Table 1.
PK Parameters of Selected Studies in Healthy Subjects After Single or Multiple Doses of CLB
| Reference (Study Type) | Treatment | Plasma Analyte | Cmax, Mean (% CV), ng/mL | Tmax, Median (range), h | AUC0‐t, Mean (% CV), ng•h/mL | t½, Mean (% CV), h | Vd/F, Mean (% CV), L | CL/F, Mean (% CV), L/h |
|---|---|---|---|---|---|---|---|---|
| OV‐101611 (bioequivalence) | CLB 4 × 5‐mg tablet, Catalent (N = 40) | CLB | 367.9 (24) | 2.0 (0.5‐4.1) | 10 693 (32) | 39.6 (36) | 99 (21) | 2.0 (27) |
| N‐CLB | 87.2 (35) | 48.0 (24‐216) | 12 731 (46) | 58.6 (30) | ND | ND | ||
| CLB 4 × 5‐mg tablet, Pharmascience (N = 39) | CLB | 364.2 (20) | 2.0 (0.5‐5.0) | 10 897 (31) | 41.5 (40) | 100 (22) | 1.9 (28) | |
| N‐CLB | 91.9 (58) | 72.0 (36‐168) | 13 638 (73) | 60.3 (29) | ND | ND | ||
| OV‐101732 (relative BA) | CLB, 20‐mg tablet (N = 18, crossover) | CLB | 392 (25) | 1.5 (0.5‐3.0) | 9384 (26) | 36.5 (34) | 109 (23) | 2.2 (28) |
| N‐CLB | 82 (34) | 48 (24‐120) | 11 451 (48) | 66.2 (34)a | ND | ND | ||
| CLB, 20‐mg solution (N = 18, crossover) | CLB | 376 (21) | 1 (0.5‐2.0) | 8871 (22) | 37.1 (30) | 119 (26) | 2.3 (24) | |
| N‐CLB | 74 (25) | 36 (36‐120) | 10 366 (34) | 62.8 (22)b | ND | ND | ||
| OV‐101839, 41 (food effect) | 4 × 5‐mg tablets crushed with applesauce (N = 16) | CLB | 373 (24) | 2 (1.0‐4.0) | 9962 (30) | 38.5 (28) | 112 (24) | 2.1 (28) |
| N‐CLB | 84 (33) | 72 (36‐72) | 12 399 (49) | 73.6 (35) | ND | ND | ||
| 4 × 5‐mg intact tablets without applesauce (N = 16) | CLB | 379 (30) | 2 (0.5‐3.0) | 9771 (31) | 37.8 (27) | 113 (28) | 2.2 (37) | |
| N‐CLB | 81 (25) | 48 (36‐168) | 11 451 (31) | 68.7 (29) | ND | ND | ||
| 1 × 20‐mg intact tablet, high‐fat meal (N = 16) | CLB | 310 (30) | 3 (1.0‐8.0) | 9987 (17) | 37.2 (26) | 108 (34) | 2.0 (21) | |
| N‐CLB | 81 (30) | 48 (36‐72) | 11 378 (27) | 69.1 (23) | ND | ND | ||
| 1 × 20‐mg intact tablet, fasted state (N = 16) | CLB | 390 (21) | 2 (1.0‐3.0) | 9579 (17) | 36.7 (30) | 112 (39) | 2.1 (22) | |
| N‐CLB | 84 (26) | 42 (36‐72) | 11 453 (24) | 71.3 (27) | ND | ND | ||
| LC‐010c (dose proportionality) | CLB tablet (N = 12, Latin square) | |||||||
| CLB 10 mg | CLB | 107 (32)d | 1.9 (1.0)d | 3518 (923)d,e | 25.5 (18)d | ND | ND | |
| CLB 20 mg | CLB | 375 (51)d | 1.9 (0.6)d | 7190 (2091)d,e | 17.4 (5)d | ND | ND | |
| CLB 40 mg | CLB | 683 (117)d | 2.6 (0.8)d | 13 980 (3608)d,e | 17.8 (5)d | ND | ND | |
| OV‐102234 (multiple dose‐1) | 40‐mg TDD CLB, duration for ≥16 days (N = 70) | CLB | 1076 (24) | 1.6 (0.6‐6.1) | 17 649 (28)f | ND | 113 (27)g | 2.1 (26) |
| N‐CLB | 2783 (71) | 4.1 (0‐12.1) | 57 693 (65)f | ND | ND | ND | ||
| 160‐mg TDD CLB, duration for ≥3 days (N = 70) | CLB | 2884 (18) | 1.9 (0.6‐6.1) | 41 389 (20)f | ND | 128 (26)g | 3.3 (20) | |
| N‐CLB | 11 020 (60) | 4.1 (0‐12.1) | 223 023 (55)f | ND | ND | ND | ||
| OV‐1038c (multiple dose‐2) | 160‐mg TDD CLB, duration for ≥3 days (N = 11) | CLB | 3091 (10) | 2.0 (1.0‐2.5) | 26 092 (13) | 38.0 (32) | 166 (23) | 3.1 (13) |
| N‐CLB | 7361 (30) | 3.0 (0‐12.0) | 84 401 (29) | 71.4 (39) | ND | ND | ||
| 120‐mg TDD CLB, duration for ≥11 daysh (N = 10) | CLB | 2629 (17) | 1.5 (0.5‐2.5) | 19 867 (19) | 37.9 (26) | 167 (23) | 3.1 (20) | |
| N‐CLB | 8090 (38) | 2.5 (1.0‐4.0) | 89 539 (39) | 81.9 (42) | ND | ND |
AUC0‐t, area under the plasma drug concentration‐time curve up to the last measurable concentration; BA, bioavailability; CLB, clobazam; CL/F, apparent clearance; Cmax, maximum plasma concentration; CV, coefficient of variation; N‐CLB, N‐desmethylclobazam; ND, not determined; SD, standard deviation; t1/2, elimination half‐life of drug; TDD, total daily dose; Tmax, time to Cmax; Vd/F, apparent volume of distribution; Vss/F, volume of distribution at steady state.
a
n = 15; bn = 14; cdata on file; dvariance is ±SD; eAUC is 0‐144 h after dose; fAUC is 0‐24 h after dose; gVss/F; hexcluding a poor metabolizer.