Table 4.
Pharmacokinetic parameters: (a) single‐dose phase; (b) multiple‐dose phase
| (a) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Parametera, units | 3 mg | 10 mg | 30 mg | 100 mg | 200 mg | 400 mg | 800 mg | 800 mg | 800 mg |
| Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 | Cohort 5 | Cohort 6 | Cohort 7 | Cohort 8 | Cohorts 7 + 8 | |
| N = 6 | N = 6 | N = 6 | N = 7 | N = 6 | N = 6 | N = 6 | N = 10 | N = 16 | |
| n 1 , n 2 | 6, 5 | 6, 5 | 6, 6 | 7, 5 | 6, 6 | 6, 6 | 5, 5 | 10, 9 | 15, 14 |
| AUC last , ng h ml –1 | 36.8 (84) | 135.1 (40) | 386.6 (44) | 1226 (60) | 2878 (29) | 10 150 (28) | 27 480 (35) | 19 810 (53) | 22 090 (49) |
| AUC inf , ng h ml –1 | 48.8 (64) | 142.8 (44) | 392.3 (43) | 1465 (41) | 2886 (29) | 10 180 (28) | 27 540 (35) | 21 860 (43) | 23 740 (40) |
| Cmax, ng ml–1 | 17.1 (27) | 47.0 (21) | 142.5 (50) | 459.7 (53) | 1072 (35) | 2291 (42) | 3819 (26) | 3660 (48) | 3712 (41) |
| T max , h | 0.634 (0.517–1.27) | 0.750 (0.500–1.00) | 0.792 (0.500–1.08) | 0.550 (0.500–1.03) | 0.767 (0.500–1.17) | 1.50 (0.517–4.03) | 4.03 (2.00–4.30) | 2.02 (1.00–4.00) | 3.92 (1.00–4.30) |
| t ½ , h | 2.09 ± 0.87 | 1.94 ± 0.55 | 2.53 ± 1.32 | 3.59 ± 2.08 | 3.89 ± 2.20 | 3.55 ± 1.11 | 5.27 ± 2.92 | 4.67 ± 1.57 | 4.88 ± 2.06 |
| CL/F, l h–1 | 61.44 (65) | 70.02 (44) | 76.41 (43) | 68.34 (41) | 69.31 (29) | 39.32 (28) | 29.00 (35) | 36.61 (43) | 33.69 (41) |
| V z /F, l | 172.5 (26) | 190.1 (18) | 256.2 (63) | 318.5 (66) | 343.0 (46) | 193.3 (39) | 197.1 (77) | 235.0 (64) | 220.7 (66) |
| (b) | ||||||||
|---|---|---|---|---|---|---|---|---|
| Parameterb, units | 30 mg QD | 100 mg QD | 200 mg QD | 100 mg BID | 200 mg BID | 200 mg BID | 200 mg BID | 400 mg QD |
| Cohort 3 | Cohort 4 | Cohort 5 | Cohort 6 | Cohort 7 | Cohort 8 | Cohorts 7 + 8 | Cohort 9 | |
| N = 6 | N = 5 | N = 6 | N = 6 | N = 5 | N = 9 | N = 14 | N = 8 | |
| n 1 , n 2 | 5, 5 | 5, 5 | 6, 6 | 6, 6 | 5, 5 | 6, 6 | 11, 11 | 6, 6 |
| Plasma | ||||||||
| AUC τ , ng h ml –1 | 500 (38) | 1977 (47) | 4277 (34) | 3107 (31) | 13 680 (27) | 8754 (30) | 10 720 (36) | 18 230 (24) |
| C max , ng ml –1 | 161 (50) | 700 (31) | 1199 (23) | 773.0 (36) | 2691 (8) | 2294 (27) | 2467 (22) | 3334 (17) |
| T max , h | 0.55 (0.50–1.03) | 0.55 (0.50–2.02) | 1.05 (1.02–1.05) | 0.759 (0.50–1.02) | 1.02 (0.50–1.07) | 0.50 (0.50–1.00) | 0.50 (0.50–1.07) | 0.767(0.50–2.05) |
| t ½ , h | 2.76 ± 1.11 | 2.99 ± 0.76 | 3.06 ± 0.24 | 5.03 ± 2.34 | 5.17 ± 1.60 | 3.64 ± 0.83 | 4.34 ± 1.42 | 4.85 ± 1.86 |
| CL/F, l h –1 | 59.93 (38) | 50.56 (47) | 46.76 (34) | 32.16 (31) | 14.61 (27) | 22.86 (29) | 18.65 (36) | 21.99 (24) |
| V z /F, l | 223.0 (43) | 212.9 (43) | 206.0 (29) | 212.3 (65) | 104.7 (42) | 117.8 (31) | 111.6 (35) | 145.4 (34) |
| Urine | ||||||||
| Ae τ % | 1.03 (74) | 1.17 (99) | 1.42 (49) | NCc | 4.38 (51) | 2.60 (25) | 3.30 (47) | 2.64 (37) |
| CL r , l h –1 | 0.618 (33) | 0.590 (41) | 0.665 (20) | NCc | 0.639 (40) | 0.596 (13) | 0.615 (27) | 0.579 (23) |
Notes (a): Data for one subject in Cohort 7 (800 mg) were excluded due to vomiting.
Values are geometric mean (geometric percent coefficient of variation) for all except: median (range) for Tmax; arithmetic mean ± standard deviation for t ½.
AUClast, area under the concentration–time profile from time zero to the time of the last quantifiable concentration; AUCinf, area under the concentration–time profile from time zero extrapolated to infinite time; CL/F, apparent clearance; Cmax, maximum plasma concentration; N, number of subjects in the treatment group; n1, number of subjects contributing to the mean; n2, number of subjects where t ½, AUCinf, CL/F and Vz/F were determined; t ½, terminal half‐life; Tmax, time at which Cmax occurred; Vz/F, apparent volume of distribution.
Notes (b): Data for one subject in the 400 mg QD (Cohort 9) group were excluded due to vomiting.
Values are geometric mean (percent coefficient of variation) for all except: median (range) for Tmax; arithmetic mean ± SD for t ½.
Protocol deviation in urine collection for Cohort 6.
Aeτ %, cumulative percent of dose recovered unchanged in urine over the dosing interval τ; AUCτ, area under the concentration–time curve from time zero to time τ, the dosing interval, where τ = 24 h for QD dosing and 12 h for BID dosing; BID, twice daily; CL/F, apparent clearance; CLr, renal clearance; Cmax, maximum plasma concentration; N, number of subjects in the treatment group (start of multiple dosing on day 1); n1, number of subjects contributing to the mean (completed multiple dosing through day 10); n2, number of subjects where t ½ and Vz/F were determined; NC, not calculated; QD, once daily; SD, standard deviation; t ½, terminal half‐life; Tmax, time at which Cmax occurred; Vz/F, apparent volume of distribution.