Table 2.
Pharmacokinetics and central nervous system penetrance of vafidemstat
| Cohort and parameter | Dose level and results | ||||||
|---|---|---|---|---|---|---|---|
| SADa | I: 0.2 mg (n = 6) | II: 0.6 mg (n = 6) | III: 1.5 mg (n = 6) | IV: 2.5 mg (n = 6) | V: 4.0 mg (n = 3) | ||
| tmax (h) | 2.75 (59) | 1.83 (36) | 0.92 (56) | 1.58 (83) | 1.71 (73) | ||
| Cmax (ng/mL) | 1.11 (24) | 3.21 (12) | 11.95 (29) | 18.78 (30) | 38.05 (33) | ||
| AUC0–t (ng·h/mL) | 28.03 (12) | 83.32 (13) | 297.12 (50) | 402.09 (20) | 550.01 (17) | ||
| AUC0–inf (ng·h/mL) | 30.93 (16) | 90.67 (13) | 427.58 (80) | 438.11 (25) | 568.46 (18) | ||
| Vd/F (L) | 260 (20) | 256 (14) | 213 (9.7) | 203 (9.5) | 204 (17) | ||
| CL/F (L/h) | 6.59 (14) | 6.72 (14) | 5.34 (52) | 6.03 (26) | 7.20 (15) | ||
| t½ (h) | 28 (28) | 27 (6.6) | 41 (76) | 25 (28) | 20 (17) | ||
| MADa | I: 0.2 mg/day (n = 6) | II: 0.6 mg/day (n = 6) | III: 1.0 mg/day (n = 6) | IV: 1.5 mg/day (n = 6) | V: 2.5 mg/day (n = 6) | Older adult: 2.5 mg/day (n = 6) | VI: 4.0 mg/day (n = 3) |
|---|---|---|---|---|---|---|---|
| tmax, ss (h after last dosing) | 5.1 (1.7) | 2.25 (1.4) | 1.83 (1.7) | 1.17 (0.4) | 2.17 (1.7) | 2.33 (1.6) | 1.33 (1.1) |
| Cmax (ng/mL) (D1) | 1.28 (23) | 3.69 (22) | 6.83 (56) | 11.35 (30) | 26.64 (54) | 24.28 (12) | 55.97 (27) |
| Cmax,ss (ng/mL) (D5) | 2.32 (17) | 7.65 (39) | 14.11 (43) | 23.61 (18) | 49.92 (59) | 41.00 (42) | 109.73 (50) |
| AUC0–t (ng·h/mL) (D1) | 18.73 (21) | 50.57 (28) | 95.08 (35) | 137.96 (17) | 292.25 (45) | 257.53 (33) | 563.85 (28) |
| AUC0–t,ss (ng·h/mL) (D5) | 37.69 (18) | 113.68 (49) | 198.74 (38) | 298.69 (17) | 634.21 (65) | 442.23 (39) | 994.50 (49) |
| RAC | 1.91 (17) | 1.90 (22) | 1.92 (9.2) | 1.87 (7.0) | 1.86 (7.2) | 1.92 (6.7) | 1.79 (15) |
| t½ (h) | 22 (25) | 22 (33) | 23 (14) | 22 (11) | 22 (11) | 23 (10) | 20 (23) |
| CSFb | 2.0 mg ( n = 3) | 4.0 mg ( n = 3) | |||||
|---|---|---|---|---|---|---|---|
| CSF (pg/mL) @ 2 h | 239.42 (56) | 387.34 (41) | |||||
| CSF (pg/mL) @ 6 h | 181.47 (11) | 733.75 (27) | |||||
| CSF (pg/mL) @ 12 h | 169.68 (14) | 549.93 (5.3) | |||||
| Plasmau (pg/mL) @ 2 h | 315.68 (56) | 589.71 (56) | |||||
| Plasmau (pg/mL) @ 6 h | 248.31 (17) | 870.66 (13) | |||||
| Plasmau (pg/mL) @ 12 h | 186.35 (23) | 609.11 (12) | |||||
| CSF/plasmau @ 2 h | 0.78 (15) | 0.69 (18) | |||||
| CSF/plasmau @ 6 h | 0.74 (7.8) | 0.83 (14) | |||||
| CSF/plasmau @ 12 h | 0.92 (8.9) | 0.91 (15) |
Data are presented as mean (coefficient of variation, %)
aPlasma pharmacokinetic parameters of the SAD and MAD (after single [D1] and 5-day repeated [D5] dose) cohorts. n = 6 healthy young volunteers per cohort (0.2–4 mg SAD and 0.2–2.5 mg/day MAD), n = 3 healthy young volunteers in the 4 mg/day MAD cohort, and n = 3 older healthy adult volunteers in the 2.5 mg/day cohort. MAD AUCinf (D1) not reported as extrapolated AUC was > 20%
bPharmacokinetic parameters in the CSF cohort after administration of a single dose. CSF and plasmau concentrations, and CSF-to-plasmau ratios after a single dose of vafidemstat 2 or 4 mg. n = 3 subjects per timepoint
AUC0–inf area under the concentration–time curve within time 0 to infinity, AUC0–t area under the concentration–time curve within time 0–24 h, CL/F apparent clearance, Cmax maximum (peak) concentration, CSF cerebrospinal fluid, D1 day 1, D5 day 5, MAD multiple ascending dose, plasmau plasma unbound, RAC ratio of accumulation (calculated from t½/Ke; Ke elimination rate constant), SAD single ascending dose, ss steady state, t½ terminal half-life, tmax time to reach Cmax, Vd/F apparent volume of distribution