Table 5.
Pharmacokinetic parameters following single oral dose administration of risdiplam (Part 1) and for risdiplam with or without itraconazole (Part 3)
| Part 1 | Part 3 | ||||||
|---|---|---|---|---|---|---|---|
| Cohort | 1 | 2 | 3 | 4 & 6 | 5 | N/A | N/A |
| Food state | Fasted | Fasted | Fasted | Fasted | Fed | Fed | Fed |
| Dose | 0.6 mg | 2 mg | 6 mg | 18 mga | 6 mg | 6 mgb | 6 mg plus itraconazole 200 mg BIDc |
| Male, n (%) | 3 (100) | 3 (100) | 3 (100) | 6 (100) | 3 (100) | 8 (100) | 7 (100) |
| t max mean h ± SD | 3.17 ± 1.26 | 2.67 ± 1.53 | 2.00 ± 1.00 | 2.33 ± 10.3 | 4.67 ± 0.29 | 3.38 ± 0.74 | 3.29 ± 1.11 |
| C max mean ng ml –1 ± SD | 2.88 ± 0.79 | 8.36 ± 0.77 | 24.9 ± 5.15 | 94.0 ± 13.6 | 25.1 ± 4.71 | 27.1 ± 4.46 | 23.6 ± 2.91 |
| AUC 0‐24h mean h ng ml –1 ± SD | 41.9 ± 6.71 | 119 ± 27.8 | 394 ± 56.9 | 1300 ± 107 | 374 ± 64.2 | 410 ± 58.9 | 398 ± 41.1 |
| AUC 0‐120h mean h ng ml –1 ± SD | – | – | – | – | – | 935 ± 148 | 1030 ± 149 |
| AUC ∞ mean h ng ml –1 ± SD | 87.3 ± 11.7 | 303 ± 86.3 | 1100 ± 291 | 3300 ± 241 | 1020 ± 168 | 1090 ± 219 | 1300 ± 269 |
| t ½ mean h ± SD | 25.8 ± 9.06 | 40.1 ± 0.92 | 48.3 ± 9.42 | 68.9 ± 5.85 | 43.3 ± 3.58 | 44.1 ± 6.75 | 60.0 ± 14.6 |
| Cl/F mean l h –1 ± SD | 6.96 ± 1.00 | 7.00 ± 2.06 | 5.70 ± 1.40 | 5.48 ± 0.41 | 6.00 ± 1.09 | 5.71 ± 1.15 | 4.79 ± 0.93 |
| V z /F mean l ± SD | 254 ± 70.2 | 405 ± 120 | 385 ± 25.0 | 256 ± 76.7 | 377 ± 90.0 | 356 ± 46.5 | 400 ± 51.4 |
Values for AUC0‐24h, AUC∞, t1/2, Cl/F, and Vz/F were not determined for one subject who withdrew from the study because of personal reasons on Day 2. bValues for AUC0‐120h, AUC∞, t1/2, Cl/F, and Vz/F were not determined for one subject who withdrew from the study because of personal reasons after completing follow‐up visit 2. cIn Part 3, eight subjects received risdiplam in Period 1 but one subject withdrew during Period 2 due to a protocol violation before receiving risdiplam plus itraconazole. Therefore, the PK analysis and safety populations in Period 2 included seven subjects.
AUC∞, area under the plasma concentration vs. time curve extrapolated to infinity; AUC0 – 24h, area under the plasma concentration vs. time curve over 24 h after risdiplam administration; AUC0 – 120h, area under the plasma concentration vs. time curve over 120 h after risdiplam administration; BID, twice a day; Cl/F, apparent oral plasma clearance (for risdiplam only); N/A, not applicable; tmax, time to maximum observed plasma concentration; t½, apparent terminal elimination half‐life; Vz/F, apparent volume of distribution (for risdiplam only) ; SD, standard deviation