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Copyright © 2009 Phase Forward Incorporated. All rights reserved.
Roger Landau
Principal Consultant, Lincoln Safety Group, Phase Forward10 Sep 2009
Converting Pharmacokinetic Data to the PP and PC Domains
IntroductionSupport for Pharmacokinetic (PK) data
new in SDTM 3.1.2PK data combines
•CRF timing variables
•Lab findings
•Derived data
Converting to SDTM can be difficult Will present my recommendations Interactive participation encouraged
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Overview
Typical Pharmacokinetic Data Workflow
Logical Data ModelSDTM Data ModelRecommendations for converting
data•Use of RELREC
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Typical Pharmacokinetic Data Workflow
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PK Data Consists of two types of data
1) 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)
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PK Data
2) 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
Phase I Crossover StudiesPK 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
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Typical PK Data Workflow
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Bioanalytical Lab
Clinical DB Management
System
Concentration Results
CRF Timepoints
Merged Concentration Data
Clinical Study Report
Statistical Analysis
Biostatistics
Pharmacokineticist
PK Parameters
WinNonLin
Issues: • Three different data sources• Three different departments• Three different systems• No data standards
Logical Data Model
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Logical Data Model
Three entities • 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
CRF Timepoints
PK Subject NoPK PeriodPK Timepoint
Date-Time Sample ID Sample Condition Not Done Vomited?
Concentration
PK Subject NoPK PeriodPK TimepointPK MatrixPK Analyte
Concentration Conc Units Exclude
PK Parameters
PK Subject NoPK PeriodPK MatrixPK AnalytePK PK Parameter
Value Units Exclude
SDTM Data Model
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SDTM PK Data Model
Two 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
PC Domain
PC Domain
PC Domain
PP Domain
PP Domain
Recommendations for Converting PK Data
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Converting PK Data - RecommendationsSource 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
Converting PK Data - RecommendationsUnits
• 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
Converting PK Data - RecommendationsStatus 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
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 relationshipOR• RELREC used to represent how to join PP and
PCRELREC method will be discussed
IG – Section 6.3.10.5
Relating PP Records to PC RecordsReading this section of IG will either
Make you head spin Put you to sleep
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
CRF Timepoints
PK Subject NoPK PeriodPK Timepoint
Date-Time Sample ID Sample Condition Not Done Vomited?
Concentration
PK Subject NoPK PeriodPK TimepointPK MatrixPK Analyte
Concentration Conc Units Exclude
PK Parameters
PK Subject NoPK PeriodPK MatrixPK AnalytePK PK Parameter
Value Units Exclude
RELREC
Can be used in one of two methods• Relating Datasets (simpler)• Relating Records (more complex)
RELREC - Relating DatasetsCan only be used if:
• For all subjects• All concentrations at all timepoints used for all PK
parametersPCGPRID, 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
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
RELREC – Relating RecordsRecommendations 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
RELREC – Relating RecordsRecommendations
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
RELREC – Relating RecordsRecommendations (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?
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
