Generating Cmax at end of infusion

Title: Paul R G'day. I would like to generate a concentration at the end of an infusion of duration DUR. I am using ADVAN3 TRANS4 with log transformed data. Here is what I have tried, but I am getting an error that the parameter 'T' that I understood to be the machine time is undefined. Can anyone suggest a proper way to give set Cmax=exp(Y) at the end of the infusion of length DUR? Many thanks in advance. Paul $PK ... TT=TIME $ERROR ;I've also tried ;TT=TIME ;TT=T IPRE=F EDV=EXP(DV) W=1 IF(F.GT.0) W=F IRES=F-EDV IWRE=IRES/W LOGF=LOG(0.0001) IF (F.GT.0) LOGF=LOG(F) Y=LOGF+EPS(1) ;GENERATE CMAX AT END OF INFUSION (DUR) IF(DUR.EQ.TT) CMAX=EXP(Y) -- 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

Hi Paul, You cannot use T in ADVAN3. ADVAN3 uses the exact solution to advance between TIME points. If you include the end of infusion as EVID=2 time point, you can get it there. Otherwise, I am not sure how to get hold on the solution at that specific time. It could be possible, because the end-of infusion should be (at least internally) the point to which the system is advanced, but I do not know how to get data at that (internal) point. An easier way would be to rewrite the system in differential equations (ADVAN6). Then you can get the solution at any time point T (in he $DES block) but you will have to output it on the next TIME point. Hope this helps Leonid -------------------------------------- Leonid Gibiansky, Ph.D. President, QuantPharm LLC web: www.quantpharm.com e-mail: LGibiansky at quantpharm.com tel: (301) 767 5566 Paul Hutson wrote: > G'day. > > I would like to generate a concentration at the end of an infusion of duration DUR. I am using ADVAN3 TRANS4 with log transformed data. Here is what I have tried, but I am getting an error that the parameter 'T' that I understood to be the machine time is undefined. Can anyone suggest a proper way to give set Cmax=exp(Y) at the end of the infusion of length DUR? > > Many thanks in advance. > Paul > $PK > ... > TT=TIME > > $ERROR > ;I've also tried > ;TT=TIME > ;TT=T > IPRE=F > EDV=EXP(DV) > W=1 > IF(F.GT.0) W=F > IRES=F-EDV > IWRE=IRES/W > LOGF=LOG(0.0001) > IF (F.GT.0) LOGF=LOG(F) > Y=LOGF+EPS(1) > ;GENERATE CMAX AT END OF INFUSION (DUR) > IF(DUR.EQ.TT) CMAX=EXP(Y) > -- > > 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

Hi Paul, If you have a row in your data file at TIME == DUR, then something like the following should work (you would need to have DUR on each row for this; there are other ways to do it that you don't have to have DUR on each row): $ERROR CMAX = 0 IPRE=F EDV=EXP(DV) W=1 IF(F.GT.0) W=F IRES=F-EDV IWRE=IRES/W LOGF=LOG(0.0001) IF (F.GT.0) LOGF=LOG(F) Y=LOGF+EPS(1) ;GENERATE CMAX AT END OF INFUSION (DUR) IF(DUR.EQ.TIME) CMAX=EXP(Y) Thanks, Bill

Hi Paul, Is DUR modeled or explicit? If explicit then it seems as easy approach would be to include an EVID=2 record at the stated end of infusion and calculate the anti-log as you and Nick indicate. Steve Stephen C. Olson [email protected] 734 268 6867 www.clinpharmres.com From: [email protected] [mailto:[email protected]] On Behalf Of Nick Holford Sent: Tuesday, April 06, 2010 1:03 PM Cc: [email protected] Subject: Re: [NMusers] Generating Cmax at end of infusion Paul, TIME is the data record time in $PK and $ERROR. T is the time between record TIMEs in $DES. In order to use your method you need to have a record with TIME in your data set that is equal to DUR. In that case you can use this code which also sets CMAX to 0 if an individual does not have DUR.EQ.TIME. If you don't do this then you will get the CMAX from the last individual who did have DUR.EQ.TIME. IF (DUR.EQ.TIME) THEN CMAX=EXP(Y) ELSE CMAX=0 ENDIF Paul Hutson wrote: G'day. I would like to generate a concentration at the end of an infusion of duration DUR. I am using ADVAN3 TRANS4 with log transformed data. Here is what I have tried, but I am getting an error that the parameter 'T' that I understood to be the machine time is undefined. Can anyone suggest a proper way to give set Cmax=exp(Y) at the end of the infusion of length DUR? Many thanks in advance. Paul $PK ... TT=TIME $ERROR ;I've also tried ;TT=TIME ;TT=T IPRE=F EDV=EXP(DV) W=1 IF(F.GT.0) W=F IRES=F-EDV IWRE=IRES/W LOGF=LOG(0.0001) IF (F.GT.0) LOGF=LOG(F) Y=LOGF+EPS(1) ;GENERATE CMAX AT END OF INFUSION (DUR) IF(DUR.EQ.TT) CMAX=EXP(Y) -- 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 -- Nick Holford, Professor Clinical Pharmacology Dept Pharmacology & Clinical Pharmacology University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand tel:+64(9)923-6730 fax:+64(9)373-7090 mobile:+64(21)46 23 53 email: [email protected]<mailto:[email protected]> http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford

Paul, TIME is the data record time in $PK and $ERROR. T is the time between record TIMEs in $DES. In order to use your method you need to have a record with TIME in your data set that is equal to DUR. In that case you can use this code which also sets CMAX to 0 if an individual does not have DUR.EQ.TIME. If you don't do this then you will get the CMAX from the last individual who did have DUR.EQ.TIME. IF (DUR.EQ.TIME) THEN CMAX=EXP(Y) ELSE CMAX=0 ENDIF Paul Hutson wrote: > G'day. > > I would like to generate a concentration at the end of an infusion of duration DUR. I am using ADVAN3 TRANS4 with log transformed data. Here is what I have tried, but I am getting an error that the parameter 'T' that I understood to be the machine time is undefined. Can anyone suggest a proper way to give set Cmax=exp(Y) at the end of the infusion of length DUR? > > Many thanks in advance. > Paul > $PK > ... > TT=TIME > > $ERROR > ;I've also tried > ;TT=TIME > ;TT=T > IPRE=F > EDV=EXP(DV) > W=1 > IF(F.GT.0) W=F > IRES=F-EDV > IWRE=IRES/W > LOGF=LOG(0.0001) > IF (F.GT.0) LOGF=LOG(F) > Y=LOGF+EPS(1) > ;GENERATE CMAX AT END OF INFUSION (DUR) > IF(DUR.EQ.TT) CMAX=EXP(Y) > -- > > 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 -- Nick Holford, Professor Clinical Pharmacology Dept Pharmacology & Clinical Pharmacology University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand tel:+64(9)923-6730 fax:+64(9)373-7090 mobile:+64(21)46 23 53 email: [email protected] http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford

Hi, As others have suggested making an additional record at the known desired time is probably the most straightforward manner to get what you want. So this should probably be a preferred solution. If you for some reason you cant to add a record (maybe you dont know the time beforehand), I think you can achieve what you want using MTIME(). This has the added advantage of working without going the $DES route and the associated slower run-times. I'll see if I can get something like that to work tomorrow, just as an excercise. Can the experts give an opinion as to whether MTIME() should work or not? Regards, Douglas Eleveld

Hi Douglas, Paul, The help on mtime suggests that it should work. " When the time is reached, indicator variables are set and a call to PK is made. At this call (and/or subsequent to this call) PK or DES or AES or ERROR can use the indicator variables to change some aspect of the system, e.g., a term in a differential equation, or the rate of an infusion. This feature may be used with any ADVAN routine. " The following code (tested with nm6.2.0) however does not work in the $ERROR block, where the model predictions are available. As one can see, CP is only set at the data time event, not at the MTIME. CP2 is not set at all. So it seems $ERROR is not called upon the MTIME event. An indicator in $PK works properly (tested, not shown). Can anyone confirm this behavior? If so, this looks like a bug to me. Best regards, Jeroen ____model____ $PROB structural model 1comp.rep single subject $INPUT ID TIME DV AMT EVID TRT $DATA iv_ss.csv IGN=I $SUBR ADVAN1 TRANS2 $PK TVCL=THETA(1) CL=TVCL TVV=THETA(2) V=TVV S1=V/1000 ;mtime piece MTIME(1)=.075 ; .075 h not in dataset MTIME(2)=.5 ; .5 h not in dataset IF(TIME.EQ.0)CP=0 IF(TIME.EQ.0)CP2=0 $ERROR IPRED=F Y=F+F*ERR(1) IF(TIME.EQ.0)MYFLAG=0 ; 0 h IN dataset IF(MPAST(1).EQ.1.AND.MYFLAG.EQ.0)THEN CP=F MYFLAG=1 ENDIF CP2=CP2+MNEXT(2)*F $THETA (0,10) (0,1) $OMEGA .05 $SIM (123456789) $EST PRINT=1 MAXEVAL90 SIG=3 NOABORT METHOD=0 ;$COV PRINT=E $TABLE ID TIME CP CP2 IPRED NOPRINT ONEHEADER FILEmp.txt ____dataset___ ID,time h,conc nM,amt,evid,dose mol 1,0,.,30,1,10 1,0.05,0,.,0,10 1,0.166666667,0,.,0,10 1,0.333333333,0,.,0,10 1,0.683,0,.,0,10 1,1,0,.,0,10 1,2,0,.,0,10 1,4,0,.,0,10 1,8,0,.,0,10 ____table file_____ TABLE NO. 1 ID TIME CP CP2 IPRE DV 1.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 3.2044E+04 0.0000E+00 1.0000E+00 5.0000E-02 0.0000E+00 0.0000E+00 1.9459E+04 1.6272E+04 1.0000E+00 1.6667E-01 6.0768E+03 0.0000E+00 6.0768E+03 7.7936E+03 1.0000E+00 3.3333E-01 6.0768E+03 0.0000E+00 1.1524E+03 1.0149E+03 1.0000E+00 6.8300E-01 6.0768E+03 0.0000E+00 3.5213E+01 2.8321E+01 1.0000E+00 1.0000E+00 6.0768E+03 0.0000E+00 1.4905E+00 1.5249E+00 1.0000E+00 2.0000E+00 6.0768E+03 0.0000E+00 6.9328E-05 7.8605E-05 1.0000E+00 4.0000E+00 6.0768E+03 0.0000E+00 1.4999E-13 1.5736E-13 1.0000E+00 8.0000E+00 6.0768E+03 0.0000E+00 7.0211E-31 6.9514E-31

Hi Douglas, Paul, The help on mtime suggests that it should work. " When the time is reached, indicator variables are set and a call to PK is made. At this call (and/or subsequent to this call) PK or DES or AES or ERROR can use the indicator variables to change some aspect of the system, e.g., a term in a differential equation, or the rate of an infusion. This feature may be used with any ADVAN routine. " The following code (tested with nm6.2.0) however does not work in the $ERROR block, where the model predictions are available. As one can see, CP is only set at the data time event, not at the MTIME. CP2 is not set at all. So it seems $ERROR is not called upon the MTIME event. An indicator in $PK works properly (tested, not shown). Can anyone confirm this behavior? If so, this looks like a bug to me. Best regards, Jeroen ____model____ $PROB structural model 1comp.rep single subject $INPUT ID TIME DV AMT EVID TRT $DATA iv_ss.csv IGN=I $SUBR ADVAN1 TRANS2 $PK TVCL=THETA(1) CL=TVCL TVV=THETA(2) V=TVV S1=V/1000 ;mtime piece MTIME(1)=.075 ; .075 h not in dataset MTIME(2)=.5 ; .5 h not in dataset IF(TIME.EQ.0)CP=0 IF(TIME.EQ.0)CP2=0 $ERROR IPRED=F Y=F+F*ERR(1) IF(TIME.EQ.0)MYFLAG=0 ; 0 h IN dataset IF(MPAST(1).EQ.1.AND.MYFLAG.EQ.0)THEN CP=F MYFLAG=1 ENDIF CP2=CP2+MNEXT(2)*F $THETA (0,10) (0,1) $OMEGA .05 $SIM (123456789) $EST PRINT=1 MAXEVAL=9990 SIG=3 NOABORT METHOD=0 ;$COV PRINT=E $TABLE ID TIME CP CP2 IPRED NOPRINT ONEHEADER FILE=1cmp.txt ____dataset___ ID,time h,conc nM,amt,evid,dose æmol 1,0,.,30,1,10 1,0.05,0,.,0,10 1,0.166666667,0,.,0,10 1,0.333333333,0,.,0,10 1,0.683,0,.,0,10 1,1,0,.,0,10 1,2,0,.,0,10 1,4,0,.,0,10 1,8,0,.,0,10 ____table file_____ TABLE NO. 1 ID TIME CP CP2 IPRE DV 1.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 3.2044E+04 0.0000E+00 1.0000E+00 5.0000E-02 0.0000E+00 0.0000E+00 1.9459E+04 1.6272E+04 1.0000E+00 1.6667E-01 6.0768E+03 0.0000E+00 6.0768E+03 7.7936E+03 1.0000E+00 3.3333E-01 6.0768E+03 0.0000E+00 1.1524E+03 1.0149E+03 1.0000E+00 6.8300E-01 6.0768E+03 0.0000E+00 3.5213E+01 2.8321E+01 1.0000E+00 1.0000E+00 6.0768E+03 0.0000E+00 1.4905E+00 1.5249E+00 1.0000E+00 2.0000E+00 6.0768E+03 0.0000E+00 6.9328E-05 7.8605E-05 1.0000E+00 4.0000E+00 6.0768E+03 0.0000E+00 1.4999E-13 1.5736E-13 1.0000E+00 8.0000E+00 6.0768E+03 0.0000E+00 7.0211E-31 6.9514E-31

Hi Jeroen, The part of the manual that you described did not mention that the call to ERROR is done. And indeed, you can use MTIME in any subsequent calls to ERROR (that are made at event times). So I do not think this is a bug. Since call to PK is done, you can try to get A() value in the PK block, something like $PK ... C=A(*)/V1 IF(C.GE.CMAX) THEN TMAX=TSTATE CMAX=C ENDIF ... If the end-of-infusion concentration is CMAX, this code may get it out (and TMAX should point to the end-of-infusion; both of them should be taken from the first event record following the end-of-infusion) but I have not tried it. ----------- Here is the part of the manual that discussed use of A(*) in the PK block: A(n) TSTATE A(n) are the latest computed compartment amounts, and TSTATE is the time at which they were computed. That is, A(n) are the amounts at the previous event time, or if at a later time, but before the time for which PK is being called, a lagged or additional dose was given, or a regular infusion was terminated, or a modeled event occurred, then A(n) are the amounts at the latest such time. If there are population etas, and A(n) are used in the $PK abbreviated code, then any $OMEGA records referring to etas explicitly used in this code should precede the $PK record, or if an $MSFI record is used, it should precede the $PK record and include the option NPOP=m. ------------------- Could someone explain why "If there are population etas, and A(n) are used in the $PK abbreviated code, then any $OMEGA records referring to etas explicitly used in this code should precede the $PK record" Thanks Leonid -------------------------------------- Leonid Gibiansky, Ph.D. President, QuantPharm LLC web: www.quantpharm.com e-mail: LGibiansky at quantpharm.com tel: (301) 767 5566 Elassaiss - Schaap, J. (Jeroen) wrote: > Hi Douglas, Paul, > > The help on mtime suggests that it should work. > > " When the time is reached, indicator variables > are set and a call to PK is made. At this call (and/or subsequent to > this call) PK or DES or AES or ERROR can use the indicator variables > to change some aspect of the system, e.g., a term in a differential > equation, or the rate of an infusion. This feature may be used with > any ADVAN routine. " > > The following code (tested with nm6.2.0) however does not work in the $ERROR block, where the model predictions are available. As one can see, CP is only set at the data time event, not at the MTIME. CP2 is not set at all. So it seems $ERROR is not called upon the MTIME event. An indicator in $PK works properly (tested, not shown). Can anyone confirm this behavior? If so, this looks like a bug to me. Best regards, > > Jeroen > > ____model____ > > $PROB structural model 1comp.rep single subject > $INPUT ID TIME DV AMT EVID TRT > $DATA iv_ss.csv IGN=I > $SUBR ADVAN1 TRANS2 > > $PK > > TVCL=THETA(1) > CL=TVCL > TVV=THETA(2) > V=TVV > > S1=V/1000 ;mtime piece > > MTIME(1)=.075 ; .075 h not in dataset > MTIME(2)=.5 ; .5 h not in dataset > IF(TIME.EQ.0)CP=0 > IF(TIME.EQ.0)CP2=0 > > $ERROR > > IPRED=F > Y=F+F*ERR(1) > IF(TIME.EQ.0)MYFLAG=0 ; 0 h IN dataset > IF(MPAST(1).EQ.1.AND.MYFLAG.EQ.0)THEN > CP=F > MYFLAG=1 > ENDIF > > CP2=CP2+MNEXT(2)*F $THETA > > (0,10) > (0,1) > > $OMEGA > > .05 > > $SIM (123456789) > > $EST PRINT=1 MAXEVAL=9990 SIG=3 NOABORT METHOD=0 > ;$COV PRINT=E > $TABLE ID TIME CP CP2 IPRED > NOPRINT ONEHEADER FILE=1cmp.txt > > ____dataset___ > > ID,time h,conc nM,amt,evid,dose æmol > 1,0,.,30,1,10 > 1,0.05,0,.,0,10 > 1,0.166666667,0,.,0,10 > 1,0.333333333,0,.,0,10 > 1,0.683,0,.,0,10 > 1,1,0,.,0,10 > 1,2,0,.,0,10 > 1,4,0,.,0,10 > 1,8,0,.,0,10 > ____table file_____ > > TABLE NO. 1 ID TIME CP CP2 IPRE DV 1.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 3.2044E+04 0.0000E+00 1.0000E+00 5.0000E-02 0.0000E+00 0.0000E+00 1.9459E+04 1.6272E+04 1.0000E+00 1.6667E-01 6.0768E+03 0.0000E+00 6.0768E+03 7.7936E+03 1.0000E+00 3.3333E-01 6.0768E+03 0.0000E+00 1.1524E+03 1.0149E+03 1.0000E+00 6.8300E-01 6.0768E+03 0.0000E+00 3.5213E+01 2.8321E+01 1.0000E+00 1.0000E+00 6.0768E+03 0.0000E+00 1.4905E+00 1.5249E+00 1.0000E+00 2.0000E+00 6.0768E+03 0.0000E+00 6.9328E-05 7.8605E-05 1.0000E+00 4.0000E+00 6.0768E+03 0.0000E+00 1.4999E-13 1.5736E-13 1.0000E+00 8.0000E+00 6.0768E+03 0.0000E+00 7.0211E-31 6.9514E-31 > > ------------------------------------------------------------------------ > > *From:* [email protected] [ mailto: [email protected] ] *On Behalf Of *Eleveld, DJ > > *Sent:* Tuesday, 06 April, 2010 20:22 > *To:* [email protected]; [email protected] > *Subject:* RE: [NMusers] Generating Cmax at end of infusion > > Hi, > > As others have suggested making an additional record at the known desired time is probably the most straightforward manner to get what you want. So this should probably be a preferred solution. > > If you for some reason you cant to add a record (maybe you dont know the time beforehand), I think you can achieve what you want using MTIME(). This has the added advantage of working without going the $DES route and the associated slower run-times. I'll see if I can get something like that to work tomorrow, just as an excercise. Can the experts give an opinion as to whether MTIME() should work or not? > > Regards, > > Douglas Eleveld >