Table 1.
Parameter Estimation for N-Acetylgalactosamine Small Interfering RNAs
| Species | K-PD model parameter |
siRNA |
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| |
Revusiran |
Vutrisiran |
Cemdisiran |
Givlaari |
Lumasiran |
Fitusiran |
Inclisiran |
ALN-HBV02 |
ARO-APOC3 |
ARO-ANG3 |
Olpasiran |
|
| Type | WT | AGXT KO | WT | WT | TG | WT | TG | |||||
| Mouse | IDK 50 (mg/[kg·d]) | 7.98e-3 | 2.41e-2 | 2.57e-2 | 6.79e-4 | 5.59e-3 | 4.86e-3 | 1.72e-5 | ||||
| CI (5th, 95th Perc.) | (7.4e-3, 8.7e-3) | (1.5e-2, 4.9e-2) | (2.0e-2, 3.0e-2) | (4.5e-4, 9.2e-4) | (5.1e-3, 6.2e-3) | (3.1e-3, 5.6e-3) | (1.3e-6, 6.9e-4) | |||||
| PK t-half (d) | 15.7 | 6.26 | 11.3 | 21.4 | 10.2 | 16.7 | 4.48 | |||||
| CI (5th, 95th Perc.) | (14, 17) | (4.9, 12) | (7.5, 17) | (15, 34) | (8.3, 13) | (10, 39) | (3.2, 14) | |||||
| PD t-half (d) | 2.11 | 12.6 | 1.19 | 1.54 | 1.82 | 1.17 | 1.64 | |||||
| CI (5th, 95th Perc.) | (1.8, 3.4) | (5.8, 17) | (0.68, 2.3) | (1.2, 2.5) | (1.1, 2.2) | (0.4, 1.7) | (0.98, 2.3) | |||||
| Monkey | IDK 50 (mg/[kg·d]) | 0.281 | 7.06e-3 | 4.91e-2 | 1.36e-2 | 2.06e-2 | 3.09e-2 | 7.36e-3 | 4.79e-3 | |||
| CI (5th, 95th Perc.) | (0.20, 0.37) | (7.9e-6, 8.7e-3) | (4.9e-2, 5.1e-2) | (3.7e-3, 2.5e-2) | (1.5e-2, 2.5e-2) | (2.4e-2, 4.6e-2) | (7.5e-7, 1.6e-2) | (4.1e-3, 5.5e-3) | ||||
| PK t-half (d) | 7.36 | 42.8 | 1.81 | 6.02 | 52.5 | 45.4 | 53.8 | 14.3 | ||||
| CI (5th, 95th Perc.) | (5.6, 9.7) | (30, 4.9e4) | (1.7, 1.9) | (4.2, 7.4) | (34, 83) | (22, 80) | (12, 1.9e5) | (12, 17) | ||||
| PD t-half (d) | 4.91 | 5.26 | 7.08 | 6.01 | 3.70 | 3.46 | 2.37 | 4.56 | ||||
| CI (5th, 95th Perc.) | (3.9, 6.1) | (4.5, 6.3) | (6.9, 7.1) | (5.1, 7.1) | (2.4, 5.0) | (1.8, 4.8) | (0.5, 4.3) | (3.8, 5.2) | ||||
| Human | IDK 50 (mg/[kg·d]) | 0.217 | 3.06e-4 | 1.00e-3 | 5.57e-4 | 6.86e-3 | 3.20e-3 | 5.71e-3 | 2.52e-5 | 6.27e-4 | 4.00e-3 | 1.00e-4 |
| CI (5th, 95th Perc.) | (0.19, 0.25) | (2.5e-4, 3.6e-4) | (7.2e-4, 1.4e-3) | (3.1e-4, 6.8e-4) | (2.9e-3, 1.1e-2) | (2.2e-3, 4.5e-3) | (5.1e-3, 6.2e-3) | (6.1e-8, 1.6e-4) | (5.1e-4, 7.3e-4) | (3.5e-3, 4.5e-3) | (7.2e-5, 1.3e-4) | |
| PK t-half (d) | 12.3 | 121 | 112 | 50.9 | 9.99 | 19.9 | 82.4 | 98.4 | 62.8 | 53.0 | 33.8 | |
| CI (5th, 95th Perc.) | (10, 16) | (93, 163) | (99, 124) | (21, 130) | (6.6, 16) | (16, 25) | (73, 92) | (52, 8.1e4) | (50, 90) | (44, 66) | (27, 42) | |
| PD t-half (d) | 4.82 | 8.16 | 4.98 | 5.25 | 15.9 | 12.3 | 4.07 | 9.49 | 3.79 | 4.43 | 8.41 | |
| CI (5th, 95th Perc.) | (4.1, 5.4) | (7.0, 9.7) | (4.3, 5.7) | (0.60, 12) | (10, 21) | (9.5, 16) | (3.7, 4.5) | (7.2, 12) | (3.2, 4.5) | (3.7, 5.0) | (7.7, 9.2) | |
Summary of estimated parameters for the 10 GalNAc–siRNAs in mouse, monkey, and human. Body weight assumed 70 kg.
AGXT, alanine–glyoxylate aminotransferase-deficient; CI, confidence interval; d, day; KO, knockout; KPD, kinetic-pharmacodynamic; Perc., percentile; PK, pharmacokinetic; TG, transgenic; WT, wildtype.