Re: how to model blood volume change during and after hemodialysis?

On 21/01/2013 09:21, Kaessner, Nele wrote: > Hi James, dear all, > > Thanks for your answer. I have understood what you were writing, however I still have problems to implement the suggestions in NONMEM. This is mainly due to the somewhat inflexible way NONMEM works. My problems are the following: > > * The final V1 needs to be defined in $DES, as otherwise I cannot use T > * V1 is used as a scaling factor to determine concentration. This > would normally be done in $PK, where I cannot use parameters that > are defined in $DES > * Y and IPRED are calculated using A(1) and V1, but again $ERROR > does not allow the use of T. My code circumvents this now by using > TIME in $ERROR and T in $DES, but I don't like the solution of > defining everything twice. > * Basically, my major issue is that I can use T in $DES, but any PK > parameter I calculate from this can then not be used in $PK or > $ERROR, where I would actually need this. I am sure there must be > a solution, but I cannot see it… > * Additional problem: My code only allows for continuous volume > decrease over the first hemodialysis session. Also, after dialysis > it jumps directly back to the volume that I had before dialysis. > What I would like to model instead would be a continuous drop in > volume over dialysis, and then a reincrease to pre-dialysis levels > over the next ~2h. You mentioned a linear rate after dialysis. How > do you implement this? Any suggestions, preferably in NONMEM code? > > What I have right now: > $SUBROUTINE ADVAN13 TOL=5 > $MODEL NCOMP=2 > COMP=(CENTRAL) > COMP=(PERIPH) > ; ----------------[ Structural Model ]---------------- > $PK > TVVM=THETA(1) > VM=TVVM*EXP(ETA(1)) > TVKM=THETA(2) > KM=TVKM > TVV1=THETA(3) > VC=TVV1*EXP(ETA(2)) > TVQ=THETA(4) > Q=TVQ > TVV2=THETA(5) > V2=TVV2 > TVCL=THETA(6) > CL=TVCL > TVVAC=THETA(7) > V1ACC=TVVAC > ; ----------------[ Error Model ]---------------- > $ERROR > ;parameter to describe volume decrease over dialysis > VEDD=V1ACC > ;after dialysis end (3h) volume back to higher levels > IF (TIME.GT.3) VEDD=0 > > VD1=VC -VEDD*TIME ;I would like to use T, but get an error message if I do > > CE1=A(1)/VD1 > IPRED=CE1 > DEL=0 > IF (IPRED.EQ.0) DEL=0.01 > W=CE1 > IRES=DV-IPRED > IWRES=IRES/(W+DEL) > Y=CE1+CE1*ERR(1) > ;----------------[differential equations]------------- > $DES > VADD=V1ACC > IF (T.GT.3) VADD=0 > V1=VC-VADD*T > ;Scaling needed to be shifted from $PK as it uses V1 > S1=V1 > K12=Q/V1 > K21=Q/V2 > K10=CL/V1 > DADT(1) = - K12*A(1) + K21*A(2) - A(1)*VM/(KM+A(1)) -K10*A(1) > DADT(2) = K12*A(1) - K21*A(2) > Thanks again for your help. It is very much appreciated! > Best > Nele > ______________________________________________________________ > Dr. Nele Käßner > Principal Scientist Modeling and Simulation > Global Pharmacometrics > Experimental Medicine > Takeda Pharmaceuticals International GmbH > Thurgauerstrasse 130 > 8152 Glattpark-Opfikon (Zürich) > Switzerland > Visitor address: > Alpenstrasse 3 > 8152 Glattpark-Opfikon (Zürich) > Switzerland > Phone: (+41) 44 / 55 51 404 > Mobile: (+41) 79 / 654 33 99 > mailto: [email protected] > http://www.takeda.com > -----Original Message----- > From: James G Wright [mailto:[email protected]] > Sent: Freitag, 18. Januar 2013 5:10 > To: Kaessner, Nele > Cc: Ahmed N Mohamed; [email protected] > > Subject: Re: [NMusers] how to model blood volume change during and after hemodialysis? > > Dear Nele, > You can use T if you just re-write the model using $DES and ADVAN13. > What is slightly unusual and quite nice about dialysis volume changes is > that you can model them with just one additional parameter. This > fortunate situation arises because you know the times of dialysis > (hopefully precisely). In-between dialysis occasions the plasma volume > rises, as most subjects must/will consume more water than they can > excrete, and then plasma volume falls back to the baseline during > dialysis. So all you need to do is define you central volume as V1 > (usually immediately post-dialysis) and then an additional parameter > V1acc which is the impact of V1 on the additional accumulation of fluid > per day since the last dialysis, so it has units of L/day, and multiply > by the time since the last dialysis finished. Provided dialysis is > completed, you can generally assume that all of V1acc*days is removed at > an approximately linear rate during dialysis. This model can account > for differences in dialysis schedule (e.g. weekends) and you can put a > random effect on V1acc to account for differences in fluid accumulation > between different patients. > It's not perfect, but it is simple. Usually, peripheral volumes are > less sensitive to body water so you don't see anything on these. This > simple model can often be successfully superimposed on a dialysis > clearance model. > Best regards, James > On 18/01/2013 15:12, Kaessner, Nele wrote: > > Dear Ahmed and all, > > > > First of all, thank you for your response. > > > The reason I believe that blood volume is altered is because I see an increase in concentrations until the end of hemodialysis, despite the fact that compound infusion ended two hours earlier. I would want to estimate the decreasing volume using information from both subjects with and without hemodialysis (for those without dialysis, concentrations drop as expected after the end of the infusion). Clearance via hemodialysis is not a problem by the way, compound is too big :-) > My problem mostly relates to the coding in NONMEM. How do I model a continuous change in V1 over time? $PK does not allow the variable 'T' to be used, and I don't just want to use TIME, as this would only consider time points actually contained in the data set. > > > Any suggestions? > > > > Thank you and best regards > > Nele > > ______________________________________________________________ > > > > Dr. Nele Käßner > > Principal Scientist Modeling and Simulation > > Global Pharmacometrics > > Experimental Medicine > > > > Takeda Pharmaceuticals International GmbH > > Thurgauerstrasse 130 > > 8152 Glattpark-Opfikon (Zürich) > > Switzerland > > > > Visitor address: > > Alpenstrasse 3 > > 8152 Glattpark-Opfikon (Zürich) > > Switzerland > > > > Phone: (+41) 44 / 55 51 404 > > Mobile: (+41) 79 / 654 33 99 > > > > mailto: [email protected] > > http://www.takeda.com > > > > > > -----Original Message----- > > From: Ahmed N Mohamed [mailto:[email protected]] > > Sent: Freitag, 18. Januar 2013 3:28 > > To: Kaessner, Nele > > Cc: [email protected] > > > Subject: Re: [NMusers] how to model blood volume change during and after hemodialysis? > > > > > Hello, > > > > > In terms of how long it takes to restore blood volume, i think it should be immediate because they usually give fluids during the dialysis to replace lost blood volume. Otherwise, there will be a significant drop in BP. You may have the volumes of fluid given in the patient charts if you have that. > > > > > In terms of changing volume you can do that in two ways: > > > 1. If you have serial measurements of patient body weight, you can link that to volume as a covariate and it will change with change in weight (time-varying covariate). But this needs hourly or even more frequent weight measurements. > > > > > > 2. You can model the change in volume with time using a simple linear slope model where volume decreases with time during dialysis and increases with time after dialysis and estimate the slope for each process. However, i think this will be difficult to estimate separate from changes in clearance and the slope estimates you get will just be arbitrary. If you have samples from dialysate, it might be better. > > > > > I hope this helps. > > > > ----- Original Message ----- > > From: "Nele Kaessner" <[email protected]> > > To: [email protected] > > Sent: Friday, January 18, 2013 8:24:05 AM > > > Subject: [NMusers] how to model blood volume change during and after hemodialysis? > > > > > > > > > > > Dear nmusers, > > > > > > > > > I would like to model PK profiles of a compounds which mostly distributes in blood volume. The subjects which were investigated underwent hemodialysis for approx. the first three hours after infusion start, and the compound was given over a time period of ~5-10 min. > > > > > > It is well known that during hemodialysis, blood volume changes. Therefore, I would like to add a dynamic component to the central volume parameter, allowing it to decrease during hemodialysis and then to reincrease after dialysis has ended. I have all information about start and end time of both dosing and dialysis. Individual times between subjects differed. Unfortunately, I have not been creative enough to come up with a NONMEM code that can do this. Could any of you help out? > > > > > > Also, I probably do not have late enough time points to estimate when exactly blood volume would be restored. Does anyone know how much time the body needs after dialysis has ended until it is back to the original blood volume? > > > > > > > > > Thanks for your help and best > > > > Nele > > > > ______________________________________________________________ > > > > > > > > Dr. Nele Käßner > > > > Principal Scientist Modeling and Simulation > > > > Global Pharmacometrics > > > > Experimental Medicine > > > > > > > > Takeda Pharmaceuticals International GmbH > > > > Thurgauerstrasse 130 > > > > 8152 Glattpark-Opfikon (Zürich) > > > > Switzerland > > > > > > > > Visitor address: > > > > Alpenstrasse 3 > > > > 8152 Glattpark-Opfikon (Zürich) > > > > Switzerland > > > > > > > > Phone: (+41) 44 / 55 51 404 > > > > Mobile: (+41) 79 / 654 33 99 > > > > > > > > mailto: [email protected] > > > > http://www.takeda.com > > > > -------------------------------------------------------------------- > > > > > The content of this email and of any files transmitted may contain confidential, proprietary or legally privileged information and is intended solely for the use of the person/s or entity/ies to whom it is addressed. If you have received this email in error you have no permission whatsoever to use, copy, disclose or forward all or any of its contents. Please immediately notify the sender and thereafter delete this email and any attachments. > > > > > -------------------------------------------------------------------- > > > > -------------------------------------------------------------------- > > > > > The content of this email and of any files transmitted may contain confidential, proprietary or legally privileged information and is intended solely for the use of the person/s or entity/ies to whom it is addressed. If you have received this email in error you have no permission whatsoever to use, copy, disclose or forward all or any of its contents. Please immediately notify the sender and thereafter delete this email and any attachments. > > > > > -------------------------------------------------------------------- > > > -- > James G Wright PhD, > Scientist, Wright Dose Ltd > Tel: UK (0)772 5636914 > -------------------------------------------------------------------- > > The content of this email and of any files transmitted may contain > confidential, proprietary or legally privileged information and is intended > solely for the use of the person/s or entity/ies to whom it is addressed. If > you have received this email in error you have no permission whatsoever to use, > copy, disclose or forward all or any of its contents. Please immediately notify > the sender and thereafter delete this email and any attachments. > > -------------------------------------------------------------------- -- James G Wright PhD, Scientist, Wright Dose Ltd Tel: UK (0)772 5636914