TABLE 1.
Noncompartmental PK parameters of PSI-6130 after i.v. and oral administration of 33.3 mg/kg to three rhesus monkeys
| Parametera | Unit | Value following i.v. administration
|
Value following oral administration
|
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| M-1b | M-2 | M-3 | Mean | SD | Pooled | M-1 | M-2 | M-3 | Mean | SD | Pooled | ||
| r2 | 1.00 | 0.97 | 0.86 | 0.94 | 0.07 | 0.98 | 0.92 | 0.43 | 0.44 | 0.60 | 0.28 | 0.56 | |
| λz | h−1 | 0.08 | 0.40 | 0.25 | 0.24 | 0.16 | 0.16 | 0.14 | 0.10 | 0.14 | 0.13 | 0.02 | 0.14 |
| t1/2β | h | 9.09 | 1.74 | 2.78 | 4.54 | 3.98 | 4.25 | 5.08 | 6.94 | 4.90 | 5.64 | 1.13 | 5.09 |
| Tmax | h | 0.25 | 0.25 | 0.25 | 0.25 | 0.00 | 0.25 | 2.00 | 3.00 | 1.00 | 2.00 | 1.00 | 2.00 |
| Cmax | μM | 146 | 142 | 174 | 154.2 | 17.4 | 154 | 10.2 | 11.9 | 6.81 | 9.64 | 2.59 | 8.45 |
| AUC | μM h | 147 | 253 | 303 | 235.2 | 79.7 | 235 | 36.4 | 69.2 | 26.8 | 44.1 | 22.2 | 52.7 |
| Vβ/(Vβ/F) | liters kg−1 | 11.4 | 1.3 | 1.7 | 4.8 | 5.7 | 3.5 | 23.5 | 13.1 | 29.2 | 21.9 | 8.1 | 17.6 |
| CL/(CL/F) | liters h−1 kg−1 | 0.87 | 0.51 | 0.42 | 0.60 | 0.24 | 0.55 | 3.21 | 1.31 | 4.13 | 2.88 | 1.44 | 2.39 |
| MRT | h | 2.59 | 2.29 | 2.62 | 2.50 | 0.18 | 2.40 | 5.09 | 10.25 | 5.99 | 7.11 | 2.76 | 7.21 |
| Vss | liters kg−1 | 2.26 | 1.16 | 1.11 | 1.51 | 0.65 | 1.31 | ||||||
| AUMC | μM h2 | 383 | 581 | 795 | 586 | 205 | 564 | 203 | 1004 | 186 | 464 | 467 | 386 |
| %Exp6206 | % | 33.7 | 20.1 | 10.0 | 19.7 | 11.9 | 19.4 | 81.1 | 50.9 | 79.2 | 69.9 | 17.0 | 69.2 |
| CSF6130 | μM | 6.49 | 0.98 | 3.58 | 3.67 | 2.78 | 0.38 | 0.45 | 0.0 | 0.28 | 0.25 | ||
| CSF6206 | μM | 2.45 | 0.99 | 1.00 | 1.38 | 0.66 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | ||
| MAT | h | 2.49 | 7.96 | 3.38 | 4.61 | 2.93 | 4.81 | ||||||
| F | % | 27.1 | 38.6 | 10.2 | 24.0 | 14.3 | 22.8 | ||||||
| Ftotal | % | 95.2 | 62.8 | 44.3 | 63.9 | 25.7 | 59.6 | ||||||
Cmax and Tmax, observed peak concentration in serum and time of maximum concentration after dose administration, respectively; λz, first-order elimination rate constant from serum; t1/2β, apparent half-life; AUC, area under the serum concentration-versus-time curve extrapolated to infinity; CL, systemic clearance after i.v. administration; Vβ, distribution volume after i.v. administration; CL/F, systemic clearance/F after oral administration; Vβ/F, distribution volume/F after oral administration; Vss, steady-state distribution volume; AUMC, area under first-moment curve extrapolated to infinity; r2, linear correlation coefficient of observed versus predicted concentrations in serum for the terminal phase of elimination used to calculate λz; %Exp6206 = AUC6206/(AUC6130 + AUC6206) × 100; F, PSI-6130 oral bioavailability; Ftotal, total bioavailability (PSI-6130 plus PSI-6206); MAT, mean absorption time.
M-1, monkey 1; M-2, monkey 2; M-3, monkey 3.