Altria Group, Inc. · NYSE:MO
Altria — CORESTA Smoke-Techno (SSPT) Conference 2021
12 slides from Altria's conference presentation, Oct 25, 2021
Slide 1: In Vitro to In Vivo Extrapolation (IVIVE) for Evaluating Exposure and Potential Health Impacts of E-Vapor Products
In Vitro to In Vivo Extrapolation (IVIVE) for Evaluating Exposure and Potential Health Impacts of E-Vapor Products J. Zhang1, X. Chang2, D. Hines2, S. Bell2, and K.M. Lee1 1 Altria Client Services LLC, Richmond, VA 23219 Center for Research and Technology 2 ILS, RTP, NC, United States CORESTA Smoke-
Slide 2: Outline
Outline • Background • Overview of the Approach • Results of a Case Study • Key Learning Altria Client Services | Regulatory Affairs | FINAL 2
Slide 3: Background
Background Preclinical Toxicity Testing Whole Animal In Vivo Dose-Response Chemical Risk Testing In Vitro Testing In Vitro Testing in Non- Human Cells In Vitro Testing in Human Cells Altria Client Services | Regulatory Affairs | FINAL
Slide 4: Background: A Case Study
Background: A Case Study • How much exposure in human could result in the cytotoxic concentrations in vivo approximating the in vitro? In Vitro IC50 “the concentrations of nicotine and some flavor chemicals … are Concentration-Response Curves high enough to be cytotoxic in acute in vitro assays, ...
Slide 5: Overview of the IVIVE Approach
Overview of the IVIVE Approach • In Vitro to In Vivo Extrapolation (IVIVE) is a computational approach that calculates an equivalent in vivo administered dose based on the in vitro response concentration. In Vitro IC50 from the In Vitro Assay ≈ Cmax in Plasma In vitro activity concentration (ACx) AC
Slide 6: Equivalent Administered Dose (EAD) Calculation for Mixtures
Equivalent Administered Dose (EAD) Calculation for Mixtures • Additional Assumptions for Mixtures • Only ingredients with provided analytical quantity are considered. • No interaction between ingredients • Additive effect • Equivalent Administered Dose (EAD) Mixture 𝐴𝐴𝐴𝐴50𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡…
Slide 7: Results – Estimated EADs Based on Mixture Cytotoxicity
Results – Estimated EADs Based on Mixture Cytotoxicity Based on the single cytotoxicity assay, a person • Nicotine + Flavor needs to consume a large quantity of the e-vapor • EADs Ranging from 1,000 – 4,000 products to get the toxic level in the plasma. mg/kg BW • Several thousands of pods per perso
Slide 8: Results – Estimated EADs Based on cHTS
Results – Estimated EADs Based on cHTS • Curated High Throughput Screening (HTS) • A single ingredient in the mixture drives the toxicity database 𝐸𝐸𝐸𝐸𝐸𝐸𝑖𝑖 𝐴𝐴𝐴𝐴 /𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝑖𝑖 • 𝐸𝐸𝐸𝐸𝐸𝐸𝑚𝑚𝑚𝑚𝑚𝑚−𝑖𝑖 = = 𝑖𝑖 ToxCast / Tox21 programs 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑖𝑖…
Slide 9: Results - Estimated EADs Based on cHTS Cytotoxicity
Results - Estimated EADs Based on cHTS Cytotoxicity • The same toxicity outcome: Cytotoxicity • Different weight factor: to obtain relative Cmax assuming the potency of ingredients is inversely proportional to AC50 • EAD 𝐴𝐴𝐴𝐴50𝑐𝑐 𝐸𝐸𝐸𝐸𝐸𝐸𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡_𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 =…
Slide 10: Conclusion and Opportunity
Conclusion and Opportunity • Fit-for-purpose IVIVE approaches demonstrated translation of in vitro data to in vivo human exposure. • In this case study, the EAD predictions were dependent on both the bioactivity of the chemical and the content levels in the mixture. • There are additional challenges
Slide 11: Questions?
Thank You Questions? Altria Client Services | Regulatory Affairs | FINAL
Slide 12: Abstract
Abstract In Vitro to In Vivo Extrapolation (IVIVE) uses reverse dosimetry to translate in vitro bioactivity data to clinically relevant exposure metrics. This study applies the IVIVE approach to e-vapor products using reported in vitro cytotoxicity data of the e-liquids and in vitro high-throughput
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