Summary of primary pharmacokinetic parameters for PDA and HVA in 14 healthy volunteers
All study drugs were given orally. PROB was dosed 1 h prior to FSM administration in the coadministration treatment group. Pharmacokinetic parameters were determined as described in Materials and Methods. Data are shown as the mean ± S.D. The fu of HVA was not determined because the bioanalytical method could not achieve adequate sensitivity. As a result, the CLsec value was not calculated.
| Parameter | Prestudy Value | Phase I (PROB Alone) | Phase II (FSM Alone) | Phase III (FSM with PROB) | ||
|---|---|---|---|---|---|---|
| Value | GMR (90% CI)a | Value | Value | GMR (90% CI)b | ||
| PDA | ||||||
| Cmax (nM) | 18.1 ± 24.9 | 50.5 ± 62.7** | 3.1 (2.7–3.7) | 19.6 ± 24.4 | 55.4 ± 55.8** | 3.4 (2.4–4.9) |
| AUC0–last (nM•h) | 251 ± 293 | 634 ± 823* | 3.1 (2.2–4.3) | 316 ± 413 | 829 ± 951** | 3.2 (2.3–4.6) |
| CLR (ml/min) | 227 ± 268 | 65.6 ± 54.8* | 0.37 (0.29–0.46) | 222 ± 222 | 67.6 ± 41.2* | 0.40 (0.27–0.61) |
| CLsec (ml/min) | 215 ± 268 | 59.5 ± 54.6* | 0.31 (0.25–0.39) | 211 ± 222 | 56.1 ± 41.2* | 0.31 (0.17–0.54) |
| HVA | ||||||
| Cmax (nM) | 37.3 ± 30.2 | 38.4 ± 25.3 | 1.2 (0.85–1.7) | 56.4 ± 106 | 64.1 ± 40.9 | 1.8 (1.0–3.0) |
| AUC0–last (nM•h) | 438 ± 441 | 505 ± 321 | 1.8 (0.98–2.9) | 466 ± 480 | 868 ± 603* | 2.1 (1.2–3.7) |
| CLR (ml/min) | 163 ± 192 | 61.1 ± 33.7 | 0.73 (0.49–1.1) | 169 ± 153 | 97.2 ± 58.0 | 0.67 (0.40–1.1) |
GMR, geometric mean ratio.
↵a GMR is back-transformed from log scale of the ratio of pharmacokinetic parameter in PROB alone treatment group over that in prestudy group. The 90% distribution CI of pharmacokinetic parameter is presented under 90% CI column.
↵b GMR is back-transformed from log scale of the ratio of pharmacokinetic parameter in the coadministration treatment group over that in FSM alone group. The 90% distribution CI of pharmacokinetic parameter is presented under the 90% CI column.
↵* P < 0.05;
↵** P < 0.01, when the parameter was compared with prestudy or FSM alone.