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I am trying to simulate a 14 day (100 mg qd) regimen using a dual
input model (see below), and the predicted concentrations I am
observing are off by a factor of 1000000 for Days 2-14, although they
fit fine for Day 1 (versus observed single dose data). I look at the
code and think it is fine, but clearly am missing something. Any help?
Thanks
Kirk Bertelsen, Ph.D
Associate Director
Clinical Pharmacokinetics and Experimental Medicine Johnson & Johnson
Pharmaceutical Research & Development, L.L.C.
P: (908) 927-7358
kbertels.at.prdus.jnj.com
Input File: Workbook - [Untitled1]
Date:
04/10/2009
Time:
07:02:47
WINNONLIN NONLINEAR ESTIMATION PROGRAM
Version 5.2.1 Build 2008033011
Core Version 19Dec2006
Listing of input commands
MODEL
COMMANDS
NFUNCTIONS 1
NDERIVATIVES 1
NPARAMETERS 6
PNAMES 'Ka1', 'Ka2', 'V', 'Kel', 'frct', 'tlag'
END
1: TEMPORARY
2: T = X
3: NDOSE = CON(1)
4: DOSE1 = CON(2)
5: END
6: START
7: Z(1) = 0
8: END
9: DIFFERENTIAL
10: J=3
11: DO I = 1 TO NDOSE-1
12: IF T > CON(J) THEN
13: J = J+2
14: ELSE
15: GOTO RED
16: ENDIF
17: NEXT
18: IF INT(((J-1)/2)+.001) = NDOSE AND T > CON(J) THEN
19: LASTDOSE = CON(J-1)
20: TLSTDOSE = CON(J)
21: GOTO GREEN
22: ENDIF
23: RED:
24: IF J > 3 THEN
25: IF T = CON(J) THEN
26: LASTDOSE = CON(J-1)
27: TLSTDOSE = CON(J)
28: Z(1) = Z(1)+LASTDOSE
29: ELSE
30: LASTDOSE = CON(J-3)
31: TLSTDOSE = CON(J-2)
32: ENDIF
33: ELSE
34: LASTDOSE = DOSE1
35: TLSTDOSE = 0
36: ENDIF
37: GREEN:
38: INPUT1 = DOSE1*FRCT*KA1*EXP(-KA1*T)
39: IF T LE TLAG THEN
40: INPUT2 = 0
41: ELSE
42: INPUT2 = DOSE1*(1-FRCT)*KA2*EXP(-KA2*(T-TLAG))
43: ENDIF
44: DZ(1) = (INPUT1 + INPUT2)/V-KEL*Z(1)
45: END
46: FUNCTION 1
47: F= Z(1)
48: END
49: EOM
SIMULATE
NVARIABLES 1
PUNIT '1/hr','1/hr','mL','1/hr','~','hr'
XNUMBER 1
NCONSTANTS 29
CONSTANTS 14,100000000,0,100000000,24,100000000, &
48,100000000,72,100000000,96,100000000,120, &
100000000,144,100000000,168,100000000,192,100000000, &
216,100000000,240,100000000,264,100000000,288, &
100000000,312
INITIAL 0.054814667,2.3,57259.47684,0.4606225,0.7023715,0.571114667
NOBOUNDS
MISSING 'Missing'
DATA 'WINNLIN.DAT'
BEGIN
Date:
04/10/2009
Time:
07:03:01
WINNONLIN NONLINEAR ESTIMATION PROGRAM
*** WARNING ***
VARIANCE - COVARIANCE MATRIX IS NOT OF FULL RANK OR
IS ILL-CONDITIONED. PARAMETER ESTIMATES AND THEIR
ASSOCIATED STANDARD ERRORS SHOULD BE INTERPRETED
WITH CAUTION.
PARAMETER UNITS ESTIMATE VAR-INF_FACTOR
[SQRT(VIF)/P]
KA1 1/HR 0.054815 0.000000
0.41
KA2 1/HR 2.300000 0.000273
0.72
V ML 57259.476840 10364.387480
0.18
KEL 1/HR 0.460622 0.000000
0.00
FRCT ~ 0.702372 0.000001
0.10
TLAG HR 0.571115 0.000004
0.37
Date:
04/10/2009
Time:
07:03:01
WINNONLIN NONLINEAR ESTIMATION PROGRAM
*** CORRELATION MATRIX OF THE ESTIMATES ***
PARAMETER KA1 KA2 V
KEL FRCT TLAG
KA1 1.00000
KA2 0.344227 1.00000
V 0.714797 0.660142E-01 1.00000
KEL -0.332485 -0.576223E-01 -0.338426 1.00000
FRCT -0.406557E-01 0.475100 -0.598602
0.154532 1.00000
TLAG 0.221865 0.818283 0.764213E-01
-0.403976E-01 0.319433 1.00000
*** EIGENVALUES OF (Var - Cov) MATRIX ***
NUMBER EIGENVALUE
1 0.1307E+19
2 0.8398E+08
3 0.5211E+07
4 0.6787E+06
5 3642.
6 0.9648E-04
Condition_number= 0.1164E+12
Date:
04/10/2009
Time:
07:03:01
WINNONLIN NONLINEAR ESTIMATION PROGRAM
*** SUMMARY OF NONLINEAR ESTIMATION ***
FUNCTION 1
X CALCULATED VAR - INF
Y FACTOR
0.000 0.000 0.000
0.2500 15.77 0.2986E-02
0.5000 29.61 0.1039E-01
0.7500 209.5 0.9273
1.000 343.4 0.3769
1.250 400.6 0.3494
1.500 416.5 0.2287
1.750 411.0 0.1534
2.000 394.8 0.1328
2.250 374.0 0.1323
2.500 351.7 0.1300
2.750 329.7 0.1203
3.000 308.8 0.1054
3.250 289.4 0.8902E-01
3.500 271.6 0.7405E-01
3.750 255.3 0.6189E-01
4.000 240.5 0.5293E-01
4.250 227.1 0.4695E-01
4.500 214.9 0.4342E-01
4.750 203.9 0.4179E-01
5.000 193.9 0.4149E-01
5.250 184.8 0.4208E-01
5.500 176.5 0.4319E-01
5.750 169.0 0.4454E-01
6.000 162.1 0.4595E-01
6.250 155.8 0.4728E-01
6.500 150.1 0.4843E-01
6.750 144.8 0.4936E-01
7.000 139.9 0.5004E-01
7.250 135.5 0.5047E-01
7.500 131.3 0.5064E-01
7.750 127.5 0.5058E-01
8.000 123.9 0.5030E-01
9.000 111.9 0.4752E-01
10.00 102.6 0.4317E-01
11.00 94.95 0.3838E-01
12.00 88.53 0.3384E-01
13.00 82.96 0.2987E-01
14.00 77.99 0.2660E-01
15.00 73.49 0.2401E-01
16.00 69.36 0.2202E-01
17.00 65.52 0.2055E-01
18.00 61.94 0.1949E-01
19.00 58.58 0.1874E-01
20.00 55.43 0.1823E-01
21.00 52.45 0.1790E-01
22.00 49.64 0.1767E-01
23.00 46.98 0.1752E-01
24.00 0.1000E+09 0.1740E-01
24.25 0.8912E+08 0.1583E-01
24.50 0.7943E+08 0.1530E-01
24.75 0.7079E+08 0.1523E-01
25.00 0.6309E+08 0.1537E-01
25.25 0.5623E+08 0.1557E-01
25.50 0.5011E+08 0.1574E-01
25.75 0.4466E+08 0.1584E-01
26.00 0.3980E+08 0.1588E-01
26.25 0.3547E+08 0.1584E-01
26.50 0.3161E+08 0.1576E-01
26.75 0.2818E+08 0.1563E-01
27.00 0.2511E+08 0.1549E-01
27.25 0.2238E+08 0.1533E-01
27.50 0.1995E+08 0.1517E-01
27.75 0.1778E+08 0.1502E-01
28.00 0.1584E+08 0.1488E-01
28.25 0.1412E+08 0.1476E-01
28.50 0.1258E+08 0.1466E-01
28.75 0.1121E+08 0.1457E-01
29.00 0.9995E+07 0.1451E-01
29.25 0.8908E+07 0.1446E-01
29.50 0.7939E+07 0.1442E-01
29.75 0.7075E+07 0.1440E-01
30.00 0.6306E+07 0.1439E-01
30.25 0.5620E+07 0.1439E-01
30.50 0.5008E+07 0.1440E-01
30.75 0.4464E+07 0.1440E-01
31.00 0.3978E+07 0.1441E-01
31.25 0.3545E+07 0.1443E-01
31.50 0.3160E+07 0.1444E-01
31.75 0.2816E+07 0.1445E-01
32.00 0.2510E+07 0.1445E-01
33.00 0.1583E+07 0.1444E-01
34.00 0.9990E+06 0.1433E-01
35.00 0.6302E+06 0.1414E-01
36.00 0.3976E+06 0.1386E-01
37.00 0.2509E+06 0.1352E-01
38.00 0.1583E+06 0.1313E-01
39.00 0.9986E+05 0.1270E-01
40.00 0.6301E+05 0.1224E-01
41.00 0.3976E+05 0.1177E-01
42.00 0.2509E+05 0.1128E-01
43.00 0.1583E+05 0.1079E-01
44.00 9994. 0.1030E-01
45.00 6310. 0.9815E-02
46.00 3985. 0.9335E-02
47.00 2518. 0.8864E-02
48.00 0.1000E+09 0.8403E-02
48.25 0.8912E+08 0.7350E-02
48.50 0.7943E+08 0.7133E-02
48.75 0.7079E+08 0.7321E-02
49.00 0.6309E+08 0.7655E-02
49.25 0.5623E+08 0.7987E-02
49.50 0.5011E+08 0.8245E-02
49.75 0.4466E+08 0.8396E-02
50.00 0.3980E+08 0.8439E-02
50.25 0.3547E+08 0.8384E-02
50.50 0.3161E+08 0.8249E-02
50.75 0.2818E+08 0.8053E-02
51.00 0.2511E+08 0.7815E-02
51.25 0.2238E+08 0.7552E-02
51.50 0.1995E+08 0.7278E-02
51.75 0.1778E+08 0.7003E-02
52.00 0.1584E+08 0.6736E-02
52.25 0.1412E+08 0.6483E-02
52.50 0.1258E+08 0.6246E-02
52.75 0.1121E+08 0.6029E-02
53.00 0.9995E+07 0.5833E-02
53.25 0.8908E+07 0.5656E-02
53.50 0.7939E+07 0.5498E-02
53.75 0.7075E+07 0.5357E-02
54.00 0.6306E+07 0.5233E-02
54.25 0.5620E+07 0.5123E-02
54.50 0.5009E+07 0.5026E-02
54.75 0.4464E+07 0.4939E-02
55.00 0.3978E+07 0.4862E-02
55.25 0.3545E+07 0.4792E-02
55.50 0.3160E+07 0.4728E-02
55.75 0.2816E+07 0.4670E-02
56.00 0.2510E+07 0.4615E-02
57.00 0.1583E+07 0.4420E-02
58.00 0.9990E+06 0.4235E-02
59.00 0.6302E+06 0.4045E-02
60.00 0.3976E+06 0.3846E-02
61.00 0.2509E+06 0.3640E-02
62.00 0.1583E+06 0.3431E-02
63.00 0.9985E+05 0.3224E-02
64.00 0.6300E+05 0.3021E-02
65.00 0.3974E+05 0.2824E-02
66.00 0.2508E+05 0.2636E-02
67.00 0.1582E+05 0.2456E-02
68.00 9983. 0.2286E-02
69.00 6299. 0.2126E-02
70.00 3975. 0.1975E-02
71.00 2509. 0.1833E-02
72.00 0.1000E+09 0.1700E-02
72.25 0.8912E+08 0.1505E-02
72.50 0.7943E+08 0.1966E-02
72.75 0.7079E+08 0.2686E-02
73.00 0.6309E+08 0.3432E-02
73.25 0.5623E+08 0.4077E-02
73.50 0.5011E+08 0.4565E-02
73.75 0.4466E+08 0.4883E-02
74.00 0.3980E+08 0.5038E-02
74.25 0.3547E+08 0.5053E-02
74.50 0.3161E+08 0.4955E-02
74.75 0.2818E+08 0.4771E-02
75.00 0.2511E+08 0.4525E-02
75.25 0.2238E+08 0.4240E-02
75.50 0.1995E+08 0.3933E-02
75.75 0.1778E+08 0.3619E-02
76.00 0.1584E+08 0.3310E-02
76.25 0.1412E+08 0.3012E-02
76.50 0.1258E+08 0.2732E-02
76.75 0.1121E+08 0.2472E-02
77.00 0.9995E+07 0.2235E-02
77.25 0.8908E+07 0.2022E-02
77.50 0.7939E+07 0.1831E-02
77.75 0.7075E+07 0.1662E-02
78.00 0.6306E+07 0.1514E-02
78.25 0.5620E+07 0.1385E-02
78.50 0.5009E+07 0.1274E-02
78.75 0.4464E+07 0.1177E-02
79.00 0.3978E+07 0.1095E-02
79.25 0.3545E+07 0.1024E-02
79.50 0.3160E+07 0.9635E-03
79.75 0.2816E+07 0.9123E-03
80.00 0.2510E+07 0.8687E-03
81.00 0.1583E+07 0.7497E-03
82.00 0.9990E+06 0.6828E-03
83.00 0.6302E+06 0.6382E-03
84.00 0.3976E+06 0.6014E-03
85.00 0.2508E+06 0.5666E-03
86.00 0.1583E+06 0.5320E-03
87.00 0.9984E+05 0.4974E-03
88.00 0.6299E+05 0.4632E-03
89.00 0.3974E+05 0.4298E-03
90.00 0.2507E+05 0.3979E-03
91.00 0.1582E+05 0.3675E-03
92.00 9980. 0.3389E-03
93.00 6297. 0.3122E-03
94.00 3973. 0.2873E-03
95.00 2507. 0.2641E-03
96.00 0.1000E+09 0.2427E-03
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Hello,
In my opinion, the discrepancy in values may be due to the way in
which the extra doses are handled during superposition. Line 28 adds
new dose in amounts and line 44 is a rate equation for concentrations.
Try the following change to the current code and see if it works:
44. DZ(1) = (INPUT1 + INPUT2)-KEL*Z(1)
47. F= Z(1)/_V_
Thanks
[_V_ <- V (underlined for emphasis - db]
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