Table 2.
Plasma pharmacokinetic parameters for dantrolene (free acid) and 5-hydroxydantrolene following single intravenous infusion of 60 mg Dantrium®, 60 mg NPJ5008 and 120 mg NPJ5008 in healthy volunteers
| Analyte | Dantrolene | 5-Hydroxydantrolene | ||||
| Treatment dose level | Dantrium® 60 mgan = 16 | NPJ5008 60 mgan = 16 | NPJ5008 120 mgbn = 5 | Dantrium® 60 mgan = 16 | NPJ5008 60 mgan = 16 | NPJ5008 120 mgbn = 5 |
| Tmax (h) | 0.155 [0.14 to 4.16] | 0.100 [0.01 to 4.01] | 0.149 [0.07 to 0.80] | 10.135 [1.64 to 16.15] | 6.017 [4.00 to 10.02] | 10.064 [10.05 to 16.17] |
| Cmax (ng ml−1) | 1170 (34.8) | 1090 (29.7) | 2090 (24.2) | 138 (34.1) | 114 (25.3) | 208 (22.5) |
| Cmax/Dc (ng ml−1 mg−1) | 24.9 (34.8) | 23.1 (29.7) | 22.1 (24.2) | 2.93 (34.1) | 2.40 (25.3) | 2.20 (22.5) |
| AUC0 to 6 (ng h ml−1) | 4790 (18.8) | 4230 (15.4) | 9400 (25.7) | 581 (40.0) | 497 (27.4) | 765 (17.4) |
| AUC0 to 72 (ng h ml−1) | 13 500 (23.9) | 12 200 (20.8) | 30 500 (31.1) | 3380 (21.2) | 2890 (19.9) | 6150 (23.6) |
| AUC0 to last (ng h ml−1) | 13 200 (23.9) | 11 900 (20.6) | 30 400 (31.7) | 3370 (21.1) | 2880 (19.6) | 6150 (23.6) |
| AUC0 to last/Dc (ng h ml−1 mg−1) | 279 (23.9) | 252 (20.6) | 322 (31.7) | 71.4 (21.1) | 60.9 (19.6) | 65.2 (23.6) |
| AUC0 to ∞ (ng h ml−1) | 13 600 (24.2) | 12 300 (21.1) | 30 900 (31.5) | 3420 (20.8) | 2920 (19.9) | 6270 (23.9) |
| AUC0 to ∞/Dc (ng h ml−1 mg−1) | 287 (24.2) | 260 (21.1) | 327 (31.5) | 72.4 (20.8) | 61.9 (19.9) | 66.4 (23.9) |
| T1/2 (h) | 8.476 (21.8) | 9.041 (27.9) | 10.993 (18.5) | 9.488 (24.0) | 10.171 (20.3) | 11.212 (19.4) |
| λz (h−1) | 0.08178 (21.8) | 0.07667 (27.9) | 0.06305 (18.5) | 0.07306 (24.0) | 0.06815 (20.3) | 0.06182 (19.4) |
| CL (ml min−1) | 58.2 (24.2) | 63.5 (21.1) | 50.5 (31.5) | NC | NC | NC |
| Vz (l) | 42.7 (21.1) | 49.7 (22.7) | 48.0 (29.2) | NC | NC | NC |
| Vss (l) | 46.3 (16.6) | 53.3 (14.9) | 49.2 (24.5) | NC | NC | NC |
| MPR Cmax (ratio) | NC | NC | NC | 0.112 (37.4) | 0.099 (32.8) | 0.095 (35.6) |
| MPR AUC0 to last (ratio) | NC | NC | NC | 0.243 (30.3) | 0.230 (23.3) | 0.193 (24.0) |
| MPR AUC0 to ∞ (ratio) | NC | NC | NC | 0.240 (29.9) | 0.227 (22.9) | 0.193 (23.7) |
Data are median [range] and geomteric mean (geometric coefficient of variation%).
λz, first order rate constant associated with the terminal (log-linear) portion of the curve; AUC, area under the curve; AUC0 to ∞, area under the curve from time zero extrapolated to infinity; AUC0 to last, area under the curve from time zero to last measurable concentration; CL, total body clearance calculated after a single i.v. administration; Cmax, maximum observed drug concentration in plasma; D, dose; i.v., intravenous; MPR, metabolite to parent ratio; NC, not calculated; T1/2, terminal half-life of the analyte in plasma; Tmax, time from administration to maximum observed concentration of the analyte in plasma; truncated AUCs, time zero to 6 and 72 h post dose; Vss, predicted volume of distribution at steady state after single i.v. administration; Vz, volume of distribution based on the terminal phase calculated using AUC0 to ∞ after a single i.v. administration.
In Part 1, the actual dose received (based on the products’ Certificate of Analysis, which differed slightly from the nominal dose, and participant weight) ranged from 0.56 to 0.97 mg kg−1 of NPJ5008 and from 0.57 to 0.98 mg kg−1 of Dantrium®.
In Part 2, a range of actual doses of 1.29 to 1.43 mg kg−1 of NPJ5008 were administered. Data presented are median [range]; all other data presented are geometric mean (geometric CV%).
Dose (D)-corrected parameters were normalised by the nominal salt-corrected dose, for example, 120 mg × 0.787 (salt correction factor) = 94.44 mg.