An exploratory, randomized, parallel-group, open-label, relative bioavailability study with an additional two-period crossover food-effect study exploring the pharmacokinetics of two novel formulations of pexmetinib (ARRY-614)

Figures & data

Table 1 Treatment cohorts and periods

Cohort	Formulation (dose)	Group	N	Period 1 (Day 1)	Period 2 (Day 8)
1	LFC (400 mg)	1	6	Fasted	Fed
		2	6	Fed	Fasted
2	LOS (400 mg)	1	6	Fasted	Fed
		2	6	Fed	Fasted
3	PIC (400 mg)	1	6	Fasted	N/A

Abbreviations: LFC, liquid-filled capsule; LOS, liquid oral suspension; PIC, powder-in-capsule; N/A, not applicable.

Table 2 Summary of demographics and baseline characteristics

Demographic/characteristic	Statistics
Age (years)a	39.2 (15.0)
Sex (n)	22 Male; 8 Female
Weight (kg)a	76.8 (13.5)
Height (cm)a	173 (9.44)
Body mass index (kg/m^2)a	25.6 (3.29)
Ethnicity (n)	9 Hispanic/latino;
	21 nonhispanic/latino
Race (n)	23 White; 6 Black; 1 Asian

Note:

a Demographic characteristics are presented as arithmetic mean (standard deviation).

Figure 1 Fasted concentration-time profile of pexmetinib represented in semi-logarithmic scale. The in vitro half maximal inhibitory concentration (IC₅₀) of ARRY-614 for both p38 and Tie2 is included for reference (solid line). Points represent geometric mean values and error bars ± 1 geometric standard deviation.

Table 3 Summary of fed and fasted plasma PK parameters of ARRY-614

Parameter	LFC		LOS		PIC
	Fasted (n=12)	Fed (n=12)	Fasted (n=12)	Fed (n=11)	Fasted (n=6)
AUCinf (h · µg/mL)a	15.0 (37.2)	15.2 (31.8)d	9.46 (46.4)e	11.4 (39.4)f	4.22 (71.9)g
AUClast (h · µg/mL)a	14.8 (37.4)	14.4 (34.8)	8.67 (50.1)	11.6 (53.6)	3.84 (60.1)
Cmax (µg/mL)a	3.01 (31.1)	2.88 (30.4)	1.04 (59.6)	1.55 (35.1)	0.370 (49.6)
Tmax (h)b	2.00 (1.00–3.00)	3.00 (1.00–4.00)	3.00 (1.00–6.02)	8.00 (3.17–16.0)	3.50 (2.00–12.00)
t1/2 (h)a,c	8.50 (28.8)	6.53 (9.95)d	8.93 (34.7)e	5.72 (12.5)f	14.2 (20.5)g
C24 h (µg/mL)a	0.050 (60.3)	0.026 (108)	0.109 (64.8)	0.044 (229)	0.062 (78.5)

Notes: Terminal phase parameters (AUC_inf, K_el, t_1/2) were not estimated in some subjects due to a failure to meet predefined criteria for retaining parameters from extrapolated terminal phase. Number of subjects who had acceptable estimation of terminal phase is:

a Presented as geometric mean (geometric coefficient of variation [%]);

b presented as median (range);

c presented as arithmetic mean (coefficient of variation [%]);

d n=11;

e n=10;

f n=9;

g n=5.

Abbreviations: PK, pharmacokinetics; LFC, liquid-filled capsule; LOS, liquid oral suspension; PIC, powder-in-capsule; AUC_inf, area under the curve extrapolated to infinity; AUC_last, area under the curve to the last quantifiable sample; C_max, peak concentration; T_max, time-to-peak exposure; h, hours; t_1/2, elimination half-life; C_{24 h}, estimated QD regimen average trough concentration.

Figure 2 Concentration-time profile of pexmetinib comparing exposure in both fed and fasted states for both the LFC (A) and LOS (B) represented in semi-logarithmic scale. Points represent geometric mean values and error bars ± 1 geometric standard deviation.

Abbreviations: LOS, liquid oral suspension; LFC, and liquid-filled capsule.