RE: MTIME for both Single and Repeat Dose PK in NONMEM VII
Dear Donna et al.
Since the ADDL data item is used it will be necessary to use DOSTIM to
set MTIME for each non-event dose. (DOSTIM information included at the
end of message.)
The following code for $PK provides an example for using DOSTIM. An
attempt has been made to use the orignal example but not certain it has
been successfully represented.
Since the new methods function better when THETA's are linearly related
to ETA's the THETA's are in the natural log domain. Also MU modeled
parameters should not be time dependent (or change within an individual)
for the new methods. The code below attempts to meet these requirements.
KA1S, KA2S, KA1M and KA2M are each time independent. In the original
code, the KA was MU_ modeled and time-dependent.
Unless you have very informative data, this model is likely to be
over-parameterized. Fixing some OMEGA's to a modest value, say 0.0225
(15%CV), instead of zero can be useful when applying the new methods.
$PK (NONEVENT)
MTDIFF=1
IF(EVID.EQ.1.OR.EVID.EQ.4)DTIME=TIME ; event dose times
IF(DOSTIM.NE.0.)DTIME=DOSTIM ; non-event dose times (see Help Item
below).
MU_1=THETA(1) ; THETA(1) is in the LN domain
CL=EXP(MU_1+ETA(1))
MU_2=THETA(2) ; THETA(2) is in the LN domain
V2=EXP(MU_2+ETA(2))
MU_3=THETA(3) ; THETA(3) is in the LN domain
V3=EXP(MU_3+ETA(3))
MU_4=THETA(4) ; THETA(4) is in the LN domain
Q=EXP(MU_4+ETA(4))
ITFG=0
IF(TIME.GT.24)ITFG=1
; Less than 24 hrs
MU_5=THETA(5) ; THETA(5) is in the LN domain
KA1S=EXP(MU_5+ETA(5))
MU_6=THETA(6); THETA(6) is in the LN domain
KA2S=EXP(MU_6+ETA(6))
MU_7=THETA(7); THETA(7) is in the LN domain
MTIME(1)=EXP(MU_7+ETA(7))
KAS=KA1S*(1-MPAST(1))+KA2S*(MPAST(1))
;Greater than or equal to 24 hrs
MU_8=THETA(8) ; THETA(8) is in the LN domain
KA1M=EXP(MU_8+ETA(8))
MU_9=THETA(9) ; THETA(9) is in the LN domain
KA2M=EXP(MU_9+ETA(9))
MU_10=THETA(10); THETA(10) is in the LN domain
MTIME(2)=DTIME+EXP(MU_10+ETA(10))
KAM=KA1M*(1-MPAST(2))+KA2M*(MPAST(2))
;Select single dose or multiple dose KA
KA=KAS*(1-ITFG)+KAM*(ITFG)
S2=V2
************************************************************************
*************
DOSTIM Help Item
DOSTIM=0: this call to PK occurs at an event time.
DOSTIM>0: this call to PK occurs at a non-event dose time DOSTIM,
i.e., at the time of an additional or lagged dose.
Tom
with assistance from Bob Bauer regarding the need for MU_ referenced
variables to be unchanged for a given individual when using the new
methods.
Quoted reply history
________________________________
From: [email protected] [mailto:[email protected]]
On Behalf Of Donna Cox
Sent: Wednesday, July 14, 2010 9:50 AM
To: Elassaiss - Schaap, J. (Jeroen); [email protected]
Subject: RE: [NMusers] MTIME for both Single and Repeat Dose PK in
NONMEM VII
HI Jeroen-
Thanks for your response! My data follows a 2-com model. The data set
I have coded in ADDL and II (trying to avoid SS records). I have
specified MTIME(1) by time <24 hours (Day 1) and MTIME (2) by time >24
hours (Day 15). I have included some code below to be more specific.
Thanks
Donna
$PROBLEM MEK FTIH POPULATION PK MODELING
$INPUT C ID TIME CP DV AMT=DOSE WT EVID DAY ADDL II BMI
$DATA MEKALL1.CSV IGNORE=C
$SUBROUTINES ADVAN4 TRANS4
$PK
TVCL=THETA(1)
MU_1=LOG(TVCL)
CL=EXP(MU_1+ETA(1))
TVV2=THETA(2)
MU_2=LOG(TVV2)
V2=EXP(MU_2+ETA(2))
TVV3=THETA(3)
MU_3=LOG(TVV3)
V3=EXP(MU_3+ETA(3))
TVQ=THETA(4)
MU_4=LOG(TVQ)
Q=EXP(MU_4+ETA(4))
IF(TIME.LE.24)THEN
MU_5=LOG(THETA(5))
MTIME(1)=EXP(MU_5+ETA(5))
MU_6=LOG(THETA(6)*(1-MPAST(1))+THETA(9)*MPAST(1))
KA=EXP(MU_6+ETA(6))
ENDIF
IF(TIME.GT.24)THEN
MU_7=LOG(THETA(7))
MTIME(2)=EXP(MU_7+ETA(7))
MU_8=LOG(THETA(8)*(1-MPAST(1))+THETA(10)*MPAST(1))
KA=EXP(MU_8+ETA(8))
ENDIF
MTDIFF=1
S2=V2
From: Elassaiss - Schaap, J. (Jeroen)
[mailto:[email protected]]
Sent: Wednesday, July 14, 2010 9:38 AM
To: Donna Cox; [email protected]
Subject: RE: [NMusers] MTIME for both Single and Repeat Dose PK in
NONMEM VII
Hi Donna,
Could you please provide additional details, i.e. core model code
(dataset layout and crash message)? You may need to specify the MTIMEs
for each dose given to the system which may not be practical.
This may be an opportunity for future nonmem versions, to be able to
specify MTIMEs relative to the active dose in the system. Perhaps not
feasible for SS records.
Best regards,
Jeroen
Modeling & Simulation Expert
Pharmacokinetics, Pharmacodynamics & Pharmacometrics (P3) - DMPK
MSD
PO Box 20 - AP1112
5340 BH Oss
The Netherlands
[email protected]
T: +31 (0)412 66 9320
M: +31 (0)6 46 101 283
F: +31 (0)412 66 2506
www.msd.com
________________________________
From: [email protected] [mailto:[email protected]]
On Behalf Of Donna Cox
Sent: Wednesday, 14 July, 2010 14:17
To: [email protected]
Subject: [NMusers] MTIME for both Single and Repeat Dose PK in NONMEM
VII
Hi All:
I have a combined single and repeat dose data set that I am trying to
model in NONMEM VII. I can model the single dose data with MTIME
successfully (tremendous improvement in fit compared to 2-COM model
without MTIME). Does anyone have any experience modeling BOTH single
and repeat dose data with MTIME?? I have tried using 2 MTIME's (one for
single and one for the repeat dose data, but it crashes). Any
suggestions would be helpful.
Thanks much
Donna
Donna S. Cox, PhD
GlaxoSmithKline
Quantitative Sciences
Clinical Pharmacology Modeling and Simulation
UM 24-3059
King of Prussia, Philadelphia
610-270-4395
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