Table 1.
PK Parameter Estimates Following Single‐ and Multiple‐Dose Administration of Patisiran at 0.3 mg/kg Once Every 3 Weeks in the Phase 2 Open‐Label Extension Study
| ALN‐18328 | DLin‐MC3‐DMA | PEG2000‐C‐DMG | |
|---|---|---|---|
| PK Parameter | n = 27 | n = 27 | n = 27 |
| Week 1 | |||
| Cmax, μg/mL | 4.10 ± 1.28 | 42.5 ± 13.1 | 5.07 ± 1.31 |
| tmax, hour | 1.25 (1.03‐2.67) | 1.25 (1.03‐2.67) | 1.27 (1.03‐3.42) |
| AUCτ, μg·h/mL | 57.5 ± 57.4 | 796 ± 292 | 179 ± 168 |
| AUCp2, % | 81.7 | 71.0 | NA |
| Cmax2, μg/mL | 0.367 ± 0.30 | 7.94 ± 2.30 | NA |
| Cmin, μg/mL | 0.0065 ± 0.015 | 0.628 ± 1.10 | 0.0179 ± 0.007 |
| Week 34 | |||
| Cmax, μg/mL | 6.12 ± 1.69 | 41.1 ± 9.25 | 4.84 ± 1.42 |
| AUCp2, % | 91.5 | 82.2 | NA |
| Cmax2, μg/mL | 0.781 ± 0.492 | 9.65 ± 2.49 | NA |
| Cmin, μg/mL | 0.0211 ± 0.0377 | 1.50 ± 0.367 | 0.0296 ± 0.0085 |
| Week 106 | |||
| Cmax,ss, μg/mL | 7.15 ± 2.14 | 40.2 ± 11.5 | 4.22 ± 1.22 |
| tmax, hour | 1.30 (1.17‐2.10) | 1.30 (1.17‐2.10) | 1.30 (1.17‐3.10) |
| AUCτ, μg·h/mL | 184 ± 159 | 1403 ± 514 | 145 ± 65 |
| AUCp2,ss, % | 83.3 | 84.4 | NA |
| Cmax2,ss μg/mL | 1.57 ± 2.04 | 9.90 ± 4.10 | NA |
| Cmin,ss, μg/mL | 0.0210 ± 0.0442 | 1.75 ± 0.698 | 0.0236 ± 0.00930 |
| t½α,ss, hour | 0.789 ± 0.170 | 0.875 ± 0.112 | 17.1 ± 5.35 |
| t½β,ss, day | 3.16 ± 1.75 | 10.9 ± 7.9 | 3.76 ± 1.05 |
| Vss a, L/kg | 0.255 ± 0.198 | 0.470 ± 0.238 | 0.130 ± 0.050 |
| CLss a, mL/kg/h | 3.03 ± 2.50 | 2.08 ± 0.771 | 2.08 ± 0.586 |
| Rac b for Cmin | 3.23 | 2.79 | 1.32 |
| Rac b for Cmax | 1.75 | 0.95 | 0.833 |
| Rac b for AUCτ | 3.20 | 1.76 | 0.812 |
ALN‐18328, patisiran drug substance (small interfering ribonucleic acid); AUC, area under the concentration‐time curve; AUCp2, AUC in second PK phase and percent of second PK phase = AUCp2/AUCτ; AUCτ, AUC during the dosing interval; CLss, total clearance at steady state; Cmax, maximum concentration at EOI; Cmax2, the maximum concentration at the secondary peak; Cmin, concentration at the end of the dosing interval; DLin‐MC3‐DMA, (6Z,9Z,28Z,31Z)‐heptatriaconta‐6,9,28,31‐tetraen‐19‐yl‐4‐(dimethylamino)butanoate; EOI, end of infusion; NA, not applicable; PEG2000‐C‐DMG, α‐(3′‐{[1,2‐di(myristyloxy)proponoxy]carbonylamino}propyl)‐ω‐methoxy, polyoxyethylene; PK, pharmacokinetic; Rac, accumulation ratio; SD, standard deviation; t½α, half‐life of the first phase of the PK profile; t½β, terminal half‐life (half‐life of the second phase of the PK profile); tmax, time to reach Cmax; Vss, apparent volume of distribution at steady state; ss, steady state.
All PK parameters are expressed as mean ± SD, except for tmax, which is presented as median (range).
tmax occurred approximately at the EOI.