Table 3.
Steady state pharmacokinetic parameters of S-3304 and its metabolites following 14 day or 28 day twice daily multiple oral administrations
| Dose | 800 mg*(n = 6) | 1600 mg*(n = 4) | 2400 mg*(n = 5) | 3200 mg†(n = 3) |
|---|---|---|---|---|
| S-3304 | ||||
| AUC0–12 h,ss (μg ml−1h) | 411 ± 117 | 466 ± 80 | 634 ± 170 | 943 ± 317 |
| Cmax,ss (μg ml−1) | 79.9 ± 19.6 | 92.7 ± 12.7 | 120 ± 21 | 140 ± 27 |
| tmax,ss (h) | 3 (2–3) | 3 (2–3) | 3 (2–5) | 4 (3–5) |
| t1/2,ss (h) | 14.2 ± 1.2‡ | 14.8 ± 3.4 | 15.9 ± 1.8§ | ND |
| AUC0–12 h,ss:AUC0–12 h | 1.40 ± 0.32 | 1.34 ± 0.17 | 1.45 ± 0.34 | 1.48 ± 0.20 |
| 5-hydroxy-S-3304 | ||||
| AUC0–12 h,ss (μg ml−1 h) | 3.06 ± 1.49 | 5.14 ± 2.83 | 8.27 ± 3.62 | 8.81 ± 6.14 |
| Cmax,ss (μg ml−1) | 0.511 ± 0.183 | 0.939 ± 0.515 | 1.57 ± 0.67 | 1.26 ± 0.88 |
| tmax,ss (h) | 4 (4–4) | 4 (4–5) | 4 (0–6) | 5 (3–6) |
| t1/2,ss (h) | 20.7 ± 6.7 | 13.9 ± 1.0 | 17.3 ± 3.5 | ND |
| AUC0–12 h,ss:AUC0–12 h | 1.74 ± 0.43 | 1.53 ± 0.26 | 1.79 ± 0.80 | 1.66 ± 0.35 |
| Metabolite ratio | 0.0072 ± 0.0023 | 0.0105 ± 0.0043 | 0.0133 ± 0.0062 | 0.0092 ± 0.0045 |
| 6-hydroxy-S-3304 | ||||
| AUC0–12 h,ss (μg ml−1 h) | 0.486 ± 0.245 | 0.899 ± 0.558 | 1.24 ± 0.63 | 1.07 ± 0.74 |
| Cmax,ss (μg ml−1) | 0.0838 ± 0.0358 | 0.162 ± 0.117 | 0.215 ± 0.117 | 0.146 ± 0.100 |
| tmax,ss (h) | 5 (4–5) | 5 (4–5) | 5 (4–6) | 5 (4–6) |
| t1/2,ss (h) | 20.6 ± 6.5 | 16.0 ± 2.4 | 18.9 ± 4.3§ | ND |
| AUC0–12 h,ss:AUC0–12 h | 1.66 ± 0.53 | 1.79 ± 0.70 | 2.69 ± 2.42 | 2.33 ± 1.11 |
| Metabolite ratio | 0.0011 ± 0.0004 | 0.0018 ± 0.0009 | 0.0020 ± 0.0010 | 0.0011 ± 0.0004 |
Steady state pharmacokinetic parameters based on day 28 plasma concentrations.
Steady state pharmacokinetic parameters based on day 14 plasma concentrations.
n = 5.
n = 4.
Pharmacokinetic parameters were determined under fed conditions. For assessments of steady state pharmacokinetics, volunteers were subject to serial blood drawing after breakfast on day 28, except for 3200 mg BID dose level, for which all the subjects were withdrawn from the treatment but steady state pharmacokinetic data were derived from the plasma concentrations on day 14. The observed degree of accumulation is represented by AUC0–12h,ss/AUC0–12h, where is AUC0–12h on day 1. Metabolite ratio is defined as the ratio of AUC0‐12h of the metabolite to that of S-3304. Data are presented as mean ± standard deviation, except for tmax, which is presented as median (minimum–maximum).