Table 3.
Relationship between main PK parameters and dose of BIA 10‐2474
| Single Ascending Dose (SAD) | |||||
|---|---|---|---|---|---|
| Dose (mg) | Fold increase in dose# | Cmax (ng/mL) | Fold increase in Cmax # | AUC0–t (ng⋅hour/mL) | Fold increase in AUC0–t # |
| 0.25 | — | — | — | — | — |
| 1.25 | — | 16.2 | — | 98.0 | — |
| 2.5 | 2.0 | 31.2 | 1.9 | 289 | — |
| 5 | 2.0 | 85.4 | 2.7 | 693 | 2.4 |
| 10 | 2.0 | 146 | 1.7 | 1,441 | 2.1 |
| 20 | 2.0 | 308 | 2.1 | 4,073 | 2.8 |
| 40 | 2.0 | 790 | 2.6 | 8,751 | 2.2 |
| 100 | 2.5/‐ | 1,772 | 2.2 | 22,991 | 2.6 |
| Overall* | 20 | 14.5 | 19.6 | ||
| DPF+ | 1.0 | 0.8 | 0.9 | ||
| Exponent† | 0.93 (0.81; 1.05) |
1.05 (0.88; 1.21) |
|||
| Multiple Ascending Dose (MAD) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Dose (mg) | Day 1 | Day 10 | ||||||||
| Fold increase in dose# | Cmax (ng/mL) | Fold increase in Cmax # | AUC0‐τ (ng⋅h/mL) | Fold increase in AUC0–τ # | Fold increase in dose# | Cmax (ng/mL) | Fold increase in Cmax # | AUC0‐τ (ng⋅h/mL) | Fold increase in AUC0–τ # | |
| 2.5 | — | 46.0 | — | 397 | — | — | 52.6 | — | 526 | — |
| 5 | 2.0 | 76.2 | 1.7 | 708 | 1.8 | 2.0 | 85.7 | 1.6 | 909 | 1.7 |
| 10 | 2.0 | 143 | 1.9 | 1393 | 2.0 | 2.0 | 190 | 2.2 | 2198 | 2.4 |
| 20 | 2.0 | 290 | 2.0 | 2983 | 2.1 | 2.0 | 396 | 2.1 | 4651 | 2.1 |
| 50 | 2.5 | 667 | 2.3 | 7768 | 2.6 | |||||
| Overall* | 20 | 14.5 | 19.6 | 8 | 7.53 | 8.84 | ||||
| DPF+ | 1.0 | 0.8 | 0.9 | 1.0 | 0.9 | 1.1 | ||||
| Exponent† | 0.93 (0.81; 1.05) | 1.05 (0.88; 1.21) | 1.06 (0.88; 1.24) | 1.11 (0.93; 1.29) | ||||||
Relationship between main pharmacokinetic parameters and dose of BIA 10‐2474 following single oral doses (SAD part) and multiple (MAD part) oral doses.
AUC, area under plasma concentration‐time curve; Cmax, maximum observed plasma concentration; PK, pharmacokinetic; #, fold increase in dosage or parameters between adjacent dosages (start at 1.25 mg for 1Cmax and at 2.5 mg for 2AUC0–t); *, fold increase in dosage or parameter over the dosage range 0.25 to 100 mg BIA 10‐2474 (range 1.25 to 100 mg for 1Cmax and 2.5 to 100 mg for 2AUC0–t); +, DPF, dose proportionality factor, ratio of fold increase in parameter divided by fold increase in dosage; †, exponent of the power model (95% confidence interval); —, data not calculated or available.