consistent explanation of the observed variability. In such cases application of (semi) physiologically-based models facilitates incorporation of extra information such as any physicochemical, in vitro or imaging data as well as physiological knowledge in the model which can give better understanding of the drug behaviour in the body, please see: http://www.pkuk.org.uk/ContentImages/KiyohikoSugano.pdf http://www.pkuk.org.uk/ContentImages/MartinBergstrand.pdf http://www.pkuk.org.uk/ContentImages/MasoudJamei.pdf. Regards Masoud From: [email protected] [mailto:[email protected]] On Behalf Of Paul Hutson Sent: 16 December 2009 21:18 Cc: [email protected] Subject: Re: [NMusers] Duration of Absorption Time From Depot (Gut) as Covariate Leonid: Thank you very much for your clear and helpful answer. May I suggest that the Weibull distribution function might be more clearly written: B= IVIVC*PAR1 WDER=(GAMA1/B)*((T/B)**(GAMA1-1))*EXP(-(T/B)**GAMA1) Be well. Paul Leonid Gibiansky wrote: Paul, No, this is not a correct way to introduce drug to depot. The idea was: Step 1. Fit Weibull or something similar to the dissolution data: time t = 0, 1, 2,... fraction absorbed: f = 0, 0.1, 0.5 .. Use model: f(t)=1-exp(t/to)^gamma Using observed dissolution data, finds t0 and gamma that would provide good fit of the dissolution data If needed, add extra parameter f(t)=A*(1-exp(t/to)^gamma) Step 2: Assume some IVIVC model, for example: in-vivo dissolution is the same as in vitro: FF=1-exp(t/to)^gamma or in-vivo dissolution is faster/slower then in vitro: FF=1-exp(t/(THETA(IVIVC)*t0))^gamma where THETA is estimated or some other model Step 3: put drug to depot, but it should be in the $DES block, and it should be a derivative of FF, not FF itself: $DES B=THETA(IVIVC)*t0 WDER=GAMM/(B**GAMM))*T**(GAMM-1)*EXP(-(T/B)**GAMM) DADT(1)=F1*DOSE*WDER-KA*A(1) Here t0 and GAMM are fixed (from in-vitro data fit) while THETA(IVIVC) corresponds to IVIVC and need to be estimated from the data. If you would like to stop dissolution at some time TMAX, you can use: $DES B=THETA(IVIVC)*t0 WDER=GAMM/(B**GAMM))*T**(GAMM-1)*EXP(-(T/B)**GAMM) IF(T.GT.TMAX) WDER=0 DADT(1)=F1*DOSE*WDER-KA*A(1) If you would like to stop absorption at some time TMAX, you can use: $DES B=THETA()*t0 WDER=GAMM/(B**GAMM))*T**(GAMM-1)*EXP(-(T/B)**GAMM) IF(T.GT.TMAX) KA=0 DADT(1)=F1*DOSE*WDER-KA*A(1) Thanks Leonid -------------------------------------- Leonid Gibiansky, Ph.D. President, QuantPharm LLC web: www.quantpharm.com <http://www.quantpharm.com/> e-mail: LGibiansky at quantpharm.com tel: (301) 767 5566 Paul Hutson wrote: Leonid & Jeroen: Thank you for your suggestions. I incorporated Jeroen's suggestion of using MTIME below, with a slight modification (KA = TVKA *(1-MPAST(1))), since I want to turn KA off, not on, at TOFF. I try below to use Leonid's suggestion of a Weibull distribution to describe the dissolution of the oral product, rather than using multiple AMT & RATE inputs corresponding to the dissolution data for the product. My fit deteriorates both by OBj Func and VPC. Does the code below appear to be appropriate for introducing the oral drug in A(1) using a Weibull distribution? Thanks very much Paul $SUBROUTINES ADVAN6 TOL=3 $MODEL COMP=(DEPOT, DEFDOSE) COMP=(CENTRAL, DEFOBS) $PK callfl=-2 CL=THETA(1)*EXP(ETA(1)); CLEARANCE V2=THETA(2)*EXP(ETA(2)); V2 TOFF=THETA(3)*EXP(ETA(3)); DURATION OF PRESENCE IN ABSORPTION SEGMENT K=CL/V2 AUC=AMT/CL S2=V2/1000 ;CLOSE ABSORPTION AFTER SOME TIME TOFF TVKA=THETA(4)*EXP(ETA(4)) MTIME(1)=TOFF KA=TVKA*(1.001-MPAST(1)); MPAST(1) = O UNTIL MTIME(1)(TOFF) IS REACHED, THEN IS 1 ;DRUG APPEARANCE PAR1=THETA(5); SCALING CONSTANT FOR TIME GAMA1=THETA(6); SLOPE FUNCTION FOR WEIBULL WB1=1-EXP(-((TIME/PAR1)**GAMA1)) RAT1 = AMT*WB1 $DES DADT(1) = RAT1 - A(1)*KA DADT(2) = A(1)*KA - A(2)*CL/V2 $ERROR IPRE = F W1=F DEL = 0 IF(IPRE.LT.0.001) DEL = 1 IRES = DV-IPRE; NEGATIVE TREND IS OVERESTIMATING IPRED WRT DV IWRE = IRES/(W1+DEL) Y=F*(1+ERR(1))+ERR(2) $THETA (0.1,1.23, 50); CL $THETA (0.10,97.8,1000); V2 $THETA (0.1,86.5,1000); TOFF $THETA (0.0001, .7, 4); KA $THETA 176.1 FIXED; PAR1 $THETA 1.033 FIXED ; SLOPE $OMEGA 0.5; CL $OMEGA 0.3; V2 $OMEGA 0.6; TOFF $OMEGA 0.3; ka $SIGMA .5; SIG1 $SIGMA .1; SIG2 $ESTIMATION METH=1 INT SIGDIGITS=3 MAXEVAL=9999 PRINT=10 NOABORT Elassaiss - Schaap, J. (Jeroen) wrote: Leonid, Paul, Alternatively one may use the MTIME function in NM6 so the algebraic solutions in eg. ADVAN2 are still applicable: $PK .... MTIME(1)=TOFF KA=TVKA*MPAST(1) Best regards, Jeroen Jeroen Elassaiss-Schaap, PhD Modeling & Simulation Expert Pharmacokinetics, Pharmacodynamics & Pharmacometrics (P3) Early Clinical Research and Experimental Medicine Schering-Plough Research Institute T: +31 41266 9320 -------------------------------------------------------------------------- AstraZeneca UK Limited is a company incorporated in England and Wales with registered number: 03674842 and a registered office at 15 Stanhope Gate, London W1K 1LN. Confidentiality Notice: This message is private and may contain confidential, proprietary and legally privileged information. If you have received this message in error, please notify us and remove it from your system and note that you must not copy, distribute or take any action in reliance on it. 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Monitoring: AstraZeneca UK Limited may monitor email traffic data and content for the purposes of the prevention and detection of crime, ensuring the security of our computer systems and checking Compliance with our Code of Conduct and Policies. -----Original Message----- From: [email protected] [mailto:[email protected]] On Behalf Of Leonid Gibiansky Sent: Friday, 11 December, 2009 6:55 To: [email protected] Cc: [email protected] Subject: Re: [NMusers] Duration of Absorption Time From Depot (Gut) as Covariate Paul, You need to rewrite the system using differential equations rather than ADVAN2 and then use $DES FLAG=1 IF(T.GE.TOFF) FLAG=0.0001 KA=TVKA*FLAG In the PK block, this should not work because your TIME is discrete while nonmem is trying small variation of TOFF parameter to compute the gradient (which is indeed zero if you do it in the PK block) On a different note, you are assuming 1 to 1 IVIVC (in-vitro dissolution = in vivo dissolution). It is rarely the case. You may try to describe your dissolution profile by some function (Weibull is very flexible) and then use parametric expression for IVIVC (for example, time scaling) to insert the dose into the depot compartment (as input rate) Thanks Leonid -------------------------------------- Leonid Gibiansky, Ph.D. President, QuantPharm LLC web: www.quantpharm.com <http://www.quantpharm.com/> e-mail: LGibiansky at quantpharm.com tel: (301) 767 5566 Paul Hutson wrote: I have been asked to look at data that suggest a dependence of AUC and Cmax upon transit time in the gut. The elimination rates for the one compartment model are quite similar, suggesting that the variability lies in bioavailability. Preliminary data suggest that the absorption of this drug from the gut is transporter-limited, and may be dependent upon the duration of time that the drug is exposed to a specific portion of the duodenum or jejunum. Drug is observed at the earliest sampling time, so I am not including a Tlag at this point. I have in vitro dissolution data for this (hopefully) extended release formulation, which I am introducing to the gut compartment for the human subject PK data as events of AMT and RATE corresponding to each measured point in the dissolution curve. Thus I am fixing it as a time-dependent inputs over the 12 hour period following the single dose and during the plasma sampling. Because of the non-instantaneous input function, I understand I cannot use Savik's TRANSIT model (2007). I have tried the code below to try to turn off Ka after some time TOFF, the point at which the drug is estimated to have moved past the section of absorption. There is no change in the gradient for TOFF, and the fit is not improved over a simple 1 compartment absorption model (ADVAN2). I cannot turn off compartment 1 (-1) in my INPUT, since I do not know when to turn it off (I am trying to determine this in the model). There is extensive first pass of the compound - I do not know of any auto-inhibition of metabolism. I suppose that I could try to trip F1 to null at some TOFF, but tripping Ka to Null seems more physiologic. Can anyone suggest a snippet of code that might close Ka based upon a covariate THETA corresponding to the time required to move past the intestinal segment of absorption? Thanks very much. Paul $SUBROUTINES ADVAN2 ; 1 COMPARTMENT MODEL, NO LAG, NO LIMIT TO ABSORPTION PERIOD $PK TVKA=THETA(1); ABSORPTION RATE FROM GUT CL=THETA(2)*EXP(ETA(1)); CLEARANCE V2=THETA(3)*EXP(ETA(2)); V2 TOFF=THETA(4)*EXP(ETA(3)); DURATION OF PRESENCE IN ABSORPTION SEGMENT K=CL/V2 DOSE=5; MG TABLET AUC=DOSE/CL S2=V2/1000 FLAG=1 IF(TIME.GE.TOFF) FLAG=0.0001 KA=TVKA*FLAG $ERROR IPRE = F W1=F DEL = 0 IF(IPRE.LT.0.001) DEL = 1 IRES = DV-IPRE; NEGATIVE TREND IS OVERESTIMATING IPRED WRT DV IWRE = IRES/(W1+DEL) Y=F*(1+ERR(1))+ERR(2) $THETA (0.1,1.23, 50); KAGUT $THETA (0.10,97.8,1000); CL $THETA (0.1,86.5,1000); V2 $THETA (0.001, 1, 24); DUR ;$OMEGA 0.3; KA $OMEGA 0.5; CL $OMEGA 0.3; V2 $OMEGA 0.6; TOFF -- Paul R. Hutson, Pharm.D. Associate Professor UW School of Pharmacy 777 Highland Avenue Madison WI 53705-2222 Tel 608.263.2496 Fax 608.265.5421 Pager 608.265.7000, p7856 This message and any attachments are solely for the intended recipient. If you are not the intended recipient, disclosure, copying, use or distribution of the information included in this message is prohibited --- Please immediately and permanently delete. -- Paul R. Hutson, Pharm.D. Associate Professor UW School of Pharmacy 777 Highland Avenue Madison WI 53705-2222 Tel 608.263.2496 Fax 608.265.5421 Pager 608.265.7000, p7856 -- Paul R. Hutson, Pharm.D. Associate Professor UW School of Pharmacy 777 Highland Avenue Madison WI 53705-2222 Tel 608.263.2496 Fax 608.265.5421 Pager 608.265.7000, p7856
