Clin Drug Investig (2014) 34:213–222 DOI 10.1007/s40261-013-0167-9

ORIGINAL RESEARCH ARTICLE

The Pharmacokinetic and Safety Profiles of Blonanserin in Healthy Chinese Volunteers After Single Fasting Doses and Single and Multiple Postprandial Doses Xia Chen • Hongyun Wang • Ji Jiang • Rui Chen • Ying Zhou • Wen Zhong • Hongzhong Liu • Pei Hu

Published online: 8 January 2014 Ó Springer International Publishing Switzerland 2014

Abstract Background and Objectives Blonanserin is a novel atypical antipsychotic drug acting as a mixed serotonin 5-HT2A and dopamine D2 receptor antagonist. This study investigated the pharmacokinetics and safety of blonanserin in healthy Chinese males. Methods This was an open-label trial with two parts. Twenty-four subjects were enrolled in part A to receive a single fasting dose of 4 or 8 mg blonanserin (each n = 12); part B recruited 12 subjects and administered single and sequentially twice-daily multiple postprandial doses of blonanserin 2 mg for 9 days. Serial blood samples were taken for the bioassay of plasma blonanserin and its four metabolites during both sub-studies. Safety was assessed, including repeat measurements of fasting serum prolactin, insulin, triglyceride and cholesterol. Results Blonanserin was rapidly absorbed, accompanied with immediate plasma concentration elevation of the N-oxide form (M2) and gradual rises of the N-deethylated form (M1) and its downstream metabolites. The mean elimination half-life of blonanserin (7.7–11.9 h) was much longer than that of M2 (1.2–1.3 h) but shorter than that of M1 (26.4–31.4 h) after single fasting doses. After food intake, a single dose of 2 mg blonanserin resulted in total exposure and peak concentrations of blonanserin similar to those observed with a single fasting dose of blonanserin 4 mg. Moreover, the relationship of metabolite over parent compound ratio was different between M1 and M2 after

X. Chen
H. Wang
J. Jiang
R. Chen
Y. Zhou
W. Zhong
H. Liu
P. Hu (&) Clinical Pharmacology Research Center, Peking Union Medical College Hospital, 41 Damucang Alley, Xicheng District, Beijing 100032, China e-mail: [email protected]

single and multiple postprandial administrations (single dose vs multiple dose: M1, 0.33 vs 0.75; M2, 0.13 vs 0.067). Mild but transient increases of prolactin, insulin and triglyceride were observed. Conclusion The pharmacokinetics of blonanserin in Chinese subjects were similar to those observed in Japanese subjects. This study suggested that food intake not only increases the bioavailability of blonanserin but differently affects the pharmacokinetics of its metabolites as well. The drug was safe and well tolerated in healthy Chinese males.

1 Introduction Schizophrenia is a major psychiatric disorder characterized by alterations in thought, perception, affect and behaviour, which often impair personal, social and occupational functioning [1, 2]. The onset of symptoms typically occurs in young adulthood, with a global lifetime prevalence of between 0.3 and 0.7 % [3]. As of 2011, there were 24 million patients suffering from schizophrenia worldwide, accounting for about one in every 285 persons [4]. Clinical manifestations of this condition include positive symptoms (e.g. hallucinations, delusions, agitation), negative symptoms (e.g. apathy, anhedonia, avolition, alogia), disorganized symptoms, mood symptoms (e.g. depression) and possible cognitive impairment [1, 5]. Blonanserin is a novel atypical antipsychotic drug commercialized by Dainippon Sumitomo Pharma (LonasenÒ) in Japan [1] and Korea [2] for the treatment of schizophrenia. Compared with the clinically available atypical antipsychotic drugs like risperidone and olanzapine, the compound has greater binding affinity for the dopamine D2 receptors [inhibition constant (Ki) = 0.142 nM] over its affinity for

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the serotonin 5-HT2A receptors (Ki = 0.812 nM) but demonstrates low affinity for 5-HT2C, adrenergic a1, histamine H1 and muscarinic M1 receptors [6, 7]. Such pharmacological properties have been shown to cause improvement in positive symptoms of schizophrenia similar to those observed with other antipsychotic agents and resulted in greater efficacy against the negative symptoms than haloperidol [6, 8]. Meanwhile, blonanserin has demonstrated good tolerability in clinical studies, with a low propensity to induce metabolic side effects and hyperprolactinaemia. The pharmacokinetics of blonanserin have been extensively studied in healthy Japanese adults with single oral doses, repeat oral doses [9] and dosing after food intake [10]. However, Wen et al reported much higher exposure of blonanserin after single administration of 8 mg blonanserin [11] in Chinese subjects, compared with Japanese data, which was identical to the dose that subjects received in the Japanese study. Reasons for the difference are unclear, but differences in the manufacture of the study drugs, analytical methods, etc. may provide explanations to the difference. The current study was performed to delineate the pharmacokinetic profiles of blonanserin and its major metabolites and compare them with those obtained from Japanese study populations. In addition, safety profiles of blonanserin, including side effects commonly seen with other atypical antipsychotic drugs (e.g. hyperprolactinaemia, insulin resistance and hyperlipidaemia) were assessed by frequent measurements of the relevant laboratory parameters throughout the study.

X. Chen et al.

2.2 Study Design This was a single-centre, open-label study conducted in 36 Chinese males. The study was divided into two parts. Part A was a single-dose sub-study in 24 males, 12 per dose cohort. The total duration was approximately 4 weeks for each participant, including a 21-day screening session to confirm subject eligibility, a single-dose period with oral administration of 4 or 8 mg blonanserin in the fasting state on day 1 and a follow-up safety evaluation 1 week after dosing (on day 8). Part B recruited another 12 male subjects, who were dosed with 2 mg blonanserin tablets (LonasenÒ; Dainippon Sumitomo Pharma Co., Ltd, Osaka, Japan) 30 min after a standard breakfast on day 1 and then, after a wash-out period of 4 days, continued with twicedaily multiple postprandial doses of 2 mg blonanserin, also 30 min after a standard breakfast, from day 5 to the morning of day 14. This part also had a 21-day screening period prior to the first dose and a post-treatment safety evaluation on day 21. The investigational medicinal product, blonanserin tablet (for part A: 4 mg tablet, batch number 2026C; for part B: 2 mg tablet, batch number 2003F), was manufactured and supplied by Dainippon Sumitomo Pharma Co., Ltd. This study was sponsored by Dainippon Sumitomo Pharma Co., Ltd. Clinical execution was started when the study was approved by the independent ethics committee of Peking Union Medical College Hospital (PUMCH). The trial was conducted according to the ethical principles originating from the Declaration of Helsinki, as well as Good Clinical Practice and applicable local regulatory requirements. 2.3 Pharmacokinetic Assessment

2 Methods 2.1 Subjects Healthy Chinese males, aged between 18 and 40 years, with a body mass index (BMI) of 19–24 kg/m2 and a body weight no less than 50 kg, were enrolled in the study. Upon provision of written informed consent, all subjects underwent a medical screening to assure their health status based on physical examinations, medical history, electrocardiograms (ECGs) and laboratory tests within 3 weeks before the first blonanserin dose. Subjects with a history of alcohol abuse or excessive consumption of caffeinated or alcoholic drinks, or smoking more than ten cigarettes per day, were not included in the study. They were also required to refrain from using prescribed or over-the-counter medications (including traditional Chinese medicines), beverages containing grapefruit or St. John’s wort, and heavy physical activities during the study.

Blood samples for pharmacokinetic evaluation were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 5, 8, 10, 12, 14, 24, 36 and 48 h post-dose in part A. In part B, blood samples were taken at pre-dose and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 36, 48 and 72 h post-dose following the first dose on day 1; thereafter, another 22 blood samples for pharmacokinetics were drawn at various time points, i.e. at predose time points on day 5, day 7, day 9, day 11, day 13 (before breakfast) and day 14 (before breakfast), and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 36, 48, 72 and 95 h postdose following the last dose on the morning of day 14, predefined in the protocol during the multiple-dose period. Plasma concentrations of blonanserin and its four metabolites [the N-deethylated form of blonanserin (M1), N-oxide form of blonanserin (M2), ethylenediamine form of blonanserin (M3) and carboxylate form of blonanserin (M4)] were determined with a validated ultra-performance liquid chromatography coupled with tandem mass

PK and Safety of Blonanserin

spectrometry (UPLC–MS/MS) method [12]. In brief, the plasma samples were pre-purified by solid-phase extraction (SPE) and analyzed using gradient chromatographic separation on an Acquity UPLC CSH C18 column (Waters Corporation, Milford, MA, USA). The mobile phase consisted of acetonitrile–water containing 5 mM ammonium formate and 0.1 % formic acid at a flow rate of 0.5 mL/ min. Positive electrospray ionization was employed as the ionization source in the multiple reaction monitoring (MRM) mode. The analysis time for each run was about 3.5 min. The method was validated over the concentration range of 0.01–1 ng/mL for all the analytes. The lower limit of quantification (LLOQ) was 0.01 ng/mL. Inter- and intrabatch precision was less than 15 % and the accuracy was within 85–115 %. The mean extraction recoveries were 52.7 % for blonanserin, 34.9 % for M1, 58.0 % for M2, 32.8 % for M3 and 87.6 % for M4. A matrix-effect test indicated that the determination was not affected by the matrix. In addition, blonanserin and its major metabolite in plasma were proven to be stable under various storage conditions (e.g. -70 °C for at least 209 days; room temperature for 8 h; 3 freeze–thaw cycles; 10 °C in extracts for 48 h). 2.4 Safety Evaluation Safety was evaluated during each part of the study through monitoring of adverse events (AEs), and physical, ECG and laboratory examinations. Blood samples for the measurements of serum prolactin, insulin and blood chemistry (including triglyceride, cholesterol and glucose) were obtained in the fasting state at screening, on day 1, day 3 and day 8 in part A, and at screening and on day 1, day 3, day 5, day 14, day 18 and day 21 in part B. 2.5 Statistical Analysis Pharmacokinetic parameters were obtained through noncompartmental analysis using Phoenix WinNonlin version 6.3 (Pharsight Corp., Mountain View, CA, USA). The calculated pharmacokinetic parameters were the maximal plasma concentration (Cmax), time to Cmax (tmax), area under the concentration–time curve (AUC) from time zero to the time of the last quantifiable time point (AUClast), AUC from time zero to infinity (AUC?) and elimination half-life (t‘) in part A; and were defined as Cmax, tmax, AUC from time zero to 12 h post-dose (AUC12), AUC last, AUC? and t‘ after a single postprandial dose, as well as Cmax after successive twice-daily doses for 9 days and a last dose on the morning of day 14 (Cmax,Day14), trough plasma concentration on day 14 (Cmin,Day14), average plasma concentration after the last dose on day 14 (Cav,Day14), AUC from the time of dosing to the time of the

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dosing interval after the last dose on day 14 (AUCs,Day14), tmax after the last dose on day 14 (tmax,Day14) and t‘ after the last dose on day 14 (t‘,Day14) in part B. Descriptive statistics for these pharmacokinetic parameters are presented for blonanserin and its metabolites by treatment and period. The measurements of serum prolactin, insulin, glucose, triglyceride and cholesterol at each time point were summarized by treatment and period. AEs were evaluated by examining the incidence and frequency of various AEs by treatment according to the terminology of the Medical Dictionary for Regulatory Activities (MedDRA) version 15.0. All statistical analysis was performed with SAS version 9.2 (SAS Institute, Inc., Cary, NC, USA).

3 Results A total of 36 male subjects were included in this study, 24 in part A and 12 in part B. All subjects completed their study per protocol. Table 1 summarizes the demographics and baseline measurements of subjects recruited into part A and part B. In general, subjects in different treatment groups were comparable in age, weight, BMI and metabolic measurements. Standard curve and quality control samples in clinical sample analyses all met the acceptance criteria. 3.1 Pharmacokinetics In part A, following a single oral dose of 4 or 8 mg blonanserin tablets, the compound was rapidly absorbed. The plasma concentration of blonanserin peaked within 1–2 h after dosing. Thereafter, a multi-phase decline of the plasma concentration was observed. The average elimination half-life of blonanserin was longer after a single dose of 8 mg blonanserin than after 4 mg (Table 2). This difference might be related to the relatively more belowLLOQ points in the terminal phase of individual concentration–time profiles after 4 mg blonanserin compared with those after 8 mg blonanserin (Fig. 1). As the active metabolite of blonanserin generated through the cytochrome P450 3A4 (CYP3A4) pathway, the plasma concentration of the N-deethylated form (M1) rose gradually after metabolism of the parent compound. The tmax of M1 was 3–4 h longer than that of blonanserin. The elimination half-life of M1 was 2- to 3-fold longer than that of blonanserin. The ethylenediamine form (M3) and the carboxylate form (M4) are two downstream metabolites of M1. These two compounds showed time courses similar to that of M1 in their concentration–time profiles. In comparison, the N-oxide form (M2) presented a much faster

216 Table 1 Demographic and baseline characteristics of subjects

Values are expressed as mean (standard deviation) unless specified otherwise BMI body mass index

X. Chen et al.

Variable

Part A 4 mg (n = 12)

Part B 8 mg (n = 12)

2 mg (n = 12)

Age (years)

27.1 (4.89)

30.7 (6.98)

26.4 (3.99)

Male [n (%)]

12 (100 %)

12 (100 %)

12 (100 %)

Asian [n (%)]

12 (100 %)

12 (100 %)

12 (100 %)

Height (m)

1.72 (0.05)

1.68 (0.05)

1.72 (0.05)

Weight (kg)

66.9 (5.22)

62.4 (5.16)

65.7 (5.92)

BMI (kg/m2)

22.6 (1.16)

22.1 (1.60)

22.2 (1.12)

Prolactin (mIU/L)

229.18 (57.91)

211.45 (94.26)

211.75 (69.68)

Insulin (lIU/mL)

7.41 (2.45)

6.60 (3.22)

6.48 (2.08)

Triglyceride (mmol/L)

4.33 (0.80)

4.30 (0.76)

4.15 (0.68)

Cholesterol (mmol/L)

1.02 (0.73)

1.15 (0.99)

1.02 (0.50)

surge and sink of the plasma concentration after dosing with blonanserin. When subjects were administered 2 mg blonanserin after breakfast in part B, a similarly sharp rise was seen in the plasma concentration of blonanserin (Fig. 1). Because of the influence of food intake, the average Cmax and AUC values were even higher than those resulting from a single dose of 4 mg blonanserin (Tables 2, 3). The elimination half-life of blonanserin was substantially prolonged after twice-daily multiple administrations of blonanserin for 9 days, leading to a 2- to 3-fold accumulation in AUC. Notably, a single fasting dose of 4 mg blonanserin caused slightly lower average exposure of the parent compound (1.124 ng
h/mL) and M2 (0.113 ng
h/mL) but higher exposure of M1 (1.69 ng
h/mL), M3 (0.41 ng
h/mL) and M4 (4.63 ng
h/mL) compared with those observed with a single postprandial dose of 2 mg blonanserin (blonanserin, 1.4 ng
h/mL; M1, 1.071 ng
h/mL; M2, 0.144 ng
h/mL; M3, 0.043 ng
h/mL; M4, 3.547 ng
h/mL). Thus the plasma exposure of M1, M3 and M4 did not increase to an equivalent extent to the AUC elevation of the parent compound after a meal (metabolite/parent compound ratio, M1, 0.33). However, with twice-daily multiple doses of blonanserin, the geometric mean exposure relationship of the metabolite over the parent compound (M/P) for M1 (0.75) became similar to those after a single fasting dose of blonanserin 4 mg (0.74) or 8 mg (0.76). In contrast, the AUC M/P ratio for M2 was higher with a single postprandial dose of blonanserin 2 mg (0.13) than with multiple doses (0.067). The geometric mean M/P value of M4 after repeated doses (2.18) was not only higher than that after a single postprandial dose (0.55) but also higher than that after a single fasting dose of 4 or 8 mg blonanserin (1.22–1.26). The trough plasma concentrations of blonanserin and its metabolites during multiple administrations of blonanserin 2 mg indicated that the plasma exposure of blonanserin and its metabolites M1 and M4 reached steady state in 7–10 days with repeated doses, while M3 seemed to reach steady state

in more than 10 days. The trough concentrations of M2 were not measurable (Table 4). However, given its short elimination half-life, this metabolite is anticipated to reach steady state sooner than blonanserin or the other metabolites. 3.2 Safety 3.2.1 Adverse Events Single doses of 4 or 8 mg blonanserin and single and twice-daily postprandial doses of 2 mg blonanserin were generally safe and well tolerated in the selected healthy participants. A total of 31 AEs were reported by 24 subjects in part A and 55 AEs were experienced by 12 subjects in part B. All AEs were mild to moderate in severity. Except for the sparse use of paracetamol to relieve pain and fever in two subjects in part B, none of the AEs required systemic medicinal treatment. All 24 subjects in part A and 6 out of 12 subjects in part B reported ‘somnolence’, which manifested as prolongation of a daytime nap on the dosing day. All ‘somnolence’ events were mild and the severity and duration of this adverse event did not show any obvious trend of dose dependence or exposure dependence. No clinically significant changes in ECGs, vital signs or fasting blood glucose were reported in this study. 3.2.2 Endocrine Measurements Figure 2 shows individual profiles of prolactin, fasting insulin, triglyceride and cholesterol with graphical presentation of the corresponding normal range limits. 3.2.2.1 Prolactin No significant increase of average serum prolactin was observed in subjects treated with a single dose of 4 or 8 mg blonanserin in part A. Only one subject in the 8 mg group experienced mild hyperprolactinaemia (539.4 mIU/L)

PK and Safety of Blonanserin

217

Table 2 Pharmacokinetic parameters of blonanserin and its four metabolites following a single oral dose of 4 or 8 mg blonanserin Parameter

4 mg Chinese (n = 12)

8 mg Japanese (n = 8) [9]

Chinese (n = 12)

8 mg Japanese (n = 8) [9]

Chinese (n = 5) [11]

Blonanserin AUClast (ng
h/mL)

1.12 ± 0.92

0.91 ± 0.34

2.65 ± 1.59

2.82 ± 1.38

7.18 ± 2.67

Cmax (ng/mL)

0.18 ± 0.11

0.14 ± 0.04

0.40 ± 0.23

0.45 ± 0.22

1.13 ± 0.67

tmax (h)a

1.25 (0.5–5)

1.5 (1–3)

1.5 (0.5–2)

1.5 (0.5–2)

1.05 ± 0.67

t‘ (h)

7.7 ± 4.63

10.7 ± 9.36

11.9 ± 4.33

12.0 ± 4.36

14.93 ± 3.66

AUClast (ng
h/mL) Cmax (ng/mL)

1.69 ± 0.54 0.08 ± 0.02

1.12 ± 0.61 0.04 ± 0.02

3.53 ± 0.91 0.16 ± 0.04

3.67 ± 0.97 0.17 ± 0.03

4.37 ± 1.86 0.24 ± 0.12

tmax (h)

5 (3–10)

9 (5–36)

5 (5–8)

5 (3–10)

2.90 ± 1.14

t‘ (h)a

31.4 ± 11.3

29.4 ± 11.3

26.4 ± 6.1

33.1 ± 13.7

18.9 ± 4.9

M/Pb

0.74

NA

0.76

NA

NA

AUClast (ng
h/mL)

0.11 ± 0.07

0.09 ± 0.03

0.25 ± 0.11

0.27 ± 0.10

NA NA

M1 (deethylated form)

M2 (N-oxide form) Cmax (ng/mL)

0.08 ± 0.05

0.06 ± 0.03

0.17 ± 0.07

0.16 ± 0.06

tmax (h)a

0.5 (0.5–3)

0.5 (0.5–1.5)

0.5 (0.5–1.5)

0.5 (0.5–1.5)

NA

t‘ (h)

1.3 ± 0.3

1.5 ± 0.4

1.2 ± 0.3

1.6 ± 0.6

NA

M/P

0.15

NA

0.16

NA

NA

M3 (ethylenediamine form) AUClast (ng
h/mL)

0.41 ± 0.28

0.16 ± 0.07

0.97 ± 0.27

1.10 ± 0.25

NA NA

Cmax (ng/mL)

0.028 ± 0.011

0.021 ± 0.038

0.048 ± 0.011

0.057 ± 0.019

tmax (h)a

5 (2–10)

3 (1.5–8)

5 (2–10)

4 (3–10)

NA

t‘ (h) M/P

21.57 ± 10.18 0.31

15.10 ± 10.00 NA

24.73 ± 9.15 0.26

24.9 ± 10.0 NA

NA NA

M4 (carboxylate form) AUClast (ng
h/mL)

4.63 ± 1.572

4.93 ± 1.39

10.38 ± 4.56

13.70 ± 3.98

NA

Cmax (ng/mL)

0.14 ± 0.05

0.14 ± 0.03

0.30 ± 0.15

0.38 ± 0.09

NA

tmax (h)a

14 (3–24)

12 (3–24)

24 (8–24.02)

11 (3–24)

NA

t‘ (h)

88.7 ± 77.2

47.8 ± 15.4

NA

163 ± 146

NA

M/P

1.26

NA

1.22

NA

NA

Values are expressed as mean (± standard deviation) unless specified otherwise AUC area under the concentration–time curve, AUC12 AUC from time zero to 12 h post-dose, AUClast AUC from time zero to the time of the last quantifiable time point, Cmax maximal plasma concentration, NA not available, t‘ half-life, tmax time to Cmax a

Results are expressed as median (range) in the Japanese study and the present Chinese study

b

M/P is the geometric mean value of the metabolite over parent compound ratio calculated for AUC12

on day 8 of the study; the prolactin level returned to the normal range 12 days later. Nevertheless, postprandial multiple administrations of blonanserin 2 mg in part B resulted in a gradual and modest increase of the mean (± standard deviation [SD]) prolactin concentration from 230.1 (±75.2) mIU/L at baseline to 404.4 (±81.6) mIU/L on day 14, which declined rapidly to the baseline level on day 18 (223.8 ± 41.7 mIU/L) and stabilized at that level on day 21 (205.9 ± 68.6 mIU/L). Six out of the 12 subjects (incidence 50 %) had higher than normal measurements of prolactin during the study, all of whom recovered without medicinal intervention.

3.2.2.2 Insulin In part A, a small and transient elevation of fasting insulin (mean ± SD) was observed 48 h after a single oral dose of 4 mg (from 6.78 ± 2.35 lIU/mL at baseline to 11.09 ± 5.12 lIU/mL on day 3) or 8 mg blonanserin (from 5.54 ± 2.43 lIU/mL at baseline to 8.73 ± 5.30 lIU/mL on day 3). The absolute increment of serum insulin seemed to be related to the individual’s baseline level. However, the response size of serum insulin did not show an apparent trend of dose dependence or exposure dependence. Likewise, a similar change of serum insulin from baseline (5.79 ± 2.19 lIU/mL) was seen on day 3 (8.46 ± 3.49 lIU/mL) after a postprandial single dose of

218

b

Blonanserin

0.9

Plasma concentration (ng/mL)

0.8 0.7 0.6

4mgSDfast

0.5

2mgSDfed

0.4

2mgMDfed

0.3

8mgSDfast

0.2 0.1 0 -0.1 0

20

40

-0.2

60

80

100

Time(hr)

Plasma concentration (ng/mL)

M1 (Deethylated form)

0.5 0.4

4mgSDfast

0.3

2mgSDfed

0.2

2mgMDfed

0.1 0 -0.1

0

20

0

20

40

60

80

100 4mgSDfast 2mgSDfed 2mgMDfed

0.1

8mgSDfast

0.01

Time(hr)

40

60

80

100

M2 (N-oxide form)

0.14 0.12

4mgSDfast

0.1

2mgSDfed

0.08

2mgMDfed

0.06 0.04 0.02 0 -0.02 0

10

20

30

40

Time (hr)

Time (hr)

-0.2

e Plasma concentration (ng/mL)

Blonanserin 1

d 0.6

Plasma concentration (ng/mL)

c

f M3 (Ethylenediamine form) 0.07 0.06

4mgSDfast

0.05

2mgSDfed

0.04

2mgMDfed

0.03 0.02 0.01 0

0

20

40 60 Time (hr)

80

100

Plasma concentration (ng/mL)

Plasma concentration (ng/mL)

a

X. Chen et al.

M4 (Carboxylate form) 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

4mgSDfast 2mgSDfed 2mgMDfed

0

20

40 60 Time (hr)

80

100

Fig. 1 Mean plasma concentration–time profiles of a and b blonanserin (a linear scale, b semi-log scale) and its four metabolites c M1 (deethylated form), d M2 (N-oxide form), e M3 (ethylenediamine form) and f M4 (carboxylate form) after single fasting doses of 4 mg (4 mg SDfast, n = 12) and 8 mg blonanserin (8 mg SDfast, n = 12)

and single postprandial (2 mg SDfed, n = 12) and twice-daily multiple postprandial (2 mg MDfed, n = 12) doses of 2 mg blonanserin. Since M3 (ethylenediamine form) was measurable only in 7 out of 12 subjects after a single dose of 4 mg blonanserin, the average profile of M3 (ethylenediamine form) was not delineated

2 mg blonanserin. The average level of serum insulin remained higher than the baseline level on day 5 (11.41 ± 3.79 lIU/mL) and was kept at a plateau concentration when subjects were repeatedly administered blonanserin in the fed state (day 14, 9.84 ± 3.74 lIU/mL; day 18, 10.69 ± 4.99 lIU/mL). Seven days after the last dose (i.e. on day 21), the serum insulin concentration (5.60 ± 3.23 lIU/mL) returned to its pre-dose level.

3.2.2.3 Fasting Glucose No significant changes or abnormalities of fasting glucose were observed with either a single fasting dose (4 or 8 mg) or multiple postprandial doses (2 mg) of blonanserin. Average post-dose fasting glucose fluctuated between 4.64 and 5.15 mmol/L from pre-dose levels of 4.64–4.89 mmol/L during part A, and stayed between 4.34 and 4.89 mmol/L from baseline levels of 4.72–4.93 mmol/L in part B.

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219

Table 3 Pharmacokinetic parameters of blonanserin and its metabolites M1 and M2 following a single oral dose of blonanserin 2 mg and twice-daily multiple postprandial doses of blonanserin 2 mg Dosing Blonanserin Single dose

Parameter

AUC? (ng
h/mL) AUC12 (ng
h/mL) Cmax (ng/mL) tmax (h)a t‘ (h) Multiple doses AUC12,ss (ng
h/mL) Cmax,ss (ng/mL) tmax,ss (h)a t‘,ss (h) M1 (deethylated form) Single dose AUC? (ng
h/mL) AUC12 (ng
h/mL) Cmax (ng/mL) tmax (h)a t‘ (h) M/Pb Multiple doses AUC12,ss (ng
h/mL) Cmax,ss (ng/mL) tmax,ss (h)a t‘,ss (h) M/Pb M2 (N-oxide form) Single dose AUC12 (ng
h/mL) Cmax (ng/mL) tmax (h)a t‘ (h) M/Pb Multiple doses AUC12,ss (ng
h/mL) Cmax,ss (ng/mL) tmax,ss (h)a t‘,ss (h) M/Pb M3 (ethylenediamine form) Single dose AUC12 (ng
h/mL) Cmax (ng/mL) tmax (h)a t‘ (h) M/Pb Multiple dose AUC12,ss (ng
h/mL) Cmax,ss (ng/mL) tmax,ss (h)a t‘,ss (h) M/Pb M4 (carboxylate form) Single dose AUC12 (ng
h/mL) Cmax (ng/mL) tmax (h)a t‘ (h) M/Pb

Chinese (n = 12)

Japanese (n = 10) [10]

1.40 ± 0.74 0.98 ± 0.46 0.20 ± 0.11 2 (1–6) 8.5 ± 5.0 2.90 ± 1.47 0.49 ± 0.30 2 (2–3) 79.2 ± 31.3

2.27 ± 0.83 1.50 ± 0.61 0.36 ± 0.18 2 (1–4) 13.1 ± 4.0 3.22 ± 1.10 0.57 ± 0.19 2 (2–2) 67.9 ± 27.6

1.07 ± 0.58c 0.31 ± 0.10 0.04 ± 0.01 6 (5–10) 31.8 ± 10.5 0.33 2.09 ± 0.87 0.20 ± 0.09 5.5 (4–6) 38.4 ± 7.8 0.75

1.89 ± 0.63 0.37 ± 0.09 0.05 ± 0.01 5.5 (5–14) 28.9 ± 9.8 0.26 2.13 ± 0.67 0.23 ± 0.09 5 (0.5–10) 36.5 ± 10.5 0.67

0.14 ± 0.03 0.05 ± 0.02 1 (1–3) 1.5 ± 0.3 0.13 0.19 ± 0.08 0.07 ± 0.03 2 (1–3) 2.1 ± 0.6 0.067

0.11 ± 0.04 NA NA NA 0.072 0.19 ± 0.09 NA NA NA 0.055

NC 0.013 ± 0.001 5 (5–8) NC NC 0.514 ± 0.126 0.05 ± 0.013 3 (0–8) 101.4 ± 53.2 0.20

NA NA NA NA NA NA NA NA NA NA

0.52 ± 0.163 0.075 ± 0.026 10 (10–36) 54.9 ± 15.4 0.55

NA NA NA NA NA

Table 3 continued Dosing

Multiple dose

Parameter

Chinese (n = 12)

Japanese (n = 10) [10]

AUC12,ss (ng
h/mL) Cmax,ss (ng/mL) tmax,ss (h)a t‘,ss (h) M/Pb

5.762 ± 1.797 0.627 ± 0.202 4 (0–10) 155.7 ± 89.2 2.18

NA NA NA NA NA

Values are expressed as mean (± standard deviation) unless specified otherwise AUC area under the concentration–time curve, AUC12 AUC from time zero to 12 h post-dose, AUC? AUC from time zero to infinity, Cmax maximal concentration, NA not available, NC not calculated as more than one third of subjects did not have quantifiable plasma concentration of M3 during the first 12 h post-dose, ss steady state, tmax time to Cmax, t‘ halflife a M/P is the geometric mean value of the metabolite over parent compound ratio calculated for AUC12 b Results are expressed as median (range) in the Japanese study and the present Chinese study c Since the extrapolated AUC accounts for more than 20 % of AUC?, AUClast it is presented in the table for the current study

3.2.2.4 Triglyceride and Cholesterol A single fasting dose of blonanserin 4 or 8 mg did not cause significant increases of triglyceride or cholesterol in part A. In part B, a slight but consistent increase of triglyceride (mean ± SD) from baseline (1.22 ± 0.63 mmol/L) was seen on day 3 (1.35 ± 0.77 mmol/L) and day 5 (1.55 ± 1.11 mmol/L) after a single postprandial dose of 2 mg. This relatively high triglyceride level was maintained on day 14 (1.54 ± 1.13 mmol/L) with repeat doses of blonanserin 2 mg but dropped to pre-dose levels on day 18 (1.18 ± 0.48 mmol/L) and day 21 (1.13 ± 0.80 mmol/ L). However, as can be seen from Fig. 2, one subject had much higher triglyceride concentrations and larger absolute post-dose increments than the other subjects. Such an ‘outlier’ might have a significant influence on the average results. Excluding this subject, the average baseline triglyceride level became 0.89 ± 0.25 mmol/L, while the serum triglyceride concentration peaked on day 14 at 1.27 ± 0.53 mmol/L but returned to a pre-dose level (0.90 ± 0.21 mmol/L) on day 21. Conversely, no significant change in the circulating cholesterol level was observed in either part A or part B.

4 Discussion The current study characterizes the pharmacokinetic and safety profiles of blonanserin in Chinese healthy volunteers with both single fasting doses and single and twice-daily multiple postprandial dosing regimens. The pharmacokinetic parameters of blonanserin (LonasenÒ) and its four metabolites were generally similar to

220

X. Chen et al.

Table 4 Trough plasma concentrations of blonanserin and its four metabolites after repeated administration of blonanserin 2 mg Plasma concentration (ng/mL)a

Analyte

Day 1 (day 5)b

Day 3 (day 7)

Day 5 (day 9)

Day 7 (day 11)

Day 9 (day 13)

Day 10 (day 14)

Blonanserin

NA

0.082

0.080

0.124

0.110

0.128

M1

NA

0.076

0.092

0.116

0.126

0.133

M2

NA

NA

NA

NA

NA

NA

M3

NA

0.018

0.024

0029

0.032

0.041

M4

0.028

0.264

0.357

0.422

0.544

0.563

NA not available because the concentration was below the lower limit of quantification a

Geometric mean of the plasma concentrations at 1 h before administration

b

Day in parentheses is the day including the period for the single dose in the fasted state

b

Insulin

25

LLN

600

Individual Prolactin (mIU/L)

Individual Insulin (uIU/mL)

a

ULN 20

15

10

5

Prolactin

LLN ULN

500 400 300 200 100 0

0 -1

2

5

8

11

14

17

20

23

-1

2

5

8

d

Triglyceride

5 LLN

4

ULN 3 2 1 0 -1

2

5

8

11

14

17

20

23

Days

Individual Cholesterol (mmol/L)

Individual Triglyceride (mmol/L)

c

11

14

17

20

23

Days

Days 7

Cholesterol

6 5 4 3 2 LLN

1

ULN

0 -1

2

5

8

11

14

17

20

23

Days

Fig. 2 Individual safety profiles of a insulin, b prolactin, c triglyceride and d cholesterol after single postprandial and twice-daily multiple postprandial doses of blonanserin 2 mg. LLN lower limit of normal range, ULN upper limit of normal range, : demonstrates time of dosing

those reported in Japanese subjects [9]. Such pharmacokinetic similarity suggested that the higher plasma exposure of blonanserin and its active metabolite M1 in a previous Chinese pharmacokinetic study [11] might be partly explained by differences in drug manufacture and/or analytical methods between the two studies. In this study, a single postprandial dose of 2 mg blonanserin led to a plasma exposure of blonanserin that was even higher than that obtained after a single fasting dose of 4 mg blonanserin. This is consistent with the reported food effects on the bioavailability of blonanserin [10]. Moreover, distinct M/P profiles were found for M1, M2 and M4,

the three metabolites of blonanserin. Compared with the M1/P and M4/P ratios after a single fasting dose of blonanserin, the M1/P and M4/P ratios were lower after a single postprandial dose but similar or even higher after repeated postprandial doses. The lower M1/P and M4/P ratios may be attributed to the proportionally less production of M1 and M4 than those following single fasting doses. These results provide a new insight into the mechanism of the food effect. Food intake may increase the solubility of blonanserin by elevating gastric pH and enhancing biliary activity [10]. These changes may accelerate the absorption of blonanserin but may shorten the retention time of this

PK and Safety of Blonanserin

compound in the gut lumen, where CYP3A4 also exists and metabolizes blonanserin into M1 and M4 [13]. During multiple administrations, the longer elimination half-life of M1 and M4 led to greater accumulation of this metabolite than the parent compound, thus the M/P ratio increased with multiple postprandial doses. On the other hand, M2, a metabolite formed through the flavin-containing monooxygenase (FMO) pathway (Dainippon Sumitomo, data on file), is quickly generated from blonanserin and is eliminated at a much faster rate than the parent compound. As a result, the M/P ratio of M2 with a single postprandial dose is comparable to that after a single fasting dose but is reduced after multiple doses because of considerable accumulation of the parent compound. Although the M/ P value of M3 was not obtained with a single postprandial dose of 2 mg blonanserin, the scenario of M1 and M4 should be applicable for M3. The safety profiles of blonanserin in terms of endocrinal and metabolic measurements actually reflect its pharmacological properties. Hyperprolactinaemia and metabolic disturbances are common adverse drug reactions occurring in patients taking atypical antipsychotics [1, 14]. In our study, a single dose of 4 or 8 mg blonanserin only caused a slight elevation in serum insulin, while multiple postprandial doses of 2 mg blonanserin resulted in mild-to-moderate increases of both prolactin and insulin. The response of morning prolactin reached a maximal level after repeated doses but rapidly returned to normal following discontinuation of the drug. Meanwhile, the elevation of serum insulin lasted up to 3 days after the last dose (day 18). These findings indicated a concentration-dependent effect of blonanserin on the investigated endocrinal parameters. The low propensity of blonanserin to cause hyperprolactinaemia has been confirmed in patients with schizophrenia [15]. Such a favourable property was explained by the higher striatal versus pituitary D2 receptor occupancy of blonanserin [16, 17], compared with those of other atypical antipsychotics like risperidone. As for insulin, since endogenous insulin has a fast turnover rate, the maintenance of a slightly high insulin level is probably related to the pharmacological action of blonanserin and/or M1 at relevant targets in the central nervous system [18, 19]. It should be noted that blonanserin induced simultaneous elevation of fasting serum insulin and triglyceride in this study. The increment in triglyceride (i.e. around 20 % from baseline) is comparable to those reported in healthy volunteers receiving multiple doses of olanzapine 5–10 mg [20, 21]. In comparison, no significant change in insulin was identified in those studies [20, 21]. Therefore, the concurrent increase of insulin and triglyceride seen with blonanserin implies a different mechanism of hypertriglyceridaemia from those induced by olanzapine [22]. Hence

221

the metabolic side effects of blonanserin might indicate different therapies. Blonanserin was safe and well tolerated in the study population. ‘Somnolence’ was the most common adverse event reported during the study. However, the fact that all subjects were woken up very early on the morning of day 1 to start their study procedures may have somewhat contributed to their subsequent sleepiness. Since no placebo control was included in the trial, and no objective measurements were used to quantify the sedating effects, we can hardly define the actual effect size or distinguish between blonanserin-induced sedation and study-procedure-related sedation. In fact, the endocrinal findings of this study were also limited by the lack of placebo control and randomization in the study design, because the experimental settings of this study, as well as the baseline characteristics of the different dose groups, may have imposed a potential influence on those profiles. 5 Conclusion Our study in Chinese subjects presented pharmacokinetic profiles of blonanserin and its major metabolites that were similar to those reported in Japanese subjects. A distinct relationship of M/P ratios following single and multiple postprandial doses of blonanserin was identified among M1, M4 and M2. The role of gut CYP3A4 and its interaction with the change of gastrointestinal retention time with food intake may provide some explanation for such findings. Single fasting doses and single and multiple postprandial doses of blonanserin were safe and well tolerated in the selected study participants. The profiles of adverse events and endocrinal measurements reflected the pharmacological properties of the compound and were compliant with the general severity of side effects reported in schizophrenia patients treated with blonanserin. Acknowledgments The authors deeply appreciated the contributions of the study team during the conduct of this study. This study was sponsored by Dainippon Sumitomo Pharma Co., Ltd., with the assigned protocol codes of D4906009 and D4906010. This work was supported by a grant from the National Program on Key Research Project of New Drug Innovation (no. 2012ZX09303006-002). The authors have no other conflicts of interest to declare.

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