Table 2.

Relative contribution of parent and active metabolites to total Css/IC₅₀ ^a

Drug	Analyte	AUC0‐12 ng.h/mL	fup	Css nM	IC50 nM	Css/IC50	Total Css/IC50	Cell line
Abemaciclib	Parent	3,844	0.0300	18.97	19.0	1.00	4.14	EFM‐19
	M2	1,499	0.1100	28.77	19.0	1.51		EFM‐19
	M18	538	0.0900	8.18	190.0	0.04		EFM‐19
	M20	3,152	0.0600	30.16	19.0	1.59		EFM‐19
Dabrafenib	Parent	4,341	0.0040	2.79	6.0	0.46	1.57	COLO205
	M4	47751	0.0050	35.30	320.0	0.11		COLO205
	M7	3907	0.0370	22.49	23.0	0.98		COLO205
	M8	3039	0.0010	0.50	23.0	0.02		COLO205

AUC_0–12, area under the plasma concentration‐time curve from zero to 12; C_ss, steady‐state concentration; IC₅₀, half‐maximal inhibitory concentration; f_up, fraction of unbound drug in plasma.

^aM2, M18, and M20 are the N‐desethyl, hydroxy‐N‐desethyl, and hydroxy metabolites, respectively, of abemaciclib. M4, M7, and M8 are the carboxy, hydroxy, and desmethyl metabolites, respectively, of dabrafenib. For abemaciclib, metabolite AUCs were estimated from reported exposures relative to parent in a single dose study. M18 was reported to have activity 3 to 20‐fold less than parent, ¹⁵ therefore, a 10‐fold lower potency was used in the table. A 3‐fold lower potency would result in a C_ss/IC₅₀ value of 0.14 vs. 0.04 for M18 with minimal difference in the total C_ss/IC₅₀ value.