1. Converting Pharmacokinetic Data to the PP and PC Domains
Roger Landau
Principal Consultant, Lincoln Safety Group, Phase Forward
10 Sep 2009
Copyright © 2009 Phase Forward Incorporated. All rights reserved.

2. Introduction Support for Pharmacokinetic (PK) data new in SDTM 3.1.2
PK data combines
CRF timing variables
Lab findings
Derived data
Converting to SDTM can be difficult
Will present my recommendations
Interactive participation encouraged 2

3. Overview Typical Pharmacokinetic Data Workflow Logical Data Model
SDTM Data Model
Recommendations for converting data
Use of RELREC 3

4. Typical Pharmacokinetic Data Workflow
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5. PK Data Consists of two types of data
Concentration of drug or metabolite in bodily fluid/substance
Analyte – drug or metabolic product whose concentration is analyzed in biologic matrix
Parent compound or metabolite produced when body metabolizes compound
Biological Matrix – fluid or substance in a living being
Usually plasma or urine
Can also be feces, Cerebrospinal Fluid (CSF) 5

6. PK Data
PK Parameters
Derived values describing how a compound is metabolized by the body over time
T1/2: Half-life
AUC: Area Under the Curve
C Max: maximum concentration
T Max: time from drug administration to maximum concentration
Many others

7. Phase I Crossover Studies
PK analysis usually in phase I crossover studies.
Some studies only include concentration
No PK parameters
In each period/epoch:
Blood samples taken at many timepoints
Urine collected over several intervals 7

8. Typical PK Data Workflow
Issues:
Three different data sources
Three different departments
Three different systems
No data standards
Clinical DB Management System
Statistical Analysis
CRF Timepoints
Biostatistics
Merged Concentration Data
PK Parameters
Clinical Study Report
Concentration Results
WinNonLin
Pharmacokineticist
Bioanalytical Lab

9. Logical Data Model
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10. Logical Data Model Three entities Relationships Two SDTM domains
PC and PP
Relationships
CRF-Timepoints to Concentration
One-to-many
Concentration to PK Parameters
Many-to-many
Requires use of RELREC in SDTM

11. SDTM Data Model
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12. SDTM PK Data Model Two domains Both are Findings domains
PC – Concentration Data
PP – PK Parameters
Both are Findings domains
PC has more timing and qualifier variables
PC and PP related to one another
But relationship is complex

13. PC Domain
PCTEST – Represents analyte (Usually). Long, chemical names possible. Inconsistent spellings frequent. For urine samples, can contain diffferent info, e.g. specific gravity, total volume collected.
PCTESTCD – Will need to develop shortened versions of Analyte. Can be difficult for long names that are similar to one another
PCCAT – If PCTEST is an Analyte, then PCCAT = “ANALYTE”. If PCTEST is a urine descriptive variable, then PCCAT = “SPECIMEN PROPERTY”. PCCAT has very different meaning than PPCAT
PCGRPID – Use in conjunction with RELREC to relate PP to PC

14. PC Domain PCSPEC – Biological Matrix
PCSPCCND, PCSTAT – useful for relating PP to PC

15. PC Domain
PCTPT – Part of unique key for PC. Generally, VISITNUM and VISIT not as important in uniquely identifying timepoints in a crossover. PERIOD and TIMEPOINT are adequate
PCTPTREF – Generally is the first dose of the period. However, some studies can have multiple doses and profiles of samples within a period.
PCRFTDTC – Time in addition to date is critical for phase I crossovers.
PCENDTC – Used for urine collection where there is a stop and start. Should be null for blood samples.

16. PP Domain
PPCAT – In PP, represents Analyte. The same value represented by different types of variables in PP and PC PPCAT vs PCTEST
PPORRESU – Units for the same PK parameter can be different for different analytes. Some PK parameters do not have units e.g. No of points, r-squared

17. PP Domain
PPSPEC – Biological Matrix, same type of variable as in PC. Variable should probably be Required since it is part of unique key of PP

18. Recommendations for Converting PK Data
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19. Converting PK Data - Recommendations
Source Data
May be in different formats: XPT, XLS, TXT
May be one PK file per analyte
CRF Timepoint and Concentration may be in separate files
Merging/joining will probably not go smoothly
Accession number typos, missing records, etc.
Usually will need to join and/or concatenate datasets before converting
Analyte
Maps to different variables in PP and PC
Compound/metabolite names may be spelled inconsistently in different datasets

20. Converting PK Data - Recommendations
Units
Can be different for different analytes:
pg/ml
ng/ml
Some PK parameters don’t have units
No of points
R-squared
PK Parameter Test Codes
Develop library of PPTEST and PPTESTCD
Work with Pharmacokineticists
Encourage use of standard PPTESTCDs in WinNonLin

21. Converting PK Data - Recommendations
Status Flags
Useful for statistical analysis and relationship between PP and PC
Obtain flags in WinNonLin output indicating values not to be used in analysis
May be difficult to obtain due to WinNonLin shortcomings
Epoch
Include Epoch variable in PC and PP
Represents Period in crossover
Frequently included in source data

22. Relating PP to PC
Each PK Parameter in PP calculated from set of concentrations in PC
PP and PC can be joined to show related values
3.1.2 Implementation Guide
Analysis datasets may document relationship OR
RELREC used to represent how to join PP and PC
RELREC method will be discussed

23. IG – Section 6.3.10.5 Relating PP Records to PC Records
Reading this section of IG will either
Make you head spin
Put you to sleep

24. Logical Data Model Many-to-Many relationship
Each PK parameter calculated from several concentrations
Each Concentration used in the calculation of several PK parameters
RELREC provides data needed to perform many- to-many join

25. RELREC Can be used in one of two methods Relating Datasets (simpler)
Relating Records (more complex)

26. RELREC - Relating Datasets
Can only be used if:
For all subjects
All concentrations at all timepoints used for all PK parameters
PCGPRID, PPGRPID = Matrix + Analyte + Period
This situation usually doesn’t happen
Some values excluded
Acceptable if agreed that excluded values do not need to be identified in SDTM datasets

27. RELREC – Relating Records
Populate RELREC with records from both PP and PC
Use RELID to indicate related records
IG provides 4 examples (1, 2, 3, 4)
For each example, 4 possible methods (A, B, C, D) to populate RELREC
OMG!
Less would have been more

28. RELREC – Relating Records Recommendations
Only use Method A
Use PCGRPID and PPGRPID as IDVARs in RELREC
Set PPGRPID and PCGRPID to Matrix + Analyte + Period
PPGRPID = PPSPEC + PPCAT + EPOCH
PCGRPID = PCSPEC + PCTEST + EPOCH

29. RELREC – Relating Records Recommendations
Use example 2 method to indicate concentration values not used in PK parameter calculations.
Usually due to insufficient sample or subject vomited
Can be obtained from PCSPCCND and PCSTAT/PCREASND

30. RELREC – Relating Records Recommendations (cont’d)
Do not indicate concentration values not used to calculate particular PK parameters
Examples 3 and 4 in IG
Documents Pharmacokineticist’s analytical methods
Information in WinNonLin
Difficult to obtain and document
Not appropriate in SDTM tabulation datasets
Has any one used any of these methods?
Which method was used?
How did it work out?

31. Summary Converting PK data to PP and PC can be challenging
Source data from three different systems
PC and PP follow Findings model
Several complexities need to be taken into account
Recommendations listed for converting source data to SDTM
Relating PP to PC using RELREC
Use Method A and example 2 from IG
Complexities – Analyte variable different in PP and PC, PCTESTCDs abbreviate long chemical names,

32. Thank You roger.landau@phaseforward.com 32
© 2009 Phase Forward Incorporated. All rights reserved. 32