Subject: stepwise zero order input
Date: Tue, 27 Oct 1998 14:45:00 +0100

Dear NONMEM user,

Here is the next problem with the stepwise zero order input:
; -------------2 COMP ADVAN 4 control-----------------------------------
\$PROBLEM dissolution kinetics of 60mg diltiazem tablets uses PREDPP
\$INPUT ID TIME DV AMT CMT PCMT EVID MDV RATE HGHT WGHT AGE Zeit FORM MALE

\$DATA 605data IGNORE=#

\$ABBREVIATED DERIV2=NOCOMMON

\$PK
KA = THETA(10) * EXP(ETA(2))
V2 = THETA(11) * EXP(ETA(3))
CL23 = THETA(12) * WGHT * EXP(ETA(4))
V3 = THETA(13) * EXP(ETA(5))
CL20 = THETA(14) * WGHT * EXP(ETA(6))
F2 = THETA(15) * EXP(ETA(7))

; initializiation of concomittant time varying variables

Q1 = 0
Q2 = 0
Q3 = 0
Q4 = 0
Q5 = 0
Q6 = 0
Q7 = 0
Q8 = 0
Q9 = 0

; time varying variables
;1st day

IF (TIME.GT.0.AND.TIME.LE.30) Q1 = 1
IF (TIME.GT.30.AND.TIME.LE.60) Q2 = 1
IF (TIME.GT.60.AND.TIME.LE.120) Q3 = 1
IF (TIME.GT.120.AND.TIME.LE.180) Q4 = 1
IF (TIME.GT.180.AND.TIME.LE.240) Q5 = 1
IF (TIME.GT.240.AND.TIME.LE.300) Q6 = 1
IF (TIME.GT.300.AND.TIME.LE.360) Q7 = 1

IF (TIME.GT.360.AND.TIME.LE.390) Q1 = 1
IF (TIME.GT.390.AND.TIME.LE.420) Q2 = 1
IF (TIME.GT.420.AND.TIME.LE.480) Q3 = 1
IF (TIME.GT.480.AND.TIME.LE.540) Q4 = 1
IF (TIME.GT.540.AND.TIME.LE.600) Q5 = 1
IF (TIME.GT.600.AND.TIME.LE.660) Q6 = 1
IF (TIME.GT.660.AND.TIME.LE.720) Q7 = 1
IF (TIME.GT.720.AND.TIME.LE.750) Q1 = 1
IF (TIME.GT.750.AND.TIME.LE.780) Q2 = 1
IF (TIME.GT.780.AND.TIME.LE.840) Q3 = 1
IF (TIME.GT.840.AND.TIME.LE.900) Q4 = 1
IF (TIME.GT.900.AND.TIME.LE.960) Q5 = 1
IF (TIME.GT.960.AND.TIME.LE.1020) Q6 = 1
IF (TIME.GT.1020.AND.TIME.LE.1080) Q7 = 1
IF (TIME.GT.1080.AND.TIME.LE.1200) Q8 = 1
IF (TIME.GT.1200.AND.TIME.LE.1440) Q9 = 1

;2nd day

IF (TIME.GT.1440.AND.TIME.LE.1470) Q1 = 1
IF (TIME.GT.1470.AND.TIME.LE.1500) Q2 = 1
IF (TIME.GT.1500.AND.TIME.LE.1560) Q3 = 1
IF (TIME.GT.1560.AND.TIME.LE.1620) Q4 = 1
IF (TIME.GT.1620.AND.TIME.LE.1680) Q5 = 1
IF (TIME.GT.1680.AND.TIME.LE.1740) Q6 = 1
IF (TIME.GT.1740.AND.TIME.LE.1800) Q7 = 1
IF (TIME.GT.1800.AND.TIME.LE.1830) Q1 = 1
IF (TIME.GT.1830.AND.TIME.LE.1860) Q2 = 1
IF (TIME.GT.1860.AND.TIME.LE.1920) Q3 = 1
IF (TIME.GT.1920.AND.TIME.LE.1980) Q4 = 1
IF (TIME.GT.1980.AND.TIME.LE.2040) Q5 = 1
IF (TIME.GT.2040.AND.TIME.LE.2100) Q6 = 1
IF (TIME.GT.2100.AND.TIME.LE.2160) Q7 = 1
IF (TIME.GT.2160.AND.TIME.LE.2190) Q1 = 1
IF (TIME.GT.2190.AND.TIME.LE.2220) Q2 = 1
IF (TIME.GT.2220.AND.TIME.LE.2280) Q3 = 1
IF (TIME.GT.2280.AND.TIME.LE.2340) Q4 = 1
IF (TIME.GT.2340.AND.TIME.LE.2400) Q5 = 1
IF (TIME.GT.2400.AND.TIME.LE.2460) Q6 = 1
IF (TIME.GT.2460.AND.TIME.LE.2520) Q7 = 1
IF (TIME.GT.2520.AND.TIME.LE.2640) Q8 = 1
IF (TIME.GT.2640.AND.TIME.LE.2880) Q9 = 1

;3th day

IF (TIME.GT.2880.AND.TIME.LE.2910) Q1 = 1
IF (TIME.GT.2910.AND.TIME.LE.2940) Q2 = 1
IF (TIME.GT.2940.AND.TIME.LE.3000) Q3 = 1
IF (TIME.GT.3000.AND.TIME.LE.3060) Q4 = 1
IF (TIME.GT.3060.AND.TIME.LE.3120) Q5 = 1
IF (TIME.GT.3120.AND.TIME.LE.3180) Q6 = 1
IF (TIME.GT.3180.AND.TIME.LE.3240) Q7 = 1
IF (TIME.GT.3240.AND.TIME.LE.3270) Q1 = 1
IF (TIME.GT.3270.AND.TIME.LE.3300) Q2 = 1
IF (TIME.GT.3300.AND.TIME.LE.3360) Q3 = 1
IF (TIME.GT.3360.AND.TIME.LE.3420) Q4 = 1
IF (TIME.GT.3420.AND.TIME.LE.3480) Q5 = 1
IF (TIME.GT.3480.AND.TIME.LE.3540) Q6 = 1
IF (TIME.GT.3540.AND.TIME.LE.3600) Q7 = 1
IF (TIME.GT.3600.AND.TIME.LE.3630) Q1 = 1
IF (TIME.GT.3630.AND.TIME.LE.3660) Q2 = 1
IF (TIME.GT.3660.AND.TIME.LE.3720) Q3 = 1
IF (TIME.GT.3720.AND.TIME.LE.3780) Q4 = 1
IF (TIME.GT.3780.AND.TIME.LE.3840) Q5 = 1
IF (TIME.GT.3840.AND.TIME.LE.3900) Q6 = 1
IF (TIME.GT.3900.AND.TIME.LE.3960) Q7 = 1
IF (TIME.GT.3960.AND.TIME.LE.4080) Q8 = 1
IF (TIME.GT.4080.AND.TIME.LE.4320) Q9 = 1

;4th day

IF (TIME.GT.4320.AND.TIME.LE.4350) Q1 = 1
IF (TIME.GT.4350.AND.TIME.LE.4380) Q2 = 1
IF (TIME.GT.4380.AND.TIME.LE.4440) Q3 = 1
IF (TIME.GT.4440.AND.TIME.LE.4500) Q4 = 1
IF (TIME.GT.4500.AND.TIME.LE.4560) Q5 = 1
IF (TIME.GT.4560.AND.TIME.LE.4620) Q6 = 1
IF (TIME.GT.4620.AND.TIME.LE.4680) Q7 = 1
IF (TIME.GT.4680.AND.TIME.LE.4710) Q1 = 1
IF (TIME.GT.4710.AND.TIME.LE.4740) Q2 = 1
IF (TIME.GT.4740.AND.TIME.LE.4800) Q3 = 1
IF (TIME.GT.4800.AND.TIME.LE.4860) Q4 = 1
IF (TIME.GT.4860.AND.TIME.LE.4920) Q5 = 1
IF (TIME.GT.4920.AND.TIME.LE.4980) Q6 = 1
IF (TIME.GT.4980.AND.TIME.LE.5040) Q7 = 1
IF (TIME.GT.5040.AND.TIME.LE.5070) Q1 = 1
IF (TIME.GT.5070.AND.TIME.LE.5100) Q2 = 1
IF (TIME.GT.5100.AND.TIME.LE.5160) Q3 = 1
IF (TIME.GT.5160.AND.TIME.LE.5220) Q4 = 1
IF (TIME.GT.5220.AND.TIME.LE.5280) Q5 = 1
IF (TIME.GT.5280.AND.TIME.LE.5340) Q6 = 1
IF (TIME.GT.5340.AND.TIME.LE.5400) Q7 = 1
IF (TIME.GT.5400.AND.TIME.LE.5520) Q8 = 1
IF (TIME.GT.5520.AND.TIME.LE.5760) Q9 = 1

; rates with which drug is beeing dissoluted into gut compartment during time
; intervals

A1 = THETA(1) * EXP(ETA(1))
A2 = THETA(2) * EXP(ETA(1))
A3 = THETA(3) * EXP(ETA(1))
A4 = THETA(4) * EXP(ETA(1))
A5 = THETA(5) * EXP(ETA(1))
A6 = THETA(6) * EXP(ETA(1))
A7 = THETA(7) * EXP(ETA(1))
A8 = THETA(8) * EXP(ETA(1))
A9 = THETA(9) * EXP(ETA(1))

; fractional rates

FR1 = Q1 * A1
FR2 = Q2 * A2
FR3 = Q3 * A3
FR4 = Q4 * A4
FR5 = Q5 * A5
FR6 = Q6 * A6
FR7 = Q7 * A7
FR8 = Q8 * A8
FR9 = Q9 * A9

; rate

R1 = FR1+FR2+FR3+FR4+FR5+FR6+FR7+FR8+FR9

S2 = V2
K = CL20/V2
K23 = CL23/V2
K32 = CL23/V3

\$ERROR

MEP = F
Y = MEP + (MEP*ERR(1))

\$THETA NOABORT

(0, 2 , ) ; TV A1
(0, 3.2 , ) ; TV A2
(0, 60 , ) ; TV A3
(0, 6 , ) ; TV A4
(0, 12 , ) ; TV A5
(0, 10 , ) ; TV A6
(0, 0.3 , ) ; TV A7
(0, 0.3 , ) ; TV A8
(0, 0.1 , ) ; TV A9
( 0.0269 FIXED ) ; TVka
( 118 FIXED ) ; TVVc
( 0.0149 FIXED ) ; TVCL23/kg
( 281 FIXED ) ; TVV3
( 0.0142 FIXED ) ; TVCLe/kg
( 0.508 FIXED ) ; TVF2

\$OMEGA

.25 ; Variance in r1
; .25 ; Variance in r2
; .25 ; Variance in r3
; .25 ; Variance in r4
; .25 ; Variance in r5
; .25 ; Variance in r6
; .25 ; Variance in r7
; .25 ; Variance in r8
( .320 ) ; Variance in ka
( .226 ) ; Variance in Vc
( .0611 ) ; Varianve in CL23
( .201 ) ; Variance in V3
( .0492 ) ; Variance in CLe
( .0405 ) ; Variance in F1

\$SIGMA .25 ; Variance in individual ERROR

;\$MSFI

\$ESTIMATION PRINT=5 MAXEVALS=9999 NOABORT ;POSTHOC NOABORT
METHOD=CONDITIONAL
;\$COVARIANCE

\$TABLE ID R1 TIME DV PRED FILE = testtable

Dept.Pharm.Techn.Biopharm.
University of Bonn
An der Immenburg 4
D-53121 Bonn
Germany
http://www.pharma.uni-bonn.de/pharmtech/
Tel.: ++49 228 218997
Fax.:++49 228 735268

****

From: ABoeckmann <alison@c255.ucsf.edu>
Subject: 2 recent questions
Date: Tue, 3 Nov 1998 10:02:36 -0800 (PST)

Here are comments on two recent questions that were sent to nmusers.

From: TRANCHAND Brigitte <tranchan@lyon.fnclcc.fr>
Subject: initial OMEGA

Brigitte needs to supply more detail. E.g., in her first run, does she supply good initial estimates of theta, or is she letting NONMEM compute the initial estimates of theta? Does her second run involve much better estimates of theta as well as omega? Or does she work with certain kinds of model or data sets?