Table 1.
Predictions of human PK parameters for oral nicotine obtained with two cohorts of multi-Organ Chip IVIVT platforms compared to clinical values and rodent clearance results.
| Nicotine PK Parameters (systemic compartment) |
Human (Clinical data)* | In Silico Model(Multi-Organ Chips) |
|---|---|---|
| Nicotine Gum (4.2 mg) | ||
| Cmax (μM) | 0.052 ±0.009 | 0.050 (δ=3,8 %, n.s.), 0.054 (δ=3,8 %, n.s.) |
| tmax (min) (Range: minimum – maximum) |
45 (19.8-90) |
40.0 (δ=11.1%) 38.9 (δ=13,6%) |
| t1/2, rise-phase (min) *** | 10.60 | 20.45 (δ=92,9 %) 19.9 (δ=87,7 %) |
| t1/2, fell-phase (min) *** | 203 | 160 (δ=21,1%) 263 (δ=29,7% |
| AUC(μM.hr)** | 0.08±0.02 | 0.062 (δ=22.5%, p=0.0007) 0.073 (δ=8,75%, n.s.) |
| Pouched snus(14.7 mg) | ||
| Cmax (μM) | 0.083±0.032 | 0.101 (δ=21.7%, n.s.), 0.088 (δ=6,0 %, n.s.) |
| tmax (min) (Range: minimum – maximum) |
60 (45-90) |
66.7 (δ=11.1%) 66.7(δ=11,1%) |
| t1/2, rise-phase (min) *** | 16.7 | 28,3 (δ=69.6 %) 31.7 (δ=89.9%) |
| t1/2, fell-phase (min) *** | 152.6 | 236.6 (δ=55.1%) 353.3 (δ=131.5% |
| AUC (μM.hr) ** | 0.13±0.05 | 0.13 (δ=1.5%, n.s. 0.12 (δ=9.2%, n.s.) |
| Loose snus(10.8mg) | ||
| Cmax (μM) | 0.064±0.022 | 0.081 (δ=26.5 %, p=0.003), 0.073 (δ=14.1 %, n.s.) |
| tmax (min) (Range: minimum – maximum) |
60 (45-90) |
66.7 (δ=11.1%) 66.7 (δ=11.1%) |
| t1/2, rise-phase (min) *** | 13.7 | 28.3 (δ=106.7,0 %) 30.0 (δ= 119.0%) |
| t1/2, fall-phase (min) *** | 155.6 | 238.3 (δ=53.2%) 353.3 (δ=127.1% |
| AUC (μM.hr) ** | 0.10±0.03 | 0.106 (δ=5.7%, n.s.) 0.098(δ=2.0%, n.s.) |
*
In vivo human clinical data from Digard et al.28
**
AUC was computed for t=0 to 2hrs (i.e., times when clinical measurements were available) for both in vivo and in silico studies
***
Estimated using curve fitting for in vivo (based on available clinical data); note that the estimated t1/2, fall-phase is beyond the measurement time window (therefore curve fit based estimates may not be reliable)