TABLE 6.
The simulated PK parameters in American and Chinese populations following single-dose administration and multidose administration of varenicline nasal spray, (a) systemic; (b) nasal.
| Single-dose administration | Muilt-dose administration | ||
|---|---|---|---|
| Ratio of Means (Chinese/Americans) | Americans Mean ± SD (CV%) | Chinese Mean ± SD (CV%) | Ratio of Means (Chinese/Americans) |
| 1.00 | 2 (1–2) | 2 (1–2) | 1.00 |
| 1.00 | 0.36 ± 0.11 (31.31) | 0.32 ± 0.1 (30.93) | 0.89 |
| 0.97 | 3.47 ± 1.31 (37.86) | 3.08 ± 1.18 (38.29) | 0.89 |
| 0.88 | 9.41 ± 7.39 (78.59) | 7.53 ± 5.89 (78.20) | 0.80 |
| NA | 5.49 ± 7.56 (137.83) | 3.99 ± 6.24 (156.35) | NA |
| 0.87 | 15.39 ± 9.08 (58.99) | 13.36 ± 7.88 (58.98) | 0.87 |
| 0.98 | 162097.65 ± 47063.96 (29.03) | 174458.65 ± 49971.71 (28.64) | 1.08 |
| 1.13 | 10323.09 ± 7746.61 (75.04) | 12661.31 ± 9146.65 (72.24) | 1.23 |
| NA | 2.25 | 2.00 | 0.89 |
| NA | 2.38 | 2.17 | 0.91 |
| 1.00 | 0.08(0.08–0.08) | 0.08 (0.08–0.08) | 1.00 |
| 1.00 | 7983.94 ± 0.09 (0) | 7983.91 ± 0.08 (0) | 1.00 |
| 1.00 | 1817.02 ± 1.23 (0.07) | 1816.65 ± 1.11 (0.06) | 1.00 |
| 1.00 | 7164.89 ± 6.19 (0.09) | 7163.29 ± 4.97 (0.07) | 1.00 |
| NA | 0.01 ± 0.03 (239.85) | 0.01 ± 0.02 (269.09) | 1.00 |
| 0.87 | 15.38 ± 9.07 (58.97) | 13.35 ± 7.87 (58.97) | 0.87 |
| 0.87 | 185.68 ± 109.25 (58.84) | 161.27 ± 94.92 (58.86) | 0.87 |
| 1.00 | 8.37 ± 0.01 (0.09) | 8.38 ± 0.01 (0.07) | 1.00 |
| NA | 1.00 | 1.00 | 1.00 |
| NA | 1.00 | 1.00 | 1.00 |
| PK parameter | Unit | Americans Mean ± SD (CV%) | Chinese Mean ± SD (CV%) | |
|---|---|---|---|---|
| Systemic Exposure | a T max | h | 2 (1–4) | 2 (1–4) |
| C max | ng/mL | 0.16 ± 0.06 (35.23) | 0.16 ± 0.06 (34.83) | |
| AUC0-12 | h*ng/mL | 1.46 ± 0.43 (29.46) | 1.42 ± 0.41 (28.9) | |
| AUC0-∞ | h*ng/mL | 3.51 ± 1.37 (39.18) | 3.1 ± 1.22 (39.19) | |
| AUC_%Extrap | % | 5.58 ± 7.65 (137.2) | 4.06 ± 6.32 (155.63) | |
| T 1/2 | h | 15.4 ± 9.08 (58.97) | 13.37 ± 7.88 (58.96) | |
| V/F | mL | 378736.01 ± 154695.3 (40.85) | 372023.3 ± 151874.14 (40.82) | |
| CL/F | mL/h | 19856.41 ± 8191.77 (41.26) | 22466.48 ± 9273.86 (41.28) | |
| R Cmax | NA | NA | ||
| RAUC0-12 | NA | NA | ||
| Nasal Exposure | a , b T max | h | 0.08 (0.08–0.08) | 0.08 (0.08–0.08) |
| C max | ng/mL | 7983.76 ± 0 (0) | 7983.76 ± 0 (0) | |
| AUC0-12 | h*ng/mL | 1815.12 ± 0.43 (0.02) | 1815.08 ± 0.41 (0.02) | |
| AUC0-∞ | h*ng/mL | 7159.63 ± 1.15 (0.02) | 7159.3 ± 1.03(0.01) | |
| AUC_%Extrap | % | 0 ± 0.01 (173.02) | 0 ± 0 (193.44) | |
| T 1/2 | h | 15.37 ± 9.04 (58.83) | 13.36 ± 7.84 (58.71) | |
| V/F | mL | 185.77 ± 109.27(58.82) | 161.47 ± 94.78 (58.7) | |
| CL/F | mL/h | 8.38 ± 0 (0.02) | 8.38 ± 0 (0.01) | |
| RC max | NA | NA | ||
| RAUC0-12 | NA | NA |
NA, not applicable.
T max expressed as Median (Min-Max).
Time to peak concentration (T max) after intranasal administration was the same in all simulated populations. The peak velocity after nasal administration was fast, and the simulated time points were the actual blood collection time points with short intervals. Therefore, no variability for T max was observed. In addition, it was estimated that variability for T max can be low, considering that the time to peak nasal concentration was short and the variability of parameters for nasal tissue in the PBPK model was low.
C max, maximum concentration; T max, time to C max.; AUC 0–12, area under the concentration vs. time curve from the start of the last dose to12h; AUC0-∞, area under the plasma concentration–time curve from the start of the last dose to infinity; AUC_%Extrap, the proportion of the area under the plasma concentration–time curve from the last time at which there is a quantifiable concentration to infinity to AUC0-∞; T 1/2, apparent terminal elimination half-life, V/F, apparent volume of distribution; CL/F, apparent total clearance; R Cmax, C max at day 7/C max at day1; RAUC0-12, AUC0-12 at day 7/AUC0-12 at day 1.