Table 2.

PBPK model-predicted unbound drug plasma and CNS pharmacokinetics at the steady-state following one-cycle treatment of the three HER2 inhibitors at the standard dosing regimens^a.

	Tucatinib (300 mg BID, 21 days)	Lapatinib (1,250 mg QD, 21 days)	Neratinib (240 mg QD, 21 days)
Plasma
Tss,max (h)	2.9	3.8	3.8
Css,max (nmol/L)	37.6	60.8	1.16
Css,min (nmol/L)	12.1	39.3	0.33
Css,ave (nmol/L)	22.5	49.3	0.66
AUC24h (nmol/L/hour)	606	1,321	18.0
Brain
Tss,max (h)	2.9	24.0	11.4
Css,max (nmol/L)	19.9	16.8	0.72
Css,min (nmol/L)	10.2	16.8	0.65
Css,ave (nmol/L)	14.5	16.8	0.68
AUC24h (nmol/L/hour)	456	453	19.0
Brain Kp,uub	0.65	0.34	1.06
TER for HER2c	2.1	0.15	0.12
TER for EGFRc	0.032	0.35	0.38
Cranial CSF
Tss,max (h)	2.9	21.5	8.9
Css,max (nmol/L)	20.1	15.3	0.54
Css,min (nmol/L)	10.1	15.2	0.48
Css,ave (nmol/L)	14.5	15.2	0.51
AUC24h (nmol/L/hour)	456	416	14.3
CSF Kp,uud	0.65	0.31	0.80
Spinal CSF
Tss,max (hour)	5.4	24.0	11.4
Css,max (nmol/L)	18.6	15.0	0.54
Css,min (nmol/L)	11.8	15.0	0.49
Css,ave (nmol/L)	14.9	15.0	0.51
AUC24h (nmol/L/hour)	464	405	14.3
CSF Kp,uud	0.66	0.31	0.79

Abbreviations: BID, twice daily; C_ss,max, maximum steady-state concentration; C_ss,min, trough steady-state concentration; C_ss,ave, average steady-state concentration; AUC_24h, area under the concentration–time curve during 24 hours at the steady-state; QD, once daily.

^aSimulations of 10 trials with 10 subjects in each trial were performed in the Simcyp cancer patient population. Data are presented as the population mean values.

^bBrain K_p,uu is estimated as the brain-to-plasma AUC_24h ratio of the unbound drug at the steady-state.

^cTER (target engagement ratio) is calculated as the ratio of the average steady-state unbound brain concentrations to the in vitro IC₅₀ for inhibiting HER2 or EGFR enzymes.

^dCSF K_p,uu is estimated as the CSF-to-plasma AUC_24h ratio of the unbound drug at the steady-state.