Clinical pharmacology study of cariprazine (MP-214) in patients with schizophrenia (12-week treatment)

Figures & data

Figure 1 Study flow.

Table 1 Baseline demographics and characteristics (safety population)

Baseline variable	Cariprazine 3 mg (n=11)	Cariprazine 6 mg (n=16)	Cariprazine 9 mg (n=11)	Total
Demographics
Race, n (%)
Japanese	11 (100)	16 (100)	11 (100)	38 (100)
Age, mean (SD) (years)	43.2 (13.2)	43.1 (10.7)	43.2 (13.3)	43.1 (11.9)
Male, n (%)	6 (54.5)	7 (43.8)	5 (45.5)	18 (47.4)
Weight, mean (SD) (kg)	70.6 (19.5)	67.3 (16.1)	62.8 (14.6)	66.9 (16.5)
BMI, mean (SD) (kg/m^2)	25.4 (4.4)	25.6 (4.5)	24.3 (4.1)	25.2 (4.3)
History of medical complications, n (%)	10 (90.9)	13 (81.3)	10 (90.9)	33 (86.8)
History of surgery, n (%)	1 (9.1)	0	0	1 (2.6)
Psychiatric characteristics
Duration of schizophrenia, mean (SD) (years)	14 (15.4)	15.5 (15)	14.6 (14.7)	14.8 (14.6)
Schizophrenia subtypes, n (%)
Paranoid	3 (27.3)	8 (50)	6 (54.5)	17 (44.7)
Disorganized	1 (9.1)	1 (6.3)	0 (0)	2 (5.3)
Catatonic	0 (0)	1 (6.3)	1 (9.1)	2 (5.3)
Undifferentiated	3 (27.3)	1 (6.3)	0 (0)	4 (10.5)
Residual	4 (36.4)	5 (31.3)	4 (36.4)	13 (34.2)
Psychiatric history, n (%)
First appearance	7 (63.6)	6 (37.5)	5 (45.5)	18 (47.4)
Relapse	4 (36.4)	10 (62.5)	5 (45.5)	19 (50.0)
Unknown	0	0	1 (9.1)	1 (2.6)
Previous antipsychotic drug, n (%)	11 (100)	16 (100)	11 (100)	38 (100)
PANSS total, mean (SD)a	70.5 (15.8)	60.3 (21.8)	75.4 (21.1)	NR

Note:

a Baseline PANSS values based on efficacy analysis population, which included all randomized patients with evaluable data (n=38).

Abbreviations: BMI, body mass index; NR, not reported; PANSS, Positive and Negative Syndrome Scale; SD, standard deviation.

Table 2 The ratios of plasma trough concentrations during day 2 – week 10 to the last day of treatment (week 12) (pharmacokinetic analysis population)

Treatment period/Week 12	Mean (95% CI)
	Cariprazine			Desmethyl-cariprazine			Didesmethyl-cariprazine
	3 mg (n=9)	6 mg (n=8)	9 mg (n=7)	3 mg (n=9)	6 mg (n=8)	9 mg (n=7)	3 mg (n=9)	6 mg (n=8)	9 mg (n=7)
Day 2/Week 12	0.16 (0.08, 0.24)a	0.10 (0.05, 0.14)	0.07 (0.05, 0.09)	0.10 (0.07, 0.14)b	0.09 (0.05, 0.13)	0.04 (0.02, 0.06)	0.002 (0.000, 0.004)a	0.003 (0.001, 0.005)	0.002 (0.000, 0.004)
Day 3/Week 12	1.91 (−1.01, 4.82)	0.29 (0.19, 0.40)	0.27 (0.20, 0.35)	0.49 (0.32, 0.65)a	0.31 (0.19, 0.42)	0.22 (0.11, 0.33)	0.19 (−0.19, 0.58)	0.02 (0.01, 0.04)	0.02 (0.01, 0.03)
Week 1/Week 12	1.05 (0.91, 1.18)	0.92 (0.72, 1.12)	0.93 (0.71, 1.14)	0.89 (0.71, 1.07)a	0.96 (0.76, 1.16)	0.73 (0.54, 0.92)	0.43 (0.00, 0.86)	0.32 (0.23, 0.42)	0.26 (0.16, 0.36)
Week 2/Week 12	1.04 (0.80, 1.27)	1.15 (0.86, 1.43)	1.05 (0.75, 1.35)	1.00 (0.79, 1.22)a	1.12 (0.84, 1.40)	1.03 (0.85, 1.20)	0.99 (0.09, 1.89)	0.78 (0.57, 1.00)	0.71 (0.57, 0.85)
Week 3/Week 12	0.94 (0.75, 1.14)	1.09 (0.87, 1.31)	1.04 (0.87, 1.21)	1.22 (0.91, 1.52)a	1.03 (0.91, 1.14)	0.75 (0.56, 0.95)	1.13 (0.58, 1.69)	0.89 (0.75, 1.03)	0.90 (0.72, 1.07)
Week 4/Week 12	0.79 (0.58, 0.99)	0.96 (0.79, 1.12)	1.03 (0.76, 1.30)	1.02 (0.66, 1.37)a	1.07 (0.85, 1.28)	0.83 (0.70, 0.95)	1.07 (0.71, 1.44)	0.95 (0.80, 1.11)	0.93 (0.75, 1.11)
Week 5/Week 12	1.48 (0.06, 2.89)	0.97 (0.87, 1.07)	1.03 (0.70, 1.37)	1.62 (0.20, 3.04)a	1.01 (0.78, 1.24)	0.95 (0.82, 1.09)	2.23 (−0.49, 4.95)	0.92 (0.79, 1.06)	0.95 (0.82, 1.09)
Week 6/Week 12	1.12 (0.73, 1.51)	0.99 (0.86, 1.12)	0.98 (0.65, 1.31)	1.10 (0.78, 1.42)a	1.03 (0.87, 1.20)	1.11 (0.80, 1.43)	1.14 (0.85, 1.43)	0.93 (0.74, 1.12)	1.14 (0.71, 1.57)
Week 7/Week 12	0.94 (0.79, 1.09)	1.03 (0.87, 1.20)	0.96 (0.68, 1.24)	1.02 (0.78, 1.27)a	1.10 (0.86, 1.34)	0.98 (0.78, 1.17)	1.25 (0.64, 1.86)	1.04 (0.79, 1.30)	1.04 (0.71, 1.38)
Week 8/Week 12	0.81 (0.65, 0.98)	0.95 (0.76, 1.15)	0.96 (0.77, 1.16)	1.01 (0.78, 1.23)a	1.03 (0.88, 1.19)	1.01 (0.81, 1.21)	1.09 (0.84, 1.35)	1.01 (0.86, 1.16)	1.03 (0.80, 1.26)
Week 10/Week 12	1.37 (0.36, 2.38)	0.94 (0.80, 1.08)	0.99 (0.69, 1.30)	1.00 (0.78, 1.21)a	1.11 (0.89, 1.32)	0.95 (0.71, 1.20)	1.03 (0.90, 1.17)	0.98 (0.83, 1.13)	1.02 (0.88, 1.16)

Notes:

a n=8;

b n=7.

Abbreviation: CI, confidence interval.

Figure 2 Plasma concentrations of cariprazine (A), desmethyl-cariprazine (B), didesmethyl-cariprazine (C) and total active moieties (sum of cariprazine, desmethyl-cariprazine and didesmethyl-cariprazine) (D) for each dose group during the treatment and follow-up periods.

Notes: Data are mean + standard deviation. The lower limit of quantification of analytes was 0.02 ng/mL. The mean was not plotted when at least half of the results were below the lower limit of detection except at time =0.

Table 3 Pharmacokinetic parameters measured on the first and last days of the 12-week treatment period (pharmacokinetic analysis population)

Parameter	First day of treatment period (day 1)a			Last day of treatment period (week 12)
	Cariprazine	Desmethyl-cariprazine	Didesmethyl-cariprazine	Cariprazine	Desmethyl-cariprazine	Didesmethyl-cariprazine
3 mg
n	11	11	11	9	9	9
Cmax, mean (SD) (ng/mL)	2.01 (1.16)	0.17 (0.08)	0.04 (0.05)	10.2 (4.69)	2.62 (1.52)	15.8 (10.9)
Cmax/dose, mean (SD) (ng/mL/mg/kg)	NR	NR	NR	216 (71.6)	52.7 (18.4)	316 (154)
tmax, median (range) (hours)	3.08 (2.83–5.83)	23.5 (4.08–27.1)	23.5 (6–26.6)b	3.02 (2.85–4.08)	4 (3–6.08)	3.08 (0–23.6)
AUC0–24, mean (SD) (ng·h/mL)	27.5 (17.1)c	3.14 (1.53)c	0.44 (0.65)c	156 (72)	50 (31.2)	352 (253)
AUC0–24/dose, mean (SD) (ng·h/mL/mg/kg)	NR	NR	NR	3,291 (1,098)	998 (390)	6,985 (3,570)
kel, mean (SD) (hour^−1)	NR	NR	NR	0.012 (0.004)	0.019 (0.004)	0.002 (0.0004)
t1/2,z, mean (SD) (hours)	NR	NR	NR	68.4 (46)	37.5 (6.7)	399 (84.7)
6 mg
n	16	16	16	8	8	8
Cmax, mean (SD) (ng/mL)	2.09 (0.64)	0.27 (0.18)	0.06 (0.07)	22.7 (4.18)	5.96 (1.59)	35.9 (8)
Cmax/dose, mean (SD) (ng/mL/mg/kg)	NR	NR	NR	254 (84.9)	64.6 (15.6)	403 (159)
tmax, median (range) (hours)	3.93 (2.83–7.83)	15.7 (7.75–24.6)	23.5 (23.1–25.5)d	2.99 (2.83–5.83)	3.95 (2.83–7.92)	4.86 (2.83–23.5)
AUC0–24, mean (SD) (ng·h/mL)	29.2 (8.48)e	5.17 (3.41)e	0.75 (0.95)e	358 (85.2)	115 (23.5)	800 (207)
AUC0–24/dose, mean (SD) (ng·h/mL/mg/kg)	NR	NR	NR	4,033 (1,575)	1,259 (314)	8,941 (3,819)
kel, mean (SD) (hour^−1)	NR	NR	NR	0.016 (0.003)	0.020 (0.005)	0.002 (0.0005)
t1/2,z, mean (SD) (hours)	NR	NR	NR	44.3 (6.9)	37.2 (10.6)	446 (114)
9 mg
n	11	11	11	7	7	7
Cmax, mean (SD) (ng/mL)	1.97 (0.4)	0.24 (0.13)	0.07 (0.06)	28.8 (8.02)	8.55 (3.75)	51.8 (32.7)
Cmax/dose, mean (SD) (ng/mL/mg/kg)	NR	NR	NR	193 (78.4)	54.4 (15.7)	334 (172)
tmax, median (range) (hours)	3.88 (2.88–8)	23.5 (5.83–26.8)	23.7 (23.5–25.2)f	4 (2.83–4.13)	6 (2.83–6.23)	6 (3–23.8)
AUC0–24, mean (SD) (ng·h/mL)	28.7 (4.65)	4.51 (2.36)	0.85 (0.80)	466 (154)	163 (72.7)	1,140 (712)
AUC0–24/dose, mean (SD) (ng·h/mL/mg/kg)	NR	NR	NR	3,160 (1,510)	1,038 (311)	7,351 (3,731)
kel, mean (SD) (hour^−1)	NR	NR	NR	0.024 (0.009)	0.024 (0.004)	0.002 (0.0005)
t1/2,z, mean (SD) (hours)	NR	NR	NR	31.6 (9.9)	29.7 (6.2)	314 (60.3)

Notes:

a All patients received 1.5 mg/day cariprazine on the first day of the treatment period.

b n=6.

c n=10.

d n=12.

e n=15.

F n=8.

Abbreviations: AUC_0–24, area under the plasma concentration–time curve from time zero to 24 hours; C_max, maximum plasma concentration; k_el, apparent terminal elimination rate constant; NR, not reported; SD, standard deviation; t_1/2z, terminal elimination half-life; t_max, time to C_max.

Table 4 Summary of adverse events

n (%)	Cariprazine 3 mg (n=11)	Cariprazine 6 mg (n=16)	Cariprazine 9 mg (n=11)	Total (N=38)
Summary of AEs reported during the treatment and follow-up periods
Patients with ≥1 TEAE	11 (100)	15 (93.8)	11 (100)	37 (97.4)
Patients with ≥1 SAE	0 (0)	2 (12.5)	0 (0)	2 (5.2)
Patients with ≥1 ADRa	8 (72.7)	14 (87.5)	9 (81.8)	31 (81.6)
Patients with ≥1 NEAEb	8 (72.7)	12 (75)	6 (54.5)	26 (68.4)
Incidence of TEAEs during the 12-week treatment period	c,d
Restlessness	5 (45.5)	3 (18.8)	2 (18.2)	10 (26.3)
Akathisia	3 (27.3)	2 (12.5)	3 (27.3)	8 (21.1)
Insomnia	2 (18.2)	4 (25)	2 (18.2)	8 (21.1)
Schizophrenia	1 (9.1)	5 (31.3)	1 (9.1)	7 (18.4)
Nasopharyngitis	2 (18.2)	2 (12.5)	1 (9.1)	5 (13.2)
Gastroenteritis	0 (0)	3 (18.8)	1 (9.1)	4 (10.5)
Somnolence	0 (0)	3 (18.8)	1 (9.1)	4 (10.5)
Constipation	0 (0)	2 (12.5)	1 (9.1)	3 (7.9)
Nausea	2 (18.2)	1 (6.3)	0 (0)	3 (7.9)
Vomiting	1 (9.1)	1 (6.3)	1 (9.1)	3 (7.9)
Increased ALT	1 (9.1)	1 (6.3)	0 (0)	2 (5.3)
Increased AST	0 (0)	2 (12.5)	0 (0)	2 (5.3)
Increased blood creatine phosphokinase	0 (0)	2 (12.5)	0 (0)	2 (5.3)
Increased blood prolactin	1 (9.1)	0 (0)	1 (9.1)	2 (5.3)
Gastritis	2 (18.2)	0 (0)	0 (0)	2 (5.3)
Tremor	0 (0)	2 (12.5)	0 (0)	2 (5.3)
Increased WBC count	1 (9.1)	1 (6.3)	0 (0)	2 (5.3)
URTI	1 (9.1)	0 (0)	1 (9.1)	2 (5.3)
Incidence of TEAEs during the follow-up period^b,c
Nasopharyngitis	1 (9.1)	4 (25)	0 (0)	5 (13.2)
Akathisia	2 (18.2)	1 (6.3)	0 (0)	3 (7.9)
Dental caries	1 (9.1)	1 (6.3)	1 (9.1)	3 (7.9)
Hyperkeratosis	1 (9.1)	1 (6.3)	0 (0)	2 (5.3)
Myalgia	1 (9.1)	0 (0)	1 (9.1)	2 (5.3)
Pain in extremity	0 (0)	1 (6.3)	1 (9.1)	2 (5.3)
Restlessness	1 (9.1)	1 (6.3)	0 (0)	2 (5.3)
Vomiting	0 (0)	1 (6.3)	1 (9.1)	2 (5.3)

Notes:

a Adverse drug reactions were defined as adverse events for which causal relationship with cariprazine was determined to be “reasonably possible”.

b Incidence of NEAEs is only during the follow-up period.

c Incidence of TEAEs occurring in at least two patients in any dose group during the treatment period.

d Listed in descending order of frequency for the total patient population.

Abbreviations: ADR, adverse drug reaction; AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; NEAE, newly emergent adverse event; SAE, serious adverse event; TEAE, treatment-emergent adverse event; URTI, upper respiratory tract infection; WBC, white blood cell.

Table 5 Summary of efficacy assessments (efficacy analysis population)

Parameter	Cariprazine 3 mg (n=11)	Cariprazine 6 mg (n=16)	Cariprazine 9 mg (n=11)
PANSS, total score
Baseline score, mean (SD)	70.5 (15.8)	60.3 (21.8)	75.4 (21.1)
Change from baseline at week 6, LSMa (95% CI)	−3.2 (−7.7, 1.3)	1.8 (−2.0, 5.6)	−4.2 (−8.8, 0.4)
Change from baseline at week 12, LSMa (95% CI)	−5.2 (−11.1, 0.8)	−1.1 (−6.2, 4.0)	−7.4 (−13.5, −1.3)
PANSS, positive scores
Baseline score, mean (SD)	15.4 (4.2)	12.9 (5.5)	17.6 (6.3)
Change from baseline at week 6, LSMa (95% CI)	−0.4 (−1.9, 1.2)	0.3 (−1.0, 1.6)	−1.4 (−2.9, 0.2)
Change from baseline at week 12, LSMa (95% CI)	−1.3 (−3.5, 1.0)	0 (−2.0, 1.9)	−1.3 (−3.7, 1.0)
PANSS, negative scores
Baseline score, mean (SD)	20.8 (6.0)	17.6 (7.9)	21.5 (8.5)
Change from baseline at week 6, LSMa (95% CI)	−1.8 (−4.3, 0.7)	0.1 (−2.0, 2.3)	−1.6 (−4.1, 0.9)
Change from baseline at week 12, LSMa (95% CI)	−1.9 (−4.7, 0.9)	−1.1 (−3.4, 1.2)	−2.0 (−4.8, 0.8)
CGI-S
Baseline score, mean (SD)	3.2 (0.9)	3.2 (1.2)	3.5 (1.1)
Change from baseline at week 6, LSMa (95% CI)	0.1 (−0.2, 0.4)	0.3 (0, 0.6)	0.2 (−0.1, 0.5)
Change from baseline at week 12, LSMa (95% CI)	0 (−0.4, 0.4)	0.1 (−0.3, 0.4)	0 (−0.4, 0.4)
CGI-I
Week 6 score, LSMa (95% CI)	4.2 (3.7, 4.7)	4.4 (4.0, 4.8)	3.8 (3.2, 4.3)
Week 12 score, LSMa (95% CI)	3.9 (3.2, 4.6)	4.2 (3.6, 4.8)	3.3 (2.6, 4.0)

Note:

a LSM values were calculated using the last-observation-carried-forward approach.

Abbreviations: CGI-I, Clinical Global Impressions-Improvement; CGI-S, Clinical Global Impressions-Severity; CI, confidence interval; LSM, least squares mean; PANSS, Positive and Negative Syndrome Scale; SD, standard deviation.