DEFINITIONS

PK parameter

A single value that is determined from a group of concentration values. It

is generally used to characterize a group of concentration values, similar

to the way a mean characterizes a group of numbers.

profile

A sequence of concentration measurements generally starting just before

dosing and ending either: 1) just before the next dose in a multi-dosing

study, or 2) when the concentration values have decayed significantly

in the elimination phase. Ideally, the measurements in the sequence

are dense enough to adequately define the 3 phases.

absorption phase

The processes and results of transport of the drug from the site of dosing to the

organs responsible for distribution.

distribution phase

The transport of the drug to the target sites.

elimination phase

The removal of the active drug from the body. Elimination can occur via

chemical reaction or physical elimination (usually in the urine).

Some common PK Parameters:

Cmax

Maximum concentration occurring in a profile.

Tmax

Time of maximum concentration.

Cmin

Minimum concentration occurring in a profile.

Tmin

Time of minimum concentration.

Ctrough

Predose concentration (in a multiple-dose study).

AUC

Area under the concentration vs time curve.

AUC(0-12)

AUC from 0 hours to 12 hours.

AUC(0-t)

AUC from 0 hours to the time of the last measureable concentration.

AUC(0-tau)

AUC from 0 hours to the time of next dosing.

AUC(0-)

AUC from 0 to infinity.

  • AUC(0-T), (area under the concentration = (time) curve, [time 0 to time of last quantifiable concentration]), calculated by the trapezoidal rule and expressed in units of concentration·time
  • AUC(0-inf), calculated as “AUC(0-inf) = AUC(0-Tlast) + CTlast /Kel”, where CTlast is the last measurable drug concentration and Kel is the terminal elimination rate constant, expressed in units of concentration time
  • Kel, the apparent elimination rate constant, determined by linear regression analysis of the natural log segment of the plasma concentration-time curve, expressed in time1 units
  • Cmax, the observed peak drug concentration obtained directly from the experimental data without interpolation, expressed in concentration units
  • Tmax, the observed time to reach peak drug concentration obtained directly from the experimental data without interpolation, expressed in time units
  • T1/2, the terminal half-life, calculated as “T1/2 = -ln 2/Kel”, expressed in time units
  • C1, the concentration of SUN N4057 measured at end time of the first loading dose
  • C6, the plasma concentration of SUN N4057 measured at end of time of the second loading dose
  • C24, the plasma concentration of SUN N4057 measured at the end of time of maintenance dose
  • Cltot, total clearance calculated as: Dose/AUC(0-inf)
  • Vd, volume of distribution calculated as: Cl/Ke
  • Vdss, volume of distribution at steady state calculated as: Cltot x MRT
  • MRT, mean residence time calculated as AUMC(0-inf)/AUC(0-inf), where AUMC(0inf) is defined as the area under the moment curve from time=0 (dosing) to infinity. Because adequate estimates of AUC(0-inf) cannot always be made, AUMC(0-last) and AUC(0-last) may be substituted for AUMC(0-inf) and AUC(0-inf), respectively. MRT will be presented in units of hr
  • %Fe, urinary recovery of intact drug during 0-96 hr, calculated as percent of dose
  • Clr, renal clearance calculated as CumAe (the cumulative amount of drug excreted unchanged in the urine)/AUC(0-inf)

PK DATASET

The PK dataset contains all data useful in characterizing the concentration data. For each sample (i.e., each observation) the dataset contains: concentration value, comments and footnotes relating to concentration meausrement, time of dose, time of sample, time from dose to sample, demographic info, variables for grouping data (e.g., period, day), variables for analyzing data (e.g., treatment, weight, sequence), PK parameters.

VARIABLES ON A PK DATASET:

Variable Type Len Pos Format Label

------

Demographic and vitals data

AGE Num 8 50 3. Age at screening

COMPLTE Char 1 3 Did Subject Complete

RACE Char 2 48 Ethnic Race

SEX Char 2 46 Gender

WEIGHT Char 5 130 Screening weight (lb)

Blood sampling data

TREAT Char 2 4 Treatment Received

NBLDDTE Num 8 14 MMDDYY10. Numeric blood sampling date

NBLDTME Num 8 22 HHMM7. Numeric blood sampling time

Dosing data

PKDOSDT Num 8 58 MMDDYY10. Date of dose

PKDOSTM Num 8 66 HHMM7. Clock time of dose

Variables calculated from clinical data

SCHEDTIM Num 8 38 Numeric scheduled time from dose (hr)

DELTATM Num 8 1 HHMM7. Time from start of dosing (sec)

DIFF Num 8 143 HHMM7. Difference from scheduled time

DT Num 8 275 Time for calculation of AUC (hours)

Concentration data

CONCA Num 8 122 Numeric concentration (ng/mL)

CONCEN Char 20 Character concentration

Variables for grouping data

ANALYTE Char 8 74 Name of drug whose conc. is measured

PERIOD

DAY

TREAT

PK parameters

AUC Num 8 114 AUC[0-4.5] (hr·ng/mL)

AUCI Num 8 82 AUC[0-inf] (hr·ng/mL)

CL Num 8 106 Total clearance (L/hr)

CMAX Num 8 90 Maximum concentration (ng/mL)

KE Num 8 371 Elimination rate constant (1/hr)

TLAST Num 8 339 Time of last non-zero concentration

T12 Num 8 379 Half-life (hr)

TMAX Num 8 98 Time of maximum concentration (hr)

Other

IMPCONC Num 8 315 Concentration including imputed values

PKFLAG Char 8 307 Obs flag: A=area R=regression L=lastconc

\pkclass\definit.doc 1

SAMPLE ORGANIZATION OF PK DATASET

[grahamr.fk96001.data.bio]plasma 18:07 Wednesday, March 24, 1999 1
CONTENTS PROCEDURE

Data Set Name: BIO.PLASMA Observations: 2400

Member Type: DATA Variables: 35

Engine: V612 Indexes: 0

Created: 14:57 Wednesday, March 24, 1999 Observation Length: 261

Last Modified: 14:57 Wednesday, March 24, 1999 Deleted Observations: 0

Protection: Compressed: NO

Data Set Type: Sorted: YES

Label:

-----Alphabetic List of Variables and Attributes-----

# Variable Type Len Pos Format Label

------

7 AGE Num 8 35 Subject's Age

33 AMPM Char 2 243 Time of day indicator for sample

17 ANALYTE Char 5 127 Analyte

22 AUC Num 8 162 AUC to last measureable conc (hr·units)

23 AUCINF Num 8 170 AUC to infinity (hr·units)

24 AUCTAU Num 8 178 AUC to 12 hours (hr·units)

30 CLORAL Num 8 226 Oral clearance (mL/min)

25 CMAX Num 8 186 Maximum concentration (units)

20 CONCA Num 8 146 Plasma concentration (units)

35 CP12 Num 8 253 Conc just before PM dose (units)

34 CPPRE Num 8 245 Conc just before AM dose (units)

27 CPRE Num 8 202 Predose concentration in profile (units)

13 DELTATM Num 8 95 HHMM7. Time Difference From Dose to Sample

12 DIFF Num 8 87 HHMM7. Difference From Scheduled To Actual Time

28 KEL Num 8 210 Elimination rate constant (1/hr)

21 LOQ Num 8 154 Lower limit of quantifiability (Units)

11 NBLDDTE Num 8 79 MMDDYY10. Date Blood Drawn (numeric)

10 NBLDTME Num 8 71 TIME5. Actual Time Blood Drawn (numeric)

15 NDOSEDTE Num 8 111 MMDDYY10. Dose Date (numeric)

16 NDOSETME Num 8 119 TIME5. Dose Time (numeric)

14 PKDAY Num 8 103 Day of first dose of profile

$1$DKB1:[GRAHAMR.PKCLASS]PRINTPK.SAS

[grahamr.fk96001.data.bio]plasma 18:07 Wednesday, March 24, 1999 2

CONTENTS PROCEDURE

# Variable Type Len Pos Format Label

------

31 PKFLAG Char 4 234 Regression flag for observation

5 RACE Char 2 25 Race

19 SCHEDTIM Num 8 138 Scheduled time from dosing (hrs)

6 SCREENDT Num 8 27 MMDDYY10. Screening Date

4 SEX Char 2 23 Sex

8 STDYDAY Num 8 43 Study Day

1 SUBNO Char 3 0 Subject Number

29 T12 Num 8 218 Terminal half-life (hr)

3 TERMDT Num 8 15 MMDDYY10. Date of Study Termination

9 TIMEPT Char 20 51 Time Point

26 TMAX Num 8 194 Time of maximum concentration (hr)

2 TREAT Char 12 3 Treatment

18 UNITS Char 6 132 Concentration units

32 WEIGHT Char 5 238 Weight (lbs)

-----Sort Information-----

Sortedby: ANALYTE SUBNO TREAT PKDAY SCHEDTIM

Validated: YES

Character Set: ASCII

$1$DKB1:[GRAHAMR.PKCLASS]PRINTPK.SAS

[grahamr.fk96001.data.bio]plasma 18:07 Wednesday, March 24, 1999 3

OBS ANALYTE SUBNO DAY TIMEPT SCHEDTIM CONCA PKDAY NBLDDTE NBLDTME NDOSEDTE NDOSETME DELTATM DIFF

1 AAP 001 1 PREDOSE -672.0 0.000 1 09/09/1998 6:35 09/09/1998 7:00 -0:25 -0:25

2 AAP 001 2 PREDOSE -648.0 200.540 2 09/10/1998 6:35 09/10/1998 7:00 -0:25 -0:25

3 AAP 001 3 PREDOSE -624.0 275.390 3 09/11/1998 6:35 09/11/1998 7:00 -0:25 -0:25

4 AAP 001 4 PREDOSE -600.0 302.420 4 09/12/1998 6:35 09/12/1998 7:00 -0:25 -0:25

5 AAP 001 5 PREDOSE -576.0 273.220 5 09/13/1998 6:35 09/13/1998 7:00 -0:25 -0:25

6 AAP 001 6 PREDOSE -552.0 282.400 6 09/14/1998 6:35 09/14/1998 7:00 -0:25 -0:25

7 AAP 001 8 PREDOSE -504.0 283.210 8 09/16/1998 6:35 09/16/1998 7:00 -0:25 -0:25

8 AAP 001 9 PREDOSE -480.0 275.140 9 09/17/1998 6:35 09/17/1998 7:00 -0:25 -0:25

9 AAP 001 10 PREDOSE -456.0 271.000 10 09/18/1998 6:35 09/18/1998 7:00 -0:25 -0:25

10 AAP 001 15 PREDOSE -336.0 272.780 15 09/23/1998 6:35 09/23/1998 7:00 -0:25 -0:25

11 AAP 001 16 PREDOSE -312.0 282.230 16 09/24/1998 6:35 09/24/1998 7:00 -0:25 -0:25

12 AAP 001 17 PREDOSE -288.0 291.250 17 09/25/1998 6:35 09/25/1998 7:00 -0:25 -0:25

13 AAP 001 22 PREDOSE -168.0 305.430 22 09/30/1998 6:35 09/30/1998 7:00 -0:25 -0:25

14 AAP 001 29 PREDOSE 0.0 258.050 29 10/07/1998 6:35 10/07/1998 7:00 -0:25 -0:25

15 AAP 001 29 0.5 HOUR 0.5 260.260 29 10/07/1998 7:30 10/07/1998 7:00 0:30 0:00

16 AAP 001 29 1 HOUR 1.0 277.810 29 10/07/1998 8:00 10/07/1998 7:00 1:00 0:00

17 AAP 001 29 2 HOUR 2.0 309.870 29 10/07/1998 9:00 10/07/1998 7:00 2:00 0:00

18 AAP 001 29 3 HOUR 3.0 326.740 29 10/07/1998 10:00 10/07/1998 7:00 3:00 0:00

19 AAP 001 29 4 HOUR 4.0 335.900 29 10/07/1998 11:00 10/07/1998 7:00 4:00 0:00

20 AAP 001 29 8 HOUR 8.0 325.690 29 10/07/1998 15:00 10/07/1998 7:00 8:00 0:00

21 AAP 001 29 12 HOUR 12.0 291.990 29 10/07/1998 18:35 10/07/1998 7:00 11:35 -0:25

22 AAP 001 30 24 HOUR 24.0 147.230 29 10/08/1998 7:00 10/07/1998 7:00 24:00 0:00

23 AAP 001 30 36 HOUR 36.0 53.500 29 10/08/1998 19:00 10/07/1998 7:00 36:00 0:00

24 AAP 001 31 48 HOUR 48.0 24.300 29 10/09/1998 7:00 10/07/1998 7:00 48:00 0:00

25 AAP 002 1 PREDOSE -672.0 0.000 1 09/09/1998 6:38 09/09/1998 7:03 -0:25 -0:25

26 AAP 002 2 PREDOSE -648.0 53.380 2 09/10/1998 6:38 09/10/1998 7:03 -0:25 -0:25

27 AAP 002 3 PREDOSE -624.0 62.370 3 09/11/1998 6:38 09/11/1998 7:03 -0:25 -0:25

28 AAP 002 4 PREDOSE -600.0 63.940 4 09/12/1998 6:38 09/12/1998 7:09 -0:31 -0:31

29 AAP 002 5 PREDOSE -576.0 78.980 5 09/13/1998 6:39 09/13/1998 7:03 -0:24 -0:24

30 AAP 002 6 PREDOSE -552.0 73.470 6 09/14/1998 6:41 09/14/1998 7:03 -0:22 -0:22

31 AAP 002 8 PREDOSE -504.0 57.680 8 09/16/1998 6:38 09/16/1998 7:03 -0:25 -0:25

32 AAP 002 9 PREDOSE -480.0 60.620 9 09/17/1998 6:38 09/17/1998 7:03 -0:25 -0:25

33 AAP 002 10 PREDOSE -456.0 54.070 10 09/18/1998 6:38 09/18/1998 7:03 -0:25 -0:25

34 AAP 002 15 PREDOSE -336.0 61.870 15 09/23/1998 6:38 09/23/1998 7:03 -0:25 -0:25

35 AAP 002 16 PREDOSE -312.0 67.280 16 09/24/1998 6:38 09/24/1998 7:03 -0:25 -0:25

36 AAP 002 17 PREDOSE -288.0 63.300 17 09/25/1998 6:38 09/25/1998 7:03 -0:25 -0:25

37 AAP 002 22 PREDOSE -168.0 65.070 22 09/30/1998 6:38 09/30/1998 7:03 -0:25 -0:25

38 AAP 002 29 PREDOSE 0.0 67.400 29 10/07/1998 6:38 10/07/1998 7:03 -0:25 -0:25

39 AAP 002 29 0.5 HOUR 0.5 62.870 29 10/07/1998 7:33 10/07/1998 7:03 0:30 0:00

40 AAP 002 29 1 HOUR 1.0 62.960 29 10/07/1998 8:03 10/07/1998 7:03 1:00 0:00

41 AAP 002 29 2 HOUR 2.0 61.900 29 10/07/1998 9:03 10/07/1998 7:03 2:00 0:00

42 AAP 002 29 3 HOUR 3.0 77.000 29 10/07/1998 10:03 10/07/1998 7:03 3:00 0:00

43 AAP 002 29 4 HOUR 4.0 75.410 29 10/07/1998 11:03 10/07/1998 7:03 4:00 0:00

44 AAP 002 29 8 HOUR 8.0 75.400 29 10/07/1998 15:03 10/07/1998 7:03 8:00 0:00

45 AAP 002 29 12 HOUR 12.0 63.430 29 10/07/1998 18:38 10/07/1998 7:03 11:35 -0:25

46 AAP 002 30 24 HOUR 24.0 24.780 29 10/08/1998 7:03 10/07/1998 7:03 24:00 0:00

$1$DKB1:[GRAHAMR.PKCLASS]PRINTPK.SAS

[grahamr.fk96001.data.bio]plasma 18:07 Wednesday, March 24, 1999 4

OBS ANALYTE SUBNO DAY TIMEPT SCHEDTIM CONCA PKDAY NBLDDTE NBLDTME NDOSEDTE NDOSETME DELTATM DIFF

47 AAP 002 30 36 HOUR 36.0 0.000 29 10/08/1998 19:03 10/07/1998 7:03 36:00 0:00

48 AAP 002 31 48 HOUR 48.0 0.000 29 10/09/1998 7:03 10/07/1998 7:03 48:00 0:00

49 FK960 001 1 PREDOSE 0.0 0.000 1 09/09/1998 6:35 09/09/1998 7:00 -0:25 -0:25

50 FK960 001 1 0.5 HOUR 0.5 0.000 1 09/09/1998 7:30 09/09/1998 7:00 0:30 0:00

51 FK960 001 1 1 HOUR 1.0 1.154 1 09/09/1998 8:00 09/09/1998 7:00 1:00 0:00

52 FK960 001 1 2 HOUR 2.0 4.045 1 09/09/1998 9:00 09/09/1998 7:00 2:00 0:00

53 FK960 001 1 3 HOUR 3.0 4.324 1 09/09/1998 10:00 09/09/1998 7:00 3:00 0:00

54 FK960 001 1 4 HOUR 4.0 3.101 1 09/09/1998 11:00 09/09/1998 7:00 4:00 0:00

55 FK960 001 1 8 HOUR 8.0 2.368 1 09/09/1998 15:00 09/09/1998 7:00 8:00 0:00

56 FK960 001 1 12 HOUR 12.0 1.575 1 09/09/1998 18:35 09/09/1998 7:00 11:35 -0:25

57 FK960 001 4 PREDOSE -48.0 2.100 4 09/12/1998 6:35 09/12/1998 7:00 -0:25 -0:25

58 FK960 001 4 PREDOSE -24.0 2.215 4 09/12/1998 6:35 09/12/1998 7:00 -0:25 -0:25

59 FK960 001 4 PREDOSE 0.0 2.039 4 09/12/1998 6:35 09/12/1998 7:00 -0:25 -0:25

60 FK960 001 4 0.5 HOUR 0.5 3.386 4 09/12/1998 7:30 09/12/1998 7:00 0:30 0:00

61 FK960 001 4 1 HOUR 1.0 6.217 4 09/12/1998 8:00 09/12/1998 7:00 1:00 0:00

62 FK960 001 4 2 HOUR 2.0 5.653 4 09/12/1998 9:00 09/12/1998 7:00 2:00 0:00

63 FK960 001 4 3 HOUR 3.0 4.873 4 09/12/1998 10:00 09/12/1998 7:00 3:00 0:00

64 FK960 001 4 4 HOUR 4.0 4.394 4 09/12/1998 11:00 09/12/1998 7:00 4:00 0:00

65 FK960 001 4 8 HOUR 8.0 2.549 4 09/12/1998 15:00 09/12/1998 7:00 8:00 0:00

66 FK960 001 4 12 HOUR 12.0 1.960 4 09/12/1998 18:35 09/12/1998 7:00 11:35 -0:25

67 FK960 001 8 PREDOSE -48.0 2.640 8 09/16/1998 6:35 09/16/1998 7:00 -0:25 -0:25

68 FK960 001 8 PREDOSE -24.0 2.214 8 09/16/1998 6:35 09/16/1998 7:00 -0:25 -0:25

69 FK960 001 8 PREDOSE 0.0 2.363 8 09/16/1998 6:35 09/16/1998 7:00 -0:25 -0:25

70 FK960 001 8 0.5 HOUR 0.5 2.014 8 09/16/1998 7:30 09/16/1998 7:00 0:30 0:00

71 FK960 001 8 1 HOUR 1.0 4.633 8 09/16/1998 8:00 09/16/1998 7:00 1:00 0:00

72 FK960 001 8 2 HOUR 2.0 6.162 8 09/16/1998 9:00 09/16/1998 7:00 2:00 0:00

73 FK960 001 8 3 HOUR 3.0 5.275 8 09/16/1998 10:00 09/16/1998 7:00 3:00 0:00

74 FK960 001 8 4 HOUR 4.0 4.486 8 09/16/1998 11:00 09/16/1998 7:00 4:00 0:00

75 FK960 001 8 8 HOUR 8.0 3.159 8 09/16/1998 15:00 09/16/1998 7:00 8:00 0:00

76 FK960 001 8 12 HOUR 12.0 1.985 8 09/16/1998 18:35 09/16/1998 7:00 11:35 -0:25

77 FK960 001 15 PREDOSE -48.0 1.812 15 09/23/1998 6:35 09/23/1998 7:00 -0:25 -0:25

78 FK960 001 15 PREDOSE -24.0 2.137 15 09/23/1998 6:35 09/23/1998 7:00 -0:25 -0:25

79 FK960 001 15 PREDOSE 0.0 2.073 15 09/23/1998 6:35 09/23/1998 7:00 -0:25 -0:25

80 FK960 001 15 0.5 HOUR 0.5 1.884 15 09/23/1998 7:30 09/23/1998 7:00 0:30 0:00

81 FK960 001 15 1 HOUR 1.0 2.776 15 09/23/1998 8:00 09/23/1998 7:00 1:00 0:00

82 FK960 001 15 2 HOUR 2.0 5.954 15 09/23/1998 9:00 09/23/1998 7:00 2:00 0:00

83 FK960 001 15 3 HOUR 3.0 5.333 15 09/23/1998 10:00 09/23/1998 7:00 3:00 0:00

84 FK960 001 15 4 HOUR 4.0 5.276 15 09/23/1998 11:00 09/23/1998 7:00 4:00 0:00

85 FK960 001 15 8 HOUR 8.0 3.040 15 09/23/1998 15:00 09/23/1998 7:00 8:00 0:00

86 FK960 001 15 12 HOUR 12.0 1.915 15 09/23/1998 18:35 09/23/1998 7:00 11:35 -0:25

87 FK960 001 29 PREDOSE -312.0 2.106 29 10/07/1998 6:35 10/07/1998 7:00 -0:25 -0:25

88 FK960 001 29 PREDOSE -288.0 1.942 29 10/07/1998 6:35 10/07/1998 7:00 -0:25 -0:25

89 FK960 001 29 PREDOSE -168.0 2.127 29 10/07/1998 6:35 10/07/1998 7:00 -0:25 -0:25

90 FK960 001 29 PREDOSE 0.0 2.113 29 10/07/1998 6:35 10/07/1998 7:00 -0:25 -0:25

91 FK960 001 29 0.5 HOUR 0.5 1.894 29 10/07/1998 7:30 10/07/1998 7:00 0:30 0:00

92 FK960 001 29 1 HOUR 1.0 4.477 29 10/07/1998 8:00 10/07/1998 7:00 1:00 0:00

$1$DKB1:[GRAHAMR.PKCLASS]PRINTPK.SAS

[grahamr.fk96001.data.bio]plasma 18:07 Wednesday, March 24, 1999 5

OBS ANALYTE SUBNO DAY TIMEPT SCHEDTIM CONCA PKDAY NBLDDTE NBLDTME NDOSEDTE NDOSETME DELTATM DIFF

93 FK960 001 29 2 HOUR 2.0 6.080 29 10/07/1998 9:00 10/07/1998 7:00 2:00 0:00

94 FK960 001 29 3 HOUR 3.0 5.618 29 10/07/1998 10:00 10/07/1998 7:00 3:00 0:00

95 FK960 001 29 4 HOUR 4.0 4.026 29 10/07/1998 11:00 10/07/1998 7:00 4:00 0:00

96 FK960 001 29 8 HOUR 8.0 3.361 29 10/07/1998 15:00 10/07/1998 7:00 8:00 0:00

97 FK960 001 29 12 HOUR 12.0 2.047 29 10/07/1998 18:35 10/07/1998 7:00 11:35 -0:25

98 FK960 001 30 24 HOUR 24.0 0.709 29 10/08/1998 7:00 10/07/1998 7:00 24:00 0:00

99 FK960 001 30 36 HOUR 36.0 0.172 29 10/08/1998 19:00 10/07/1998 7:00 36:00 0:00

100 FK960 001 31 48 HOUR 48.0 0.057 29 10/09/1998 7:00 10/07/1998 7:00 48:00 0:00

101 FK960 002 1 PREDOSE 0.0 0.000 1 09/09/1998 6:38 09/09/1998 7:03 -0:25 -0:25

102 FK960 002 1 0.5 HOUR 0.5 0.166 1 09/09/1998 7:33 09/09/1998 7:03 0:30 0:00

103 FK960 002 1 1 HOUR 1.0 0.407 1 09/09/1998 8:03 09/09/1998 7:03 1:00 0:00

104 FK960 002 1 2 HOUR 2.0 1.678 1 09/09/1998 9:05 09/09/1998 7:03 2:02 0:02

105 FK960 002 1 3 HOUR 3.0 1.006 1 09/09/1998 10:03 09/09/1998 7:03 3:00 0:00

106 FK960 002 1 4 HOUR 4.0 0.974 1 09/09/1998 11:03 09/09/1998 7:03 4:00 0:00

107 FK960 002 1 8 HOUR 8.0 0.656 1 09/09/1998 15:03 09/09/1998 7:03 8:00 0:00

108 FK960 002 1 12 HOUR 12.0 0.406 1 09/09/1998 18:40 09/09/1998 7:03 11:37 -0:23

109 FK960 002 4 PREDOSE -48.0 0.553 4 09/12/1998 6:38 09/12/1998 7:09 -0:31 -0:31

110 FK960 002 4 PREDOSE -24.0 0.503 4 09/12/1998 6:38 09/12/1998 7:09 -0:31 -0:31

111 FK960 002 4 PREDOSE 0.0 0.628 4 09/12/1998 6:38 09/12/1998 7:09 -0:31 -0:31

112 FK960 002 4 0.5 HOUR 0.5 0.632 4 09/12/1998 7:39 09/12/1998 7:09 0:30 0:00

113 FK960 002 4 1 HOUR 1.0 0.913 4 09/12/1998 8:16 09/12/1998 7:09 1:07 0:07

114 FK960 002 4 2 HOUR 2.0 1.079 4 09/12/1998 9:09 09/12/1998 7:09 2:00 0:00

115 FK960 002 4 3 HOUR 3.0 1.095 4 09/12/1998 10:09 09/12/1998 7:09 3:00 0:00

116 FK960 002 4 4 HOUR 4.0 1.430 4 09/12/1998 11:09 09/12/1998 7:09 4:00 0:00

117 FK960 002 4 8 HOUR 8.0 0.915 4 09/12/1998 15:11 09/12/1998 7:09 8:02 0:02

118 FK960 002 4 12 HOUR 12.0 0.582 4 09/12/1998 18:44 09/12/1998 7:09 11:35 -0:25

119 FK960 002 8 PREDOSE -48.0 0.665 8 09/16/1998 6:38 09/16/1998 7:03 -0:25 -0:25

120 FK960 002 8 PREDOSE -24.0 0.669 8 09/16/1998 6:38 09/16/1998 7:03 -0:25 -0:25

121 FK960 002 8 PREDOSE 0.0 0.532 8 09/16/1998 6:38 09/16/1998 7:03 -0:25 -0:25

122 FK960 002 8 0.5 HOUR 0.5 0.544 8 09/16/1998 7:33 09/16/1998 7:03 0:30 0:00

123 FK960 002 8 1 HOUR 1.0 1.028 8 09/16/1998 8:03 09/16/1998 7:03 1:00 0:00

124 FK960 002 8 2 HOUR 2.0 1.605 8 09/16/1998 9:03 09/16/1998 7:03 2:00 0:00

125 FK960 002 8 3 HOUR 3.0 1.903 8 09/16/1998 10:03 09/16/1998 7:03 3:00 0:00

126 FK960 002 8 4 HOUR 4.0 2.926 8 09/16/1998 11:03 09/16/1998 7:03 4:00 0:00

127 FK960 002 8 8 HOUR 8.0 0.891 8 09/16/1998 15:03 09/16/1998 7:03 8:00 0:00

128 FK960 002 8 12 HOUR 12.0 0.490 8 09/16/1998 18:38 09/16/1998 7:03 11:35 -0:25

129 FK960 002 15 PREDOSE -48.0 0.608 15 09/23/1998 6:38 09/23/1998 7:03 -0:25 -0:25

130 FK960 002 15 PREDOSE -24.0 0.534 15 09/23/1998 6:38 09/23/1998 7:03 -0:25 -0:25

131 FK960 002 15 PREDOSE 0.0 0.436 15 09/23/1998 6:38 09/23/1998 7:03 -0:25 -0:25

132 FK960 002 15 0.5 HOUR 0.5 0.587 15 09/23/1998 7:33 09/23/1998 7:03 0:30 0:00

133 FK960 002 15 1 HOUR 1.0 0.768 15 09/23/1998 8:03 09/23/1998 7:03 1:00 0:00

134 FK960 002 15 2 HOUR 2.0 1.340 15 09/23/1998 9:03 09/23/1998 7:03 2:00 0:00

135 FK960 002 15 3 HOUR 3.0 1.459 15 09/23/1998 10:03 09/23/1998 7:03 3:00 0:00

136 FK960 002 15 4 HOUR 4.0 1.426 15 09/23/1998 11:03 09/23/1998 7:03 4:00 0:00

137 FK960 002 15 8 HOUR 8.0 0.862 15 09/23/1998 15:03 09/23/1998 7:03 8:00 0:00

138 FK960 002 15 12 HOUR 12.0 0.528 15 09/23/1998 18:38 09/23/1998 7:03 11:35 -0:25

$1$DKB1:[GRAHAMR.PKCLASS]PRINTPK.SAS

[grahamr.fk96001.data.bio]plasma 18:07 Wednesday, March 24, 1999 6

OBS ANALYTE SUBNO DAY TIMEPT SCHEDTIM CONCA PKDAY NBLDDTE NBLDTME NDOSEDTE NDOSETME DELTATM DIFF

139 FK960 002 29 PREDOSE -312.0 0.707 29 10/07/1998 6:38 10/07/1998 7:03 -0:25 -0:25

140 FK960 002 29 PREDOSE -288.0 0.614 29 10/07/1998 6:38 10/07/1998 7:03 -0:25 -0:25

141 FK960 002 29 PREDOSE -168.0 0.640 29 10/07/1998 6:38 10/07/1998 7:03 -0:25 -0:25

142 FK960 002 29 PREDOSE 0.0 0.562 29 10/07/1998 6:38 10/07/1998 7:03 -0:25 -0:25

143 FK960 002 29 0.5 HOUR 0.5 0.667 29 10/07/1998 7:33 10/07/1998 7:03 0:30 0:00

144 FK960 002 29 1 HOUR 1.0 0.909 29 10/07/1998 8:03 10/07/1998 7:03 1:00 0:00

145 FK960 002 29 2 HOUR 2.0 1.176 29 10/07/1998 9:03 10/07/1998 7:03 2:00 0:00

146 FK960 002 29 3 HOUR 3.0 1.624 29 10/07/1998 10:03 10/07/1998 7:03 3:00 0:00

147 FK960 002 29 4 HOUR 4.0 1.367 29 10/07/1998 11:03 10/07/1998 7:03 4:00 0:00

148 FK960 002 29 8 HOUR 8.0 0.906 29 10/07/1998 15:03 10/07/1998 7:03 8:00 0:00

149 FK960 002 29 12 HOUR 12.0 0.691 29 10/07/1998 18:38 10/07/1998 7:03 11:35 -0:25

150 FK960 002 30 24 HOUR 24.0 0.193 29 10/08/1998 7:03 10/07/1998 7:03 24:00 0:00

151 FK960 002 30 36 HOUR 36.0 0.000 29 10/08/1998 19:03 10/07/1998 7:03 36:00 0:00

152 FK960 002 31 48 HOUR 48.0 0.000 29 10/09/1998 7:03 10/07/1998 7:03 48:00 0:00

153 PFH 001 1 PREDOSE -672.0 0.000 1 09/09/1998 6:35 09/09/1998 7:00 -0:25 -0:25

154 PFH 001 2 PREDOSE -648.0 65.900 2 09/10/1998 6:35 09/10/1998 7:00 -0:25 -0:25

155 PFH 001 3 PREDOSE -624.0 69.300 3 09/11/1998 6:35 09/11/1998 7:00 -0:25 -0:25

156 PFH 001 4 PREDOSE -600.0 69.900 4 09/12/1998 6:35 09/12/1998 7:00 -0:25 -0:25

157 PFH 001 5 PREDOSE -576.0 64.600 5 09/13/1998 6:35 09/13/1998 7:00 -0:25 -0:25

158 PFH 001 6 PREDOSE -552.0 72.700 6 09/14/1998 6:35 09/14/1998 7:00 -0:25 -0:25

159 PFH 001 8 PREDOSE -504.0 68.100 8 09/16/1998 6:35 09/16/1998 7:00 -0:25 -0:25

160 PFH 001 9 PREDOSE -480.0 58.300 9 09/17/1998 6:35 09/17/1998 7:00 -0:25 -0:25

161 PFH 001 10 PREDOSE -456.0 60.900 10 09/18/1998 6:35 09/18/1998 7:00 -0:25 -0:25

162 PFH 001 15 PREDOSE -336.0 62.300 15 09/23/1998 6:35 09/23/1998 7:00 -0:25 -0:25

163 PFH 001 16 PREDOSE -312.0 71.300 16 09/24/1998 6:35 09/24/1998 7:00 -0:25 -0:25

164 PFH 001 17 PREDOSE -288.0 74.400 17 09/25/1998 6:35 09/25/1998 7:00 -0:25 -0:25

165 PFH 001 22 PREDOSE -168.0 68.900 22 09/30/1998 6:35 09/30/1998 7:00 -0:25 -0:25

166 PFH 001 29 PREDOSE 0.0 67.600 29 10/07/1998 6:35 10/07/1998 7:00 -0:25 -0:25

167 PFH 001 29 0.5 HOUR 0.5 58.800 29 10/07/1998 7:30 10/07/1998 7:00 0:30 0:00

168 PFH 001 29 1 HOUR 1.0 107.400 29 10/07/1998 8:00 10/07/1998 7:00 1:00 0:00

169 PFH 001 29 2 HOUR 2.0 158.100 29 10/07/1998 9:00 10/07/1998 7:00 2:00 0:00

170 PFH 001 29 3 HOUR 3.0 163.300 29 10/07/1998 10:00 10/07/1998 7:00 3:00 0:00

171 PFH 001 29 4 HOUR 4.0 149.400 29 10/07/1998 11:00 10/07/1998 7:00 4:00 0:00

172 PFH 001 29 8 HOUR 8.0 82.600 29 10/07/1998 15:00 10/07/1998 7:00 8:00 0:00

173 PFH 001 29 12 HOUR 12.0 59.600 29 10/07/1998 18:35 10/07/1998 7:00 11:35 -0:25

174 PFH 001 30 24 HOUR 24.0 0.000 29 10/08/1998 7:00 10/07/1998 7:00 24:00 0:00

175 PFH 001 30 36 HOUR 36.0 0.000 29 10/08/1998 19:00 10/07/1998 7:00 36:00 0:00

176 PFH 001 31 48 HOUR 48.0 0.000 29 10/09/1998 7:00 10/07/1998 7:00 48:00 0:00

177 PFH 002 1 PREDOSE -672.0 0.000 1 09/09/1998 6:38 09/09/1998 7:03 -0:25 -0:25

178 PFH 002 2 PREDOSE -648.0 0.000 2 09/10/1998 6:38 09/10/1998 7:03 -0:25 -0:25

179 PFH 002 3 PREDOSE -624.0 0.000 3 09/11/1998 6:38 09/11/1998 7:03 -0:25 -0:25

180 PFH 002 4 PREDOSE -600.0 0.000 4 09/12/1998 6:38 09/12/1998 7:09 -0:31 -0:31

181 PFH 002 5 PREDOSE -576.0 0.000 5 09/13/1998 6:39 09/13/1998 7:03 -0:24 -0:24

182 PFH 002 6 PREDOSE -552.0 0.000 6 09/14/1998 6:41 09/14/1998 7:03 -0:22 -0:22

183 PFH 002 8 PREDOSE -504.0 0.000 8 09/16/1998 6:38 09/16/1998 7:03 -0:25 -0:25

184 PFH 002 9 PREDOSE -480.0 0.000 9 09/17/1998 6:38 09/17/1998 7:03 -0:25 -0:25

$1$DKB1:[GRAHAMR.PKCLASS]PRINTPK.SAS

[grahamr.fk96001.data.bio]plasma 18:07 Wednesday, March 24, 1999 7

OBS ANALYTE SUBNO DAY TIMEPT SCHEDTIM CONCA PKDAY NBLDDTE NBLDTME NDOSEDTE NDOSETME DELTATM DIFF

185 PFH 002 10 PREDOSE -456.0 0.000 10 09/18/1998 6:38 09/18/1998 7:03 -0:25 -0:25

186 PFH 002 15 PREDOSE -336.0 0.000 15 09/23/1998 6:38 09/23/1998 7:03 -0:25 -0:25

187 PFH 002 16 PREDOSE -312.0 0.000 16 09/24/1998 6:38 09/24/1998 7:03 -0:25 -0:25

188 PFH 002 17 PREDOSE -288.0 0.000 17 09/25/1998 6:38 09/25/1998 7:03 -0:25 -0:25

189 PFH 002 22 PREDOSE -168.0 0.000 22 09/30/1998 6:38 09/30/1998 7:03 -0:25 -0:25

190 PFH 002 29 PREDOSE 0.0 0.000 29 10/07/1998 6:38 10/07/1998 7:03 -0:25 -0:25

191 PFH 002 29 0.5 HOUR 0.5 0.000 29 10/07/1998 7:33 10/07/1998 7:03 0:30 0:00

192 PFH 002 29 1 HOUR 1.0 0.000 29 10/07/1998 8:03 10/07/1998 7:03 1:00 0:00

193 PFH 002 29 2 HOUR 2.0 0.000 29 10/07/1998 9:03 10/07/1998 7:03 2:00 0:00

194 PFH 002 29 3 HOUR 3.0 29.300 29 10/07/1998 10:03 10/07/1998 7:03 3:00 0:00

195 PFH 002 29 4 HOUR 4.0 34.000 29 10/07/1998 11:03 10/07/1998 7:03 4:00 0:00

196 PFH 002 29 8 HOUR 8.0 0.000 29 10/07/1998 15:03 10/07/1998 7:03 8:00 0:00

197 PFH 002 29 12 HOUR 12.0 0.000 29 10/07/1998 18:38 10/07/1998 7:03 11:35 -0:25

198 PFH 002 30 24 HOUR 24.0 0.000 29 10/08/1998 7:03 10/07/1998 7:03 24:00 0:00

199 PFH 002 30 36 HOUR 36.0 0.000 29 10/08/1998 19:03 10/07/1998 7:03 36:00 0:00

200 PFH 002 31 48 HOUR 48.0 0.000 29 10/09/1998 7:03 10/07/1998 7:03 48:00 0:00

\pkclass\definit.doc 1

CHECKING CREATED VARIABLES

CHECK OF SCHEDTIM

TIMEPT SCHEDTIM COUNT

0.5 HOUR 0.5 120

1 HOUR 1.0 120

12 HOUR 12.0 120

2 HOUR 2.0 120

24 HOUR 24.0 24

3 HOUR 3.0 120

36 HOUR 36.0 24

4 HOUR 4.0 120

48 HOUR 48.0 24

8 HOUR 8.0 120

PREDOSE 0.0 336

CHECK OF DELTATM

TIMEPT DELTATM COUNT

0.5 HOUR 0:30 157

0.5 HOUR 0:31 4

0.5 HOUR 0:32 4

0.5 HOUR 0:35 1

0.5 HOUR 0:44 1

0.5 HOUR 0:45 1

1 HOUR 1:00 158

1 HOUR 1:01 3

1 HOUR 1:02 1

1 HOUR 1:03 3

1 HOUR 1:04 1

1 HOUR 1:07 1

1 HOUR 1:08 1

12 HOUR 11:35 148

12 HOUR 11:36 5

12 HOUR 11:37 3

12 HOUR 11:38 1

12 HOUR 11:39 2

12 HOUR 11:40 3

12 HOUR 11:41 1

12 HOUR 11:42 3

12 HOUR 11:56 1

12 HOUR 12:03 1

2 HOUR 2:00 161

2 HOUR 2:01 1

2 HOUR 2:02 4

2 HOUR 2:03 1

2 HOUR 2:06 1

24 HOUR 24:00 57

24 HOUR 24:01 12

24 HOUR 24:06 3

3 HOUR 3:00 154

3 HOUR 3:01 5

3 HOUR 3:02 7

3 HOUR 3:03 2

36 HOUR 36:00 66

36 HOUR 36:01 3

36 HOUR 36:02 3

4 HOUR 3:52 3

4 HOUR 4:00 160

4 HOUR 4:01 1

4 HOUR 4:02 3

4 HOUR 4:03 1

48 HOUR 48:00 63
48 HOUR 48:03 3
48 HOUR 48:04 3
48 HOUR 48:05 3

8 HOUR 8:00 156

8 HOUR 8:01 5

8 HOUR 8:02 4

8 HOUR 8:03 2

8 HOUR 8:11 1

PREDOSE -1:36 3

PREDOSE -0:31 5

PREDOSE -0:29 5

PREDOSE -0:26 2

PREDOSE -0:25 866

PREDOSE -0:24 47

PREDOSE -0:23 29

PREDOSE -0:22 13

PREDOSE -0:21 16

PREDOSE -0:20 7

PREDOSE -0:19 9

PREDOSE -0:18 2

PREDOSE -0:15 2

PREDOSE -0:13 2

The SAS System 3

18:22 Wednesday, March 24, 1999

DISTRIBUTION OF DELTATM AT TIME=0

Univariate Procedure

Variable=DELTATM Time Difference From Dose to Sample

Moments

N 168 Sum Wgts 168

Mean -1514.29 Sum -254400

Std Dev 335.2728 Variance 112407.9

Skewness -12.2927 Kurtosis 156.5974

USS 4.0401E8 CSS 18772114

CV -22.1407 Std Mean 25.86686

T:Mean=0 -58.5415 Pr>|T| 0.0001

Num ^= 0 168 Num > 0 0

M(Sign) -84 Pr>=|M| 0.0001

Sgn Rank -7098 Pr>=|S| 0.0001

Quantiles(Def=5)

100% Max -1140 99% -1200

75% Q3 -1500 95% -1380

50% Med -1500 90% -1440

25% Q1 -1500 10% -1500

0% Min -5760 5% -1500

1% -1860

Range 4620

Q3-Q1 0

Mode -1500

Extremes

Lowest ID Highest ID

-5760(022 ) -1320(018 )

-1860(002 ) -1260(029 )

-1740(014 ) -1260(013 )

-1500(027 ) -1200(024 )

-1500(024 ) -1140(027 )

The SAS System 4

18:22 Wednesday, March 24, 1999

DISTRIBUTION OF DELTATM AT TIME=0

Univariate Procedure

Variable=DELTATM Time Difference From Dose to Sample

Histogram # Boxplot

-1100+* 2 *

.** 8 *

.*************************************** 155 +--*--+

.* 1 *

.* 1 *

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

-5700+* 1 *

----+----+----+----+----+----+----+----

* may represent up to 4 counts

The SAS System 6

18:22 Wednesday, March 24, 1999

DISTRIBUTION OF DIFFERENCE FROM SCHEDULED TIME FOR DELTATM > 0

Univariate Procedure

Variable=DIFF Difference From Scheduled To Actual Time

Moments

N 1392 Sum Wgts 1392

Mean -166.983 Sum -232440

Std Dev 486.6571 Variance 236835.2

Skewness -2.2838 Kurtosis 3.468428

USS 3.6825E8 CSS 3.2944E8

CV -291.442 Std Mean 13.04378

T:Mean=0 -12.8017 Pr>|T| 0.0001

Num ^= 0 260 Num > 0 90

M(Sign) -40 Pr>=|M| 0.0001

Sgn Rank -12844.5 Pr>=|S| 0.0001

Quantiles(Def=5)

100% Max 900 99% 240

75% Q3 0 95% 60

50% Med 0 90% 0

25% Q1 0 10% -1500

0% Min -1500 5% -1500

1% -1500

Range 2400

Q3-Q1 0

Mode 0

Extremes

Lowest ID Highest ID

-1500(032 ) 420(002 )

-1500(027 ) 480(006 )

-1500(024 ) 660(024 )

-1500(022 ) 840(029 )

-1500(018 ) 900(013 )

The SAS System 7

18:22 Wednesday, March 24, 1999

DISTRIBUTION OF DIFFERENCE FROM SCHEDULED TIME FOR DELTATM > 0

Univariate Procedure

Variable=DIFF Difference From Scheduled To Actual Time

Histogram # Boxplot

950+* 1 *

.* 1 *

.

.* 1 *

.

450+* 2 *

.* 8 *

.* 4 *

.** 39 *

.*********************************************** 1166 +--*--+

-50+

. +

.* 1 *

.

.* 3 *

-550+

.

.

.

.

-1050+* 3 *

.* 4 *

.* 2 *

.* 4 *

.******* 153 *

-1550+

----+----+----+----+----+----+----+----+----+--

* may represent up to 25 counts

\pkclass\definit.doc 1