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

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Thank You

roger.landau@phaseforward.com

© 2009 Phase Forward Incorporated. All rights reserved.