Table 2.

Pharmacokinetic Parameters of Givosiran and Its Active Metabolite54,67

		Givosiran	AS(N-1)3’ Givosiran
General Information
Steady-State Exposure	Cmax [Mean (CV%)]	321 ng/mL (51%)	123 ng/mL (64%)
	AUC24 [Mean (CV%)]	4130 ng·h/mL (43%)	1930 ng·h/mL (63%)
Dose Proportionality		● Steady-state maximum plasma concentration (Cmax) and area under the curve (AUC) for givosiran and AS(N-1)3′ givosiran increase proportionally over the 0.35 mg/kg to 2.5 mg/kg once monthly dose range (0.14 to 1-fold the approved recommended dosage). ● Cmax and AUC for givosiran and AS(N-1)3′givosiran increase slightly greater than proportionally at doses greater than 2.5 mg/kg once monthly
Accumulation		No accumulation of givosiran or AS(N-1)3′givosiran was observed following multiple dosing.
Absorption
Tmax [Median (range)]		3 (0.5–8) hours	7 (1.5–12) hours
Distribution
Apparent Central Volume of Distribution (Vz/F) [Mean (RSE%)]a		10.4 L (2.3%)
Protein Binding		90%b	Not evaluated
Organ Distribution		Givosiran and AS(N-1)3′givosiran distribute primarily to the liver after subcutaneous dosing.
Elimination
Half-Life [Mean (CV%)]		6 hours (46%)	6 hours (41%)
Apparent Clearance [Mean (CV%)]a		35.1 L/hr (18%)	64.7 L/hr (33%)
Metabolism
Primary Pathway		Givosiran is metabolized by nucleases to oligonucleotides of shorter lengths. Givosiran is not a substrate of CYP enzymesc.
Active Metabolite		The active metabolite, AS(N-1)3′givosiran, is equipotent to givosiran in plasma and the AUC0–24 represents 45% of givosiran AUC, at the approved recommended givosiran dosage.
Excretion
Primary Pathway		The dose recovered in urine was 5–14% as givosiran and 4–13% as AS(N-1)3′givosirand.

Notes: ^aBased on population PK model estimation. ^bGivosiran plasma protein binding was concentration-dependent and decreased with increasing givosiran concentrations (from 92% at 1 µg/mL to 21% at 50 µg/mL). ^cBased on in vitro study result. ^dAfter single and multiple subcutaneous doses of givosiran 2.5 mg/kg and 5 mg/kg.