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

Practical session metabolites Part III: plenary discussion of results. Claude Beigel, PhD. Exposure Assessment Senior Scientist Research Triangle Park, USA. Results Example 1 Visual Evaluation of Goodness of fit (Parent + Metabolite1).

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

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  1. Practical session metabolites Part III: plenary discussion of results Claude Beigel, PhD. Exposure Assessment Senior Scientist Research Triangle Park, USA

  2. 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)

  5. 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

  6. 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 >1 (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)? • Let’s 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 

  7. Results Example 1Visual Evaluation of Goodness of fit (Parent + Met1 +Met2)

  8. Hands-on Example 1Visual Assessment (Parent + Met1 +Met2)

  9. Hands-on Example 1Statistical Indices (Parent + Met1 +Met2)

  10. 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

  11. Results Example 2Visual Evaluation of Goodness of fit (Parent FOMC)

  12. Hands-on Example 2, parent FOMCVisual Assessment

  13. Hands-on Example 2, parent FOMCStatistical Indices

  14. 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

  15. Results Example 2Visual Evaluation of Goodness of fit (Parent DFOP)

  16. Hands-on Example 2, Parent DFOPVisual Assessment

  17. Hands-on Example 2, Parent DFOPStatistical Indices

  18. 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)

  19. Results Example 2Visual Evaluation of Goodness of Fit (Metabolite Decline)

  20. Hands-on Example 2, Metabolite DeclineVisual Assessment

  21. Hands-on Example 2, Metabolite DeclineStatistical Indices

  22. 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)

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