Claude Beigel, PhD'

1
Practical session metabolites Part III plenary
discussion of results

• Claude Beigel, PhD.
• Exposure Assessment Senior Scientist
• Research Triangle Park, USA

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Results Example 1Visual Evaluation of Goodness
of fit (Parent Metabolite1)
3
Hands-on Example 1Visual Assessment (Parent
Metabolite1)
4
Hands-on Example 1Statistical Indices (Parent
Metabolite1)
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Hands-on Example 1Conclusion and Endpoints
(Parent Metabolite1)

• SFO model is considered appropriate for both
  parent and metabolite
• Trigger endpoints for Metabolite 1
• DT50 6.8 d and DT90 22.6 d
• Modeling endpoints
• kP 0.0508 d-1 (equivalent to half-life of 13.7
  d), ffM1 0.5881 and kM1 0.1018 d-1 (equivalent
  to half-life of 6.8 d)
• kP_M 0.0299 d-1 (equivalent to half-life of
  23.2 d), kP_S 0.0209 d-1 (equivalent to
  half-life of 33.1 d), and kM1 0.1018 d-1
  (equivalent to half-life of 6.8 d)

or
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Hands-on Example 1Parent Metabolite1
Metabolite2

• Initial fit with flow from Metabolite 1 to sink
  results in formation fraction ffM2 of 0.98
  (stepwise fit, parent and M1 parameters fixed) or
  gt1 (simultaneous fit, all parameters free)
• The question is should we remove or keep this
  flow (does Metabolite 1 degrade exclusively to
  Metabolite 2, or does it form other metabolites
  and/or bound residues too)?
• Lets assume that additional information, e.g. a
  degradation study conducted with Metabolite 1
  also suggests 100 formation of Metabolite 2,
  ffM2 is fixed to 1, i.e. the flow from Metabolite
  1 to sink is removed

?
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Results Example 1Visual Evaluation of Goodness
of fit (Parent Met1 Met2)
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Hands-on Example 1Visual Assessment (Parent
Met1 Met2)
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Hands-on Example 1Statistical Indices (Parent
Met1 Met2)
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Hands-on Example 1Conclusion and Endpoints
(Parent Met1 Met2)

• SFO model is considered appropriate for parent
  and both metabolites
• Trigger endpoints
• Metabolite1 DT50 6.9 d and DT90 23.1 d
• Metabolite2 DT50 61.0 d and DT90 203 d
• Modeling endpoints
• kP 0.0507 d-1 (equivalent to half-life of 13.7
  d), ffM1 0.5813 and kM1 0.0999 d-1 (equivalent
  to half-life of 6.9 d), kM2 0.0114 d-1
  (equivalent to half-life of 61.0 d),
• kP_S 0.0212 d-1 (equivalent to half-life of
  32.7 d), kP_M 0.0295 d-1 (equivalent to
  half-life of 23.5 d), kM1_M2 0.0999 d-1
  (equivalent to half-life of 6.9 d), and kM2_S
  0.0114 d-1 (equivalent to half-life of 61.0 d)

or
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Results Example 2Visual Evaluation of Goodness
of fit (Parent FOMC)
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Hands-on Example 2, parent FOMCVisual Assessment

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Hands-on Example 2, parent FOMCStatistical
Indices
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Hands-on Example 2Conclusion and Trigger
Endpoints (Parent FOMC)

• SFO model is considered appropriate for
  metabolite in combination with FOMC model for
  parent
• Trigger endpoints for Metabolite
• DT50 34.7 d and DT90 115 d
• Endpoints for PEC soil calculations
• ?P 0.9425, ?P 4.436, ffM 0.8018 and kM
  0.0200 d-1

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Results Example 2Visual Evaluation of Goodness
of fit (Parent DFOP)
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Hands-on Example 2, Parent DFOPVisual Assessment

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Hands-on Example 2, Parent DFOPStatistical
Indices
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Hands-on Example 2Conclusion and Modeling
Endpoints (Parent DFOP)

• SFO model is considered appropriate for
  metabolite in combination with DFOP model for
  parent
• Modeling endpoints (higher Tier approach based on
  parent DFOP)
• g 0.5509, k1 0.3227 d-1 (equivalent to
  half-life of 2.15 d), k2 0.0340 d-1 (equivalent
  to half-life of 20.4 d), ffM 0.8332 and kM
  0.0216 d-1 (equivalent to half-life of 32.0 d)

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Results Example 2Visual Evaluation of Goodness
of Fit (Metabolite Decline)
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Hands-on Example 2, Metabolite DeclineVisual
Assessment
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Hands-on Example 2, Metabolite DeclineStatistical
Indices
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Hands-on Example 2Conclusion and Endpoints
(Metabolite Decline)

• SFO model is considered appropriate for
  metabolite decline
• Metabolite decline rate may be used as worst-case
  estimate for trigger endpoints
• Trigger endpoints DT50 49.7 d and DT90 165 d
  (compared to DT50 34.7 d and DT90 115 d from
  actual degradation rate)
• Decline rate may also be used as modeling
  endpoint for metabolite, if calculated from
  maximum observed
• Modeling endpoint kM 0.0139 d-1 (equivalent to
  half-life of 49.7 d)