. 2022 Nov 1;13:1039416. doi: 10.3389/fphar.2022.1039416

TABLE 2.

Summary of pharmacokinetic parameters of tunlametinib and M8.

Dose-escalation phase													Expansion phase
	Parameter	Unit	0.5 mg (n = 3)	1.0 mg (n = 3)	2.0 mg (n = 3)	3.0 mg (n = 3)	4.0 mg (n = 3)	6.0 mg (n = 3)	9.0 mg (n = 3)	12.0 mg (n = 3)	15.0 mg (n = 3)	18.0 mg (n = 3)	12.0 mg (n = 11)
HL-085
Single dose	AUC_0–12h	h*ng/mL	5.69 ± 0.93	17.25 ± 7.03	23.34 ± 6.85	37.20 ± 10.83	53.91 ± 12.05	84.61 ± 40.93	114.33 ± 43.22	147.6 ± 17.70	273.89 ± 21.81	488.89 ± 50.59	228.96 ± 77.81
	AUC_inf	h*ng/mL	/	42.76 ± 33.97	43.62 ± 9.57	73.49 ± 30.65	89.5 ± 25.29	144.48 ± 57.73	183.72 ± 33.90	232.69 ± 23.17	398.85 ± 34.57	635.74 ± 53.55	/
	AUC_{_%Extrap}	%	25.74 ± 4.06	17.05 ± 4.93	10.94 ± 3.66	6.86 ± 3.25	6.03 ± 1.61	6.18 ± 2.41	3.10 ± 0.97	2.61 ± 0.96	1.33 ± 0.36	0.83 ± 0.27	26.83 ± 27.56
	C_max	ng/mL	2.24 ± 0.99	6.98 ± 4.03	15.70 ± 2.39	19.60 ± 6.28	27.60 ± 4.75	54.07 ± 31.98	95.27 ± 85.79	85.63 ± 24.15	211.67 ± 68.82	349.33 ± 111.13	142.83 ± 88.63
	C_last	ng/mL	0.15 ± 0.06	0.15 ± 0.06	0.14 ± 0.03	0.12 ± 0.01	0.18 ± 0.07	0.19 ± 0.02	0.17 ± 0.03	0.16 ± 0.03	0.18 ± 0.05	0.14 ± 0.03	17.87 ± 27.52
	T_max ^a	H	0.98 (0.98.1.00)	0.92 (0.92.1.00)	0.50 (0.50.1.00)	0.50 (0.48.0.98)	0.50 (0.50.1.00)	0.50 (0.48.2.00)	0.52 (0.50.1.00)	1.00 (0.98.1.00)	0.50 (0.50.0.50)	0.52 (0.50.0.97)	0.53 (0.23.11.65)
	MRT	H	6.48 ± 2.88	19.26 ± 10.86	14.42 ± 1.69	18.02 ± 5.64	13.66 ± 3.73	15.41 ± 2.92	14.25 ± 4.57	14.99 ± 5.03	12.85 ± 4.51	10.54 ± 2.44	/
	T_1/2	H	/	34.41 ± 16.18	24.14 ± 3.15	28.2 ± 10.61	21.84 ± 5.66	30.79 ± 4.82	23.04 ± 5.52	26.18 ± 5.56	24.28 ± 10.33	29.13 ± 3.57	/
	CL/F	L/h	/	34.17 ± 27.15	47.32 ± 10.13	45.46 ± 17.04	47.43 ± 14.71	45.90 ± 16.74	50.10 ± 9.10	51.93 ± 5.47	37.81 ± 3.45	28.44 ± 2.28	/
	V_z/F	L	/	1379.52 ± 550.08	1617.46 ± 141.04	1772.99 ± 788.61	1422.54 ± 200.07	2009.26 ± 651.60	1708.45 ± 655.99	1942.20 ± 311.42	1292.35 ± 470.57	1199.36 ± 214.11	/
Multiple dose	AUC_τ	h*ng/mL	12.67 ± 3.02	31.56 ± 14.23	45.76 ± 12.31	76.42 ± 25.03	96.09 ± 47.77	163.95 ± 57.14	294.37 ± 114.84	266.55 ± 35.62	446.70 ± 73.76	906.33 ± 74.43	391.16 ± 97.85
	C_avg	ng/mL	1.06 ± 0.25	2.63 ± 1.19	3.81 ± 1.03	6.37 ± 2.09	8.01 ± 3.98	13.66 ± 4.76	24.53 ± 9.57	22.21 ± 2.97	37.23 ± 6.15	75.53 ± 6.20	32.60 ± 8.15
	C_max	ng/mL	2.52 ± 0.80	11.11 ± 9.57	14.50 ± 0.85	40.97 ± 25.44	33.23 ± 19.42	58.90 ± 37.74	109.40 ± 73.5	77.90 ± 46.49	186.33 ± 95.00	238.37 ± 168.72	140.57 ± 71.53
	C_min	ng/mL	0.74 ± 0.24	1.51 ± 0.66	2.44 ± 0.06	2.87 ± 0.60	3.29 ± 3.11	4.40 ± 0.60	6.22 ± 1.25	5.95 ± 2.01	12.05 ± 2.95	14.23 ± 4.23	10.12 ± 4.93
	Fluctuation%	%	166.40 ± 21.09	332.28 ± 204.62	331.62 ± 113.12	583.46 ± 268.56	391.32 ± 114.01	391.19 ± 174.17	384.33 ± 140.35	448.51 ± 181.90	450.60 ± 172.16	418.85 ± 33.95	435.72 ± 216.88
	T_max ^a	h	0.98 (0.97.0.98)	0.97 (0.52.1.02)	0.73 (0.50.0.97)	0.50 (0.48.0.50)	0.98 (0.95.1.00)	0.52 (0.50.1.00)	1.00 (0.50.1.02)	0.50 (0.50.2.08)	0.98 (0.53.1.00)	1.00 (0.98.4.02)	1.00 (0.48.2.03)
	R₁	-	1.44 ± 1.09	1.47 ± 0.61	0.93 ± 0.25	2.49 ± 2.27	1.28 ± 0.93	1.23 ± 0.54	1.73 ± 1.63	0.99 ± 0.63	0.97 ± 0.67	0.82 ± 0.78	0.94 ± 0.29
	R₂	-	2.32 ± 0.83	1.81 ± 0.18	2.42 ± 1.02	2.05 ± 0.36	1.83 ± 0.96	2.02 ± 0.46	2.73 ± 1.22	1.84 ± 0.55	1.64 ± 0.36	1.75 ± 0.09	1.59 ± 0.19
	R₃	-	/	0.69 ± 0.20	1.22 ± 0.49	1.08 ± 0.30	1.14 ± 0.66	1.15 ± 0.14	1.61 ± 0.61	1.08 ± 0.13	1.12 ± 0.10	1.39 ± 0.03	/
M8
Single dose	AUC_0–12h	h*ng/mL	4.23 ± 1.22	9.76 ± 6.21	7.50 ± 2.22	22.28 ± 11.53	22.82 ± 20.69	43.64 ± 31.68	60.91 ± 46.38	83.93 ± 30.01	161.99 ± 27.4	245.33 ± 16.17	120.43 ± 90.82
	AUC_inf	h*ng/mL	/	29.93 ± 27.99	9.76 ± 2.12	39.23 ± 25.87	33.00 ± 32.06	69.06 ± 46.60	89.19 ± 46.82	124.91 ± 28.5	261.27 ± 36.23	366.9 ± 48.25	/
	AUC_{_%Extrap}	%	26.39 ± 5.74	16.28 ± 6.21	17.65 ± 6.63	7.71 ± 5.84	8.70 ± 4.08	7.48 ± 7.13	5.49 ± 3.12	3.19 ± 2.24	1.40 ± 0.29	2.31 ± 1.02	19.55 ± 11.66
	C_max	ng/mL	1.19 ± 0.33	2.03 ± 0.36	2.73 ± 0.81	6.84 ± 1.86	6.70 ± 5.06	15.24 ± 11.68	23.54 ± 23.87	35.63 ± 20.53	55.10 ± 8.31	79.37 ± 10.74	42.22 ± 25.87
	C_last	ng/mL	0.13 ± 0.03	0.15 ± 0.08	0.20 ± 0.05	0.13 ± 0.03	0.17 ± 0.08	0.17 ± 0.03	0.21 ± 0.07	0.15 ± 0.08	0.20 ± 0.06	0.18 ± 0.02	12.36 ± 25.29
	T_max ^a	h	1.00 (0.98.1.93)	0.92 (0.92.2.92)	0.97 (0.50.1.00)	0.98 (0.48.1.03)	0.97 (0.95.1.00)	1.00 (0.95.2.00)	0.98 (0.50.1.00)	1.00 (0.98.1.00)	1.00 (1.00.1.03)	1.00 (0.97.1.00)	1.00 (0.50.11.65)
	MRT	h	6.81 ± 2.45	13.85 ± 10.67	6.12 ± 2.01	12.14 ± 6.72	7.31 ± 2.49	10.55 ± 5.01	10.66 ± 3.52	12.04 ± 3.47	13.94 ± 2.32	12.70 ± 2.72	/
	T_1/2	h	/	21.32 ± 13.74	6.10 ± 2.66	14.36 ± 5.22	9.89 ± 2.36	13.10 ± 3.87	12.79 ± 1.69	17.31 ± 2.74	15.75 ± 2.37	33.54 ± 11.84	/
	MPratio_{_AUC0–12h}	-	0.88 ± 00.36	0.67 ± 0.30	0.36 ± 0.01	0.65 ± 0.16	0.49 ± 0.43	0.55 ± 0.23	0.55 ± 0.22	0.65 ± 0.23	0.67 ± 0.06	0.57 ± 0.05	0.58 ± 0.31
	MPratio_{_AUCinf}	-	/	0.73 ± 0.16	0.25 ± 0.02	0.57 ± 0.15	0.42 ± 0.38	0.50 ± 0.23	0.53 ± 0.18	0.62 ± 0.21	0.75 ± 0.08	0.66 ± 0.07	/
	MPratio_{_Cmax}	-	0.76 ± 0.53	0.42 ± 0.25	0.20 ± 0.07	0.40 ± 0.02	0.28 ± 0.22	0.39 ± 0.26	0.26 ± 0.04	0.46 ± 0.18	0.31 ± 0.07	0.27 ± 0.06	0.44 ± 0.38
Multiple dose	AUC_τ	h*ng/mL	8.90 ± 4.17	22.01 ± 10.25	16.45 ± 6.06	46.35 ± 18.22	58.79 ± NaN	123.87 ± 77.48	265.25 ± 154.14	132.32 ± 3.18	576.15 ± 96.75	864.79 ± 228.01	592.28 ± 499.53
	C_avg	ng/mL	0.74 ± 0.35	1.83 ± 0.85	1.37 ± 0.51	3.86 ± 1.52	4.9 ± NaN	10.32 ± 6.46	22.1 ± 12.85	11.03 ± 0.27	48.01 ± 8.06	72.07 ± 19.00	49.36 ± 41.63
	C_max	ng/mL	2.02 ± 0.72	4.04 ± 0.88	4.24 ± 0.78	11.89 ± 4.12	11.66 ± 7.46	26.8 ± 18.87	64.63 ± 48.38	33.93 ± 11.94	125.33 ± 14.36	128.57 ± 64.55	96.31 ± 78.85
	C_min	ng/mL	0.42 ± 0.23	0.98 ± 0.50	0.78 ± 0.25	1.37 ± 0.58	1.17 ± 1.12	3.49 ± 2.21	6.55 ± 2.78	6.28 ± 2.74	23.03 ± 3.04	28.07 ± 4.80	15.95 ± 17.3
	Fluctuation%	%	234.38 ± 62.35	187.42 ± 67.37	263.39 ± 58.61	282.46 ± 53.13	152.68 ± NaN	244.76 ± 95.39	237.43 ± 76.46	279.10 ± 165.31	219.23 ± 63.51	185.78 ± 9.34	244.48 ± 77.38
	T_max ^a	h	0.98 (0.97,0.98)	1.00 (0.97,1.02)	0.98 (0.97,1.00)	1.00 (0.98,1.03)	1.90 (1.90,2.00)	1.07 (1.00,2.00)	1.03 (1.02,1.95)	1.00 (1.00,2.08)	0.98 (0.98,1.00)	1.92 (1.00,4.02)	1.02 (0.95,3.95)
	R₁	-	1.68 ± 0.19	2.01 ± 0.38	1.88 ± 0.43	1.94 ± 1.14	1.84 ± 0.20	1.81 ± 0.11	3.25 ± 1.78	1.14 ± 0.61	2.32 ± 0.50	1.65 ± 0.83	2.04 ± 0.75
	R₂	-	2.04 ± 0.67	2.44 ± 0.84	2.76 ± 1.55	2.77 ± 2.02	5.16 ± NaN	2.96 ± 0.41	4.74 ± 2.09	2.01 ± 0.51	3.57 ± 0.39	3.51 ± 1.19	2.67 ± 0.13
	R₃	-	/	0.93 ± 0.39	2.51 ± NaN	1.80 ± 1.46	3.76 ± NaN	1.86 ± 0.16	2.89 ± 0.99	1.22 ± 0.06	2.22 ± 0.37	2.52 ± 1.09	-
	MPratio_{_AUCτ}	-	0.76 ± 0.23	0.83 ± 0.24	0.40 ± 0.04	0.80 ± 0.53	0.20 ± 0.35	0.79 ± 0.30	1.00 ± 0.53	0.57 ± 0.06	1.51 ± 0.46	1.10 ± 0.38	1.26 ± 1.08
	MPratio_{_Cmax}	-	0.91 ± 0.10	0.61 ± 0.35	0.33 ± 0.08	0.38 ± 0.18	0.61 ± 0.64	0.52 ± 0.17	0.73 ± 0.55	0.67 ± 0.52	0.88 ± 0.33	0.84 ± 0.48	0.88 ± 0.85

a:T_max reported as median (range).

Blood samples were not collected after 12 h in the expansion cohort or AUC_{_%Extrap}>20%, so the parameters which related to elimination phase could not be calculated.

Abbreviations: AUC_0–12 h = Area under the concentration-time curve from 0 to 12 h after dosing, AUC_inf, Area under the plasma concentration-time curve from the time of dosing extrapolated to infinity, AUC_τ, Area under the concentration-time curve during a dosing interval at steady-state. AUC_{_%Extrap} = Extrapolated area percentage calculated by AUC_t-inf/AUC_inf. C_avg = Average concentration, C_max = Maximum concentration. C_last = The last concentration which can be measured. C_min = Minimum concentration, CL/F = Apparent clearance, Fluctuation% = Percentage of concentration fluctuation, MPratio = Ratio of metabolite M8 to tunlametinib, R₁ = Accumulation ratio calculated by C_max (day28)/C_max (PK, lead-in period or day 1), R₂ = Accumulation ratio calculatedby AUC_τ (day28)/AUC_0–12 h (PK, lead-in period or day 1), R₃ = Accumulation ratio calculatedby AUC_τ (day28)/AUC_inf (PK, lead-in period or day 1), T_1/2 = Terminal half-life, T_max = Time taken to reach maximum concentration, V_z/F = apparent distribution volume.