Use of quantitative in vitro to in vivo extrapolation (QIVIVE) for the assessment of non-combustible next-generation product aerosols

Abstract

With the use of in vitro new approach methodologies (NAMs) for the assessment of non-combustible next-generation nicotine delivery products, new extrapolation methods will also be required to interpret and contextualize the physiological relevance of these results. Quantitative in vitro to in vivo extrapolation (QIVIVE) can translate in vitro concentrations into in-life exposures with physiologically-based pharmacokinetic (PBPK) modelling and provide estimates of the likelihood of harmful effects from expected exposures. A major challenge for evaluating inhalation toxicology is an accurate assessment of the delivered dose to the surface of the cells and the internalized dose. To estimate this, we ran the multiple-path particle dosimetry (MPPD) model to characterize particle deposition in the respiratory tract and developed a PBPK model for nicotine that was validated with human clinical trial data for cigarettes. Finally, we estimated a Human Equivalent Concentration (HEC) and predicted plasma concentrations based on the minimum effective concentration (MEC) derived after acute exposure of BEAS-2B cells to cigarette smoke (1R6F), or heated tobacco product (HTP) aerosol at the air liquid interface (ALI). The MPPD-PBPK model predicted the in vivo data from clinical studies within a factor of two, indicating good agreement as noted by WHO International Programme on Chemical Safety (2010) guidance. We then used QIVIVE to derive the exposure concentration (HEC) that matched the estimated in vitro deposition point of departure (POD) (MEC cigarette = 0.38 puffs or 11.6 µg nicotine, HTP = 22.9 puffs or 125.6 µg nicotine) and subsequently derived the equivalent human plasma concentrations. Results indicate that for the 1R6F cigarette, inhaling 1/6th of a stick would be required to induce the same effects observed in vitro, in vivo. Whereas, for HTP it would be necessary to consume 3 sticks simultaneously to induce in vivo the effects observed in vitro. This data further demonstrates the reduced physiological potency potential of HTP aerosol compared to cigarette smoke. The QIVIVE approach demonstrates great promise in assisting human health risk assessments, however, further optimization and standardization are required for the substantiation of a meaningful contribution to tobacco harm reduction by alternative nicotine delivery products.

Optimisation of an in vitro human cardiovascular model on-a-chip for toxicological assessment of nicotine delivery products

“…However, it must be noted that use of multiple nicotine products during the day may increase nicotine exposure and is product and user topography dependent, for example, as seen with ENDS ( Jacobson et al, 2020 ). A recent in vitro to in vivo extrapolation study by Moreau et al (2024) predicted that due to rapid nicotine elimination, following the use of 10 cigarettes or HTP sticks, a steady state of nicotine is still only approximately double that observed following the use of one product. Therefore, the responses observed in this study are still to supraphysiological levels of nicotine exposure, the study has demonstrated that the co-culture system is responsive to nicotine delivery product extracts, and may act as a useful tool in screening for effects at physiological levels in future.…”

Image1.jpg

“…However, it must be noted that use of multiple nicotine products during the day may increase nicotine exposure and is product and user topography dependent, for example, as seen with ENDS (Jacobson et al, 2020). A recent in vitro to in vivo extrapolation study by Moreau et al (2024) predicted that due to rapid nicotine elimination, following the use of 10 cigarettes or HTP sticks, a steady state of nicotine is still only approximately double that observed following the use of one product. Therefore, the responses observed in this study are still to supraphysiological levels of nicotine exposure, the study has demonstrated that the co-culture system is responsive to nicotine delivery product extracts, and may act as a useful tool in screening for effects at physiological levels in future.…”