Table 3.
Pharmacokinetic parameters of enzastaurin and its active metabolites in cycle 0
| Analyte | Parameters | Geometric mean (coefficient of variation %) | |||
|---|---|---|---|---|---|
| Dose of enzastaurin (mg) | |||||
| 250 | 375 | 500 | 750 | ||
| Enzastaurin | N | 7 | 6 | 6 | 4 |
| Cmax (nmol/L) | 1090 (57.5) | 968 (61.3) | 2070 (40.2) | 1910 (73.3) | |
| tmax (h)* | 4.07 (2.87–8.92) | 3.96 (3.00–6.10) | 5.96 (3.00–9.03) | 3.92 (3.15–4.00) | |
| AUC0–∞ (h μmol/L) | 12.7 (78.7) | 12.9 (77.6) | 29.5 (70.2) | 23.5 (96.6) | |
| CL/F (L/h) | 38.0 (78.7) | 56.4 (77.6) | 32.9 (70.2) | 61.9 (96.6) | |
| Vz/F (L) | 651 (70.7) | 820 (69.1) | 632 (39.1) | 957 (68.5) | |
| t1/2 (h)† | 11.9 (7.6–17.0) | 10.1 (7.5–16.4) | 13.3 (8.4–20.3) | 10.7 (8.2–14.1) | |
| LY326020 | N | 7 | 6 | 6 | 4 |
| Cmax (nmol/L) | 285 (36.7) | 308 (24.3) | 494 (39.9) | 548 (53.1) | |
| tmax (h)* | 5.77 (2.87–8.97) | 5.01 (4.00–9.02) | 9.02 (4.00–24.02) | 5.00 (3.92–6.00) | |
| AUC0–∞ (h μmol/L) | 12.2 (50.2) | 14.6 (46.8) | 27.8 (61.1) | 26.3 (65.5) | |
| t 1/2 (h)† | 38.2 (27.2–55.6) | 34.8 (28.9–40.5) | 37.8 (26.6–55.6) | 38.4 (33.2–41.1) | |
| MR | 0.961 (60.7) | 1.13 (37.3) | 0.942 (46.9) | 1.12 (23.7) | |
| LY485912 | N | 7 | 6 | 6 | 4 |
| Cmax (nmol/L) | 122 (57.3) | 107 (48.8) | 258 (50.2) | 218 (77.7) | |
| tmax (h)* | 5.77 (3.93–8.97) | 6.10 (4.02–9.02) | 9.02 (6.20–24.02) | 5.00 (3.92–9.07) | |
| AUC0–∞ (h μmol/L) | 2.25 (88.4) | 2.17 (91.3) | 5.88 (103) | 4.54 (132) | |
| t 1/2 (h)† | 12.0 (7.7–19.7) | 10.5 (9.4–14.0) | 12.6 (8.7–19.6) | 11.5 (6.8–17.7) | |
| MR | 0.176 (15.3) | 0.168 (15.8) | 0.199 (33.3) | 0.193 (19.8) | |
| LSN2406799 | N | 7 | 6 | 6 | 4 |
| Cmax (nmol/L) | 145 (34.0) | 143 (41.3) | 276 (31.8) | 242 (92.8) | |
| tmax (h)* | 4.02 (2.87–6.07) | 3.96 (3.00–6.10) | 4.96 (3.00–9.03) | 3.92 (3.15–4.00) | |
| AUC0–∞ (h μmol/L) | 1.40 (68.4) | 1.49 (60.8) | 3.25 (49.6) | 2.71 (92.6) | |
| t 1/2 (h)† | 10.5 (7.1–13.7) | 8.70 (7.1–11.9) | 11.6 (6.1–17.1) | 10.3 (5.7–19.7) | |
| MR | 0.110 (9.2) | 0.115 (15.3) | 0.110 (18.7) | 0.115 (12.5) | |
*Median (range). †Geometric mean (range). AUC0–∞, area under the concentration vs time curve from 0 to infinity; CL/F, apparent total body clearance calculated after oral dosing; Cmax, maximum plasma concentration; MR, metabolic ratio; tmax, median time to reach maximum concentration; t1/2, half‐life associated with the terminal rate constant; Vz/F, apparent volume of distribution after oral administration.