T Khariton(1), P Ghahramani(1), CL Chen(1), L Phillips(2)
(1)Forest Research Institute, Jersey City, USA; (2)Cognigen Corporation, Buffalo, NY, USA
Introduction: Cariprazine is a D3-preferring dopamine D3/D2 receptor partial agonist antipsychotic in development for the treatment of schizophrenia and bipolar mania.
Objectives: To develop a population pharmacokinetic model of cariprazine (CAR) and its two main metabolites, desmethyl-cariprazine (dCAR) and didesmethyl-cariprazine (ddCAR), and to characterize their pharmacokinetic profile in schizophrenic patients following once daily dosing with CAR.
Methods: Data from one Phase I and three Phase II studies in patients with acute exacerbation of schizophrenia or schizoaffective disorder were used in the population pharmacokinetic analysis. All four studies were multiple-dose, ranging from 0.5-12.5 mg/day for up to 48 weeks of dosing. During the studies, sparse plasma samples were collected from patients in the Phase II studies. Serial plasma samples on days 1 and 22 of dosing were obtained from patients in the Phase I study. GAM was used for the initial selection of potentially significant covariates. These covariates were used as a starting point in covariate search within NONMEM (Version 7.1).
Results: The final models are based on the 10323 plasma concentrations collected from 678 patients (approximately 21 samples per patient in the Phase I study and a median of 4 samples per patient in other studies). Results of NONMEM modeling showed that the best model describing the data for CAR, dCAR and ddCAR were the sequentially fitted two-compartment distribution with first order absorption and saturable rate of transfer from central to peripheral compartment. On average, at doses ranging from 1.5 to 4.5 mg/day, it takes 4-6 days for CAR and dCAR to achieve steady-state (functional half-life 2-3 days), and 19-23 days for ddCAR to reach steady-state (functional half-life 8-10 days). No significant covariates were identified to influence the pharmacokinetics of any of the moieties.
Conclusions: The population pharmacokinetic models adequately described the pharmacokinetic profiles of cariprazine and its two major metabolites in schizophrenic patients and could be utilized in the assessment and selection of optimal therapeutic doses.
|
|
Mean Estimate |
||
|
CAR |
dCAR |
ddCAR |
|
|
Ka (h-1) |
0.88 |
– |
– |
|
CL (L/h) |
22.7 |
80.9 |
10.4 |
|
Vc (L) |
717 (fixed) |
130 |
1902.32 |
|
Vmax (mmol/h) |
9.32 (fixed) |
0.338 (fixed) |
0.274 (fixed) |
|
Km (mmol) |
0.253 (fixed) |
0.472 (fixed) |
1.13 (fixed) |
|
Intercompartment transfer rate const. |
2.75 |
0.0597 |
0.0477 |
|
Absorption lag time (h) |
0.939 |
– |
– |
|
Proportional shift in Km due to morning dosing |
1.76 |
– |
– |
|
Residual st.dev. |
0.59 |
0.51 |
0.45 |
Reference: PAGE 21 (2012) Abstr 2643 [www.page-meeting.org/?abstract=2643]
Poster: CNS