Effects of dacomitinib on the pharmacokinetics of poziotinib in vivo and in vitro

Figures & data

Figure 1. Chemical structures of poziotinib (A), M1 (B), M2 (C) and enasidenib (D).

Figure 2. MRM chromatograms of poziotinib and IS. (1) Blank plasma sample, (2) blank plasma sample with poziotinib (LLOQ) and IS, and (3) plasma sample 2 h after dosing poziotinib with oral administration.

Table 1. Inter- and intraday precision, accuracy, recovery and matrix of poziotinib in rat plasma (n = 6, mean ± SD).

Analyte	Nominal concentration	Intraday		Interday		Recovery (%)	Matrix (%)
		Precision	Accuracy	Precision	Accuracy
	(ng/mL)	RSD (%)	RE (%)	RSD (%)	RE (%)
Poziotinib	1	14.00	106.42	9.85	102.54
	2	7.47	108.44	8.67	109.38	81.80	85.36
	80	7.77	106.84	5.27	105.72	96.42	87.71
	800	6.49	107.46	9.52	102.62	93.58	91.94

Figure 3. Mean plasma concentration–time curves of poziotinib in the test and control groups.

Table 2. Main pharmacokinetic parameters of poziotinib in the two groups (n = 6, mean ± SD).

Pharmacokinetics parameters	Control group	Test group	p-Values
AUC(0–t) (µg/L h)	12506.44 ± 1981.29	20920.85 ± 2579.95**	0.000
AUC(0–∞) (µg/L h)	12597.80 ± 1994.45	22212.70 ± 2217.34**	0.000
MRT(0–t) (h)	9.01 ± 0.400	11.40 ± 0.83**	0.000
MRT(0–∞) (h)	9.26 ± 0.51	13.56 ± 2.22**	0.001
t1/2z (h)	4.53 ± 0.85	7.45 ± 1.64**	0.003
Tmax (h)	6.00 ± 0.00	7.67 ± 0.82**	0.001
Vz/F (L/kg)	5.31 ± 1.36	4.92 ± 1.37	0.639
CLz/F (L/h/kg)	0.81 ± 0.12	0.45 ± 0.05**	0.000
Cmax (µg/L)	1226.67 ± 176.84	1461.01 ± 192.05	0.053

*p < 0.05; **p < 0.01 indicate significant differences from the control.

AUC, area under the plasma concentration–time curve; CL, plasma clearance; C_max, maximum plasma concentration; MRT, mean residence time; SD, standard deviation; t_1/2, half-life; T_max, maximum plasma time; Vz/F: apparent volume of distribution.

Figure 4. Michaelis–Menten kinetics of poziotinib in RLM (A) and HLM (B).

Figure 5. Poziotinib with various concentrations to determine the IC₅₀ for the activity of RLM (A, B), HLM (C, D), CYP3A4 (E) and CYP2D6 (F).

Figure 6. Lineweaver–Burk plots and the secondary plot for K_i of the inhibition of poziotinib metabolism by dacomitinib in RLM (A, B) and HLM (C, D).

Table 3. The IC₅₀ values and inhibitory effects of dacomitinib on poziotinib metabolism in RLM, HLM, CYP3A4 and CYP2D6.

		IC50 values (μM)	Inhibition type	Ki (μM)	αKi (μM)	α
RLM	M1	21.77	Mixed	8.18	38.81	4.74
	M2	90.14	Mixed	47.48	38.07	0.81
HLM	M1	30.49	Mixed	83.74	93.73	1.12
	M2	0.34	Mixed	0.17	0.66	3.88
CYP3A4	M1	19.57
CYP2D6	M2	0.11