TABLE 8

Assessment of the clinical drug-drug interaction potential based on reversible inhibition of metabolizing enzymes and cutoff criteria from regulatory guidance

GalNAc siRNA	Enzyme	K_i	Total Plasma C_max,ss (Observed Clinical Concentration at Therapeutic Dose)^{^a}			R₁		Mechanistic Static Model (Liver)
GalNAc siRNA	Enzyme	K_i	EMA	FDA	PMDA	Plasma	Liver	Mechanistic Static Model (Liver)
			μM	μM	μM
Cemdisiran	CYP2B6	292	5.83 (0.048)	5.83 (0.048)	5.83 (0.048)	1.00	1.04	1.03
Fitusiran	CYP2C8	28	0.56 (0.0092)	0.56 (0.0092)	0.56 (0.0092)	1.00	1.15	1.12
Cemdisiran	CYP2C8	112	2.24 (0.048)	2.24 (0.048)	2.24 (0.048)	1.00	1.10	1.08
Lumasiran	CYP2C8	208	4.16 (0.061)	4.16 (0.061)	4.16 (0.061)	1.00	1.03	1.03

C_max,ss, C_max at steady state; PMDA, Pharmaceutical and Medical Devices Agency.
↵^a Total plasma C_max,ss required to cause clinically relevant inhibition based on DDI guidance criteria; cutoff = R = 1 + 50 × [I]/K_i, where I is the unbound C_max,ss, R ≥ 2.0, and F_u = 1.