TABLE 2

Predicted and observed area under the plasma concentration–time curve after oral administrations of afatinib and neratinib at the recommended doses for humans

Drug	Predicted					Observed
Drug	F_H^{^a}	CL_H^{^a}	CL_extH^{^b}	CL_tot,pred^{^c}	AUC^{^d}	AUC^{^e}
		ml/min/kg			ng⋅h/ml	ng⋅h/ml
Afatinib	0.96 ± 0.00	2.1 ± 0.1	34.7	36.8	211	299,^{^f} 324,^{^g} 549,^{^h} 662^ⁱ
Neratinib	0.55 ± 0.06	8.5 ± 1.1	4.4	12.9	799	823,^{^j} 891,^{^k} 903,^{^l} 1640^{^m}

↵^a Data taken from Table 1.
↵^b Extrahepatic clearance in humans predicted by extrapolation using simple allometry relating extrahepatic clearance for the unbound compound (CL_u,extH) in rat, dog, and monkey to BW (kg) of the corresponding species according to eq. 6.
↵^c Predicted total body (plasma) clearance in humans by summing predicted hepatic clearance (CL_H) and extrapolated CL_extH for humans (eq. 7).
↵^d Area under the plasma concentration–time curve after oral administration (AUC_oral) predicted by eq. 9 using the value of absorption fraction × intestinal availability (f_a⋅F_G) obtained in dog for each compound (Table 1).
↵^e Observed values of AUC_oral in dose-escalation studies after oral administration on day 1 in multiple dosing (AUC_0–24h) or after single oral administration (AUC_0–∞) at recommended doses (afatinib, 40 mg; neratinib, 240 mg) obtained from the sources in notes f–m.
↵^f AUC_0–24h in patients (Murakami et al., 2012).
↵^g AUC_0–24h in patients (Wind et al., 2013).
↵^h AUC_0–∞ in healthy volunteers (CDER, 2012).
↵ⁱ AUC_0–∞ in patients (Yap et al., 2010).
↵^j AUC_0–24h in patients (Wong et al., 2009).
↵^k AUC_0–24h in healthy volunteers (Abbas et al., 2012).
↵^l AUC_0–∞ in healthy volunteers (Abbas et al., 2011).
↵^m AUC_0–∞ in patients (Ito et al., 2012).