Table 4.
Pharmacokinetic parameters in rats and mice after i.v. and p.o. administration
| Route | Dose (mg/kg) | Analyte | Matrix | CL (mL/min/kg) | Vd (L/kg) | AUC0–inf (ng/mL*h or ng/g*h) | AUC0–24 h (ng/mL*h or ng/g*h) | Cmax (ng/mL or ng/g) | Tmax (h) | T1/2 (h) |
|---|---|---|---|---|---|---|---|---|---|---|
| CAR | ||||||||||
| Rat | ||||||||||
| i.v. | 1 | CAR | Plasma | 32±4.6 | 6.5±1.2 | 533±72 | 2.4±0.7 | |||
| p.o.a | 1 | CAR | Plasma | 279±48 | 91±16 | 0.5–1 | 2.2±0.4 | |||
| p.o.b | 1 | CAR | Plasma | 181 | 180 | 36 | 1 | 2.9 | ||
| Brain | 2178 | 1965 | 247 | 1 | 6.9 | |||||
| DDCAR | Plasma | 12 | 11 | 1.0 | 4 | 6.7 | ||||
| Brain | nc | 104 | 6.9 | 4 | nc | |||||
| p.o.c | 1 | CAR | Dialysate (cortex) | 12±4.1d | 4.7±1.9 | 3.3–4.7 | ||||
| Dialysate (striatum) | 11±2.9d | 4.7±1.5 | 3.0–6.3 | |||||||
| Mouse | ||||||||||
| p.o. | 1 | CAR | Plasma | 509 | 505 | 65 | 2 | 3.3 | ||
| Brain | 3977 | 3703 | 330 | 2 | 5.9 | |||||
| DDCAR | Plasma | nc | 75 | 4.2 | 8 | nc | ||||
| Brain | nc | 199 | 10 | 8 | nc | |||||
| DDCAR | ||||||||||
| Rat | ||||||||||
| i.v. | 1 | DDCAR | Plasma | 35±4.9 | 9.2±1.0 | 483±67 | 3.0±0.2 | |||
| p.o. | 0.9 | DDCAR | Plasma | 155 | 152 | 22 | 1 | 4.3 | ||
| Brain | 919 | 801 | 74 | 2 | 8.1 |
Notes: aBioavailability study. bBrain penetrability study. cMicrodialysis study (parameters calculated from the free extracellular concentrations). dAUC0–5h parameters are given as mean±SD.
Abbreviations: AUC0-24h, area under the concentration versus time curve from 0 (administration of the compound) to 24 h; AUC0-inf, area under the concentration versus time curve extrapolated to infinity; CAR, cariprazine; CL, systemic clearance; Cmax, maximum concentration; DDCAR, didesmethyl-cariprazine; i.v., intravenous; nc, not calculable; p.o., per os; SD, standard deviation; T1/2, terminal half-life; Tmax, time to maximum concentration; Vd, volume of distribution.