Asenapine pharmacokinetics and tolerability in a pediatric population

Figures & data

Figure 1 Design and dosing schedule for (A) study 1 and (B) study 2.

Notes: In study 1, screening was performed within 3 weeks of baseline. Dosing was BID, except for the last day of dosing (only morning dose administered). In study 2, screening was performed within 28 days prior to baseline. Sublingual asenapine was given BID. Cohort 3a was originally scheduled similarly to cohorts 3b–3d (5 mg BID on day 1 followed by 10 mg BID thereafter); however, after safety results of cohort two became available, a protocol amendment modified the original treatment regimen (slower titration to 10 mg asenapine) to improve tolerability. ^a≥4 subjects per group must have been between 12 and 15 years of age.
Abbreviation: BID, bis in die (twice daily).

Figure 2 Mean asenapine plasma concentration–time profiles.

Notes: Following administration of sublingual asenapine 1–10 mg BID (final dose) for study 1 (top) and study 2 (bottom). Inset represents concentrations on a semilogarithmic scale.
Abbreviation: BID, bis in die (twice daily).

Table 1 PK parameters for asenapine following multiple BID doses by dose and age

Dose	Cohort	Age, years	n	Cmax, ng/mL	Tmax, hours	AUC0–12, ng⋅h/mL	t1/2, hours
Study 1
1 mg	1	12–17	8a	1.0 (50)	0.7 (0.3–1.5)	6.6 (61)	29 (41)
3 mg	2	12–17	8b	2.6 (56)	0.9 (0–1.5)	16 (50)	26 (25)
5 mg	3	12–17	8	3.5 (48)	1.0 (0–2.8)	23 (48)	32 (38)
10 mg	4	12–17	8	2.8 (82)	1.3 (0–3.0)	20 (54)	23 (22)
Study 2
2.5 mg	1	10–11	6	1.8 (64)	1.0 (0.5–2.0)	11 (54)	22 (28)
5 mg	2	10–11	6	3.5 (18)	1.8 (1.5–3.0)	24 (17)	19 (17)
10 mg	3a–d	10–17	15	7.8 (49)	1.0 (0.5–3.0)	44 (45)	20 (45)
10 mg dose by age cohort
	3a	10–11	4	9.2 (56)	1.5 (0.5–1.5)	55 (38)	16 (15)
	3b	12–13	4	6.8 (10)	1.0 (1.0–1.0)	41 (23)	17 (20)
	3c	14–15	3	7.0 (93)	0.5 (0.5–3.0)	37 (101)	24 (61)
	3d	16–17	4	7.9 (34)	1.0 (0.5–1.5)	42 (30)	25 (45)

Notes: For both studies, T_max shown as medians (range); all other PK parameters shown as arithmetic mean (%CV).

a n=7 for t_1/2;

b n=5 for t_1/2.

Abbreviations: AUC_0–12, area under the plasma concentration–time curve from 0 to 12 hours; BID, bis in die (twice daily); C_max, maximum plasma concentration; CV, coefficient of variation; PK, pharmacokinetic; t_1/2, half-life; T_max, time to C_max.

Table 2 Treatment-emergent adverse events (TEAEs) by dose

TEAE	Study 1 (n =40)					Study 2 (n= 30)
	Placebo (n=8)	Asenapine				Asenapine
		Cohort 1, 1 mg (n=8)	Cohort 2, 3 mg (n=8)	Cohort 3, 5 mg (n=16)a	Cohort 4, 10 mg (n=8)	Cohort 1, 2.5 mg (n=6)	Cohort 2, 5 mg (n=6)	Cohort 3, 10 mg (n=6)a	Cohort 3, 10 mg (n=12)b^–d	Cohort 3, 10 mg (n=18)b
Any TEAE, n (%)	6 (75)	5 (62.5)	8 (100)	14 (87.5)	8 (100)	3 (50)	4 (67)	1 (16.7)	10 (83.3)	11 (61)
TEAEs by preferred term in ≥2 patients in any cohort, n (%)
Dysgeusia	1 (12.5)	2 (25)	4 (50)	3 (18.8)	2 (25)	1 (17)	0	0	7 (58.3)	7 (39)
Sedation	0	2 (25)	4 (50)	7 (43.8)	0	2 (33)	2 (33)	0	1 (8.3)	1 (6)
Hypoesthesia, oral	1 (12.5)	1 (12.5)	4 (50)	1 (6.3)	0	1 (17)	0	0	9 (75)	9 (50)
Somnolence	1 (12.5)	0	0	1 (6.3)	4 (50)	1 (17)	0	0	5 (41.7)	7 (39)
Dizziness	1 (12.5)	0	1 (12.5)	1 (6.3)	1 (12.5)	0	2 (33)	0	7 (58.3)	7 (39)
Headache	1 (12.5)	0	2 (25)	2 (12.5)	1 (12.5)	0	1 (17)	0	2 (16.7)	2 (11)
Glossalgia	1 (12.5)	0	0	6 (37.5)	1 (12.5)	0	0	0	0	0
Nausea	1 (12.5)	1 (12.5)	0	1 (6.3)	0	0	2 (33)	1 (16.7)	1 (8.3)	2 (11)
Dystonia	0	0	0	0	0	0	4 (67)	0	3 (25)	3 (17)
Paresthesia, oral	0	0	0	2 (12.5)	4 (50)	0	0	0	0	0
Fatigue	1 (12.5)	0	1 (12.5)	0	2 (25)	0	0	0	0	0
Contusion	0	0	2 (25)	2 (12.5)	0	0	0	0	0	0
Vomiting	0	0	0	1 (6.3)	0	0	2 (33)	0	0	0
Extrapyramidal disorder	1 (12.5)	0	0	0	2 (25)	0	0	0	0	0
Salivary hypersecretion	0	0	0	0	0	0	2 (33)	0	0	0
Hostility	0	0	0	0	2 (25)	0	0	0	0	0

Notes: TEAEs in descending order across both studies.

a Eight patients received 5 mg for 10 days (study 1, cohort 3) and another eight received 5 mg for 1 day as the titration step to subsequent 10 mg for 10 days (cohort 4);

b cohort three includes cohort 3a, which consisted of patients aged 10–11 years who received a slower uptitration regimen, as well as cohorts 3b–3d (see Figure 1).

Figure 3 Pediatric steady-state asenapine plasma concentrations (dots; studies 1 and 2) and adult model-based predictions (shaded areas) following clinically relevant doses.

Abbreviation: BID, bis in die (twice daily).

Figure 4 Goodness-of-fit plots for the final pediatric pharmacokinetic model.

Notes: (A, B) Closeness of observed plasma concentrations to population and individual predictions, respectively; (C, D) trends in residuals vs time and population predictions, respectively.

Figure 5 Visual predictive check plots for each asenapine dose.

Notes: Adequacy of model is displayed by overlaying observations (o for Phase I studies and ♦ for Phase III studies) on model-predicted 95% prediction intervals (shaded area). Dots represent plasma-concentration data since last dose. Solid and dashed lines represent medians for binned time intervals of observations and model predictions, respectively.

Figure 6 Impact of intrinsic factors on dose normalized AUC_0–12 of asenapine.

Notes: Forest plot illustrates relative differences in asenapine AUC_0–12 as a function of age, body-mass index, race, and sex. Black squares represent geometric mean ratios. Whiskers represent 90% confidence intervals. Body-mass index stratification: underweight (<18.5 kg/m²), normal (>18.5 and <25 kg/m²), overweight (≥25 and <30 kg/m²), obese (>30 kg/m²).
Abbreviation: AUC_0–12, area under the plasma concentration–time curve from 0 to 12 hours.

Table 3 Population PK-model parameter estimates

Final model parameter estimates				Estimates from bootstrap analysisa
Parameter	Population mean	RSE, %	Shrinkage, %	Median (90% CI)
Cl/F (L/h)	296	3.09	–	296 (283–312)
V2/F (L)b	2,740	–	–	–
Q/F (L/h)	120	14.3	–	120 (91.8–173)
V3/F (L)b	2,490	–	–	–
KA (hours)b	2.98	–	–	–
Interindividual variability, %CV
IIV (Cl/F)	66.2	19.5	27.3	66.4 (50.2–78.1)
Correlation (Cl/F–V2/F)	0.921	20.5	–	0.918 (0.881–0.931)
IIV (V2/F)	113	21.3	30.5	113 (87.8–137)
IIV (KA)	68.9	–	73.5	–
IIV (F)	54.0	22.7	38.0	53.1 (42.0–66.8)
IIV (RV)	19.2	29.8	45.3	18.5 (13.4–23.4)
Residual variability, %
PK studies	27.8	5.29	–	27.9 (25.6–30.3)
Efficacy studies	56.0	5.05	–	56.0 (51.5–60.9)

Notes:

a Nineteen runs with minimization terminated were excluded when calculating bootstrap results;

b V₂/F, V₃/F, and K_A parameters were fixed to the obtained by using plasma-concentration data from PK and safety studies. Correlation (Cl/F–V₂/F) calculated as covariance (Cl/F–V₂/F)/square root (variance [Cl/F] × variance [V₂/F]).

Abbreviations: Cl/F, apparent clearance; CV, coefficient of variation; F, bioavailability; IIV, interindividual variability; K_A, first-order absorption-rate constant; PK, pharmacokinetic; Q/F, apparent intercompartmental clearance; RSE, relative standard error; RV, residual variability; V₂/F, apparent central volume of distribution; V₃/F, apparent peripheral volume of distribution.

Table 4 Steady-state asenapine pharmacokinetics in adult and pediatric populations

Asenapine dose	AUC0–12, ng⋅h/mL, mean (%CV)		Cmax, ng/mL, mean (%CV)
	Adulta	Pediatricb	Adulta	Pediatricb
5 mg BID	26.6 (38.4)	19.3 (4.48–82.6)	4.23 (45.3)	4.56 (0.87–26.4)
10 mg BID	43.4 (53.1)	37.8 (8.92–162)	6.56 (50.9)	8.64 (1.64–50.1)

Notes:

a Adult data derived from a double-blind, parallel, multicenter study to assess the effect of asenapine, quetiapine, and placebo on the corrected QT interval in patients with schizophrenia.³⁶

b Pediatric data derived from simulations. Values presented as medians (90% CI).

Abbreviations: AUC_0–12, area under the plasma concentration–time curve from 0 to 12 hours; BID, bis in die (twice daily); C_max, maximum plasma concentration; CV, coefficient of variation; PK, pharmacokinetic; t_½, half-life; T_max, time to C_max.

Figure S1 Overview of population PK analysis of asenapine in a pediatric population. These studies consisted of 2 phase 1 PK studies (A7501022 and P06522), one phase 111 efficacy and safety study in pediatric patients aged 12 to 17 years with schizophrenia (P05896), and one phase 111 efficacy and safety study in pediatric patients aged 10 to 17 years with bipolar I disorder (P06107).

Abbreviation: PK, pharmacokinetic.

Table S1 PK Parameters for N-desmethylasenapine following multiple BID doses by dose and age

Dose	Cohort	Age, y	N	Cmax, ng/mL	% Cmax relative to parent	Tmax, hours	AUC0–12, ng⋅h/mL	% AUC0–12 relative to parent	t1/2, hours
Study 1
1 mg	1	12–17	8a	0.4 (68)	41.7	3.0 (0.5–12)	4.0 (60)	61.4	23 (28)
3 mg	2	12–17	8a	1.0 (63)	39.4	1.8 (0.3–6.0)	10 (73)	63.9	31 (101)
5 mg	3	12–17	8	1.4 (37)	39.5	4.0 (0–11)	13 (38)	58.1	21 (36)
10 mg	4	12–17	8b	3.0 (75)	106.9	3.6 (0.8–4.0)	26 (63)	131.0	15 (23)
Study 2
2.5 mg	1	10–11	6	0.6 (34)	35.2	4.0 (4.0–6.0)	6.5 (33)	56.9	14.6 (19)
5 mg	2	10–11	6	1.6 (43)	44.5	5.0 (3.0–6.0)	15 (44)	64.4	13.9 (21)
10 mg	3a–d	10–17	15	3.9 (67)	49.9	3.0 (0.0–6.0)	37 (65)	82.6	14.7 (13)
10 mg dose by age cohort
	3a	10–11	4	6.8 (38)	73.5	3.0 (3.0–6.0)	63 (38)	113.9	12.6 (7)
	3b	12–13	4	2.7 (34)	39.3	3.5 (2.0–4.0)	26 (35)	63.7	16.3 (10)
	3c	14–15	3	3.5 (92)	49.4	2.0 (0.0–4.0)	33 (90)	90.7	14.2 (8)
	3d	16–17	4	2.5 (46)	31.8	4.0 (0.0–6.0)	23 (31)	54.8	15.5 (11)

Notes: For both studies T_max is shown as median (range); all other PK parameters are shown as arithmetic mean (%CV).

a n=5 for t_1/2;

b n=6 for t_1/2.

Abbreviations: AUC_0–12, area under the plasma concentration-time curve from 0 to 12 hours; BID, twice daily; C_max, maximum plasma concentration; %CV, percent coefficient of variation; SD, standard deviation; t_1/2, elimination half-life; T_max, time to C_max.

Figure S2 Exposure-response relationship of AUC_0–12 and YMRS. Exposure-response relationship was examined through a visual exploration of the relationship between AUC_0–12 and individual YMRS scores at endpoint in the 3-week, phase 111 study of asenapine in pediatric patients with bipolar I disorder. The boxes reflect the interquartile range (25–75th percentiles), the median denoted as solid line in each box, with the whiskers extending to the 5th–95th percentiles, and individual data outside these percentiles presented as symbols. For each bin, n is approximately 40.

Abbreviation: YMRS, Young Mania Rating Scale.

ChapelSHutmacherMMHaigGExposure-response analysis in patients with schizophrenia to assess the effect of asenapine on QTc prolongationJ Clin Pharmacol200949111297130819843656

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