Population Pharmacokinetic Analysis of the RNAi Therapeutic Givosiran in Patients with Acute Hepatic Porphyria

Background and Objective Givosiran, approved for the treatment of acute hepatic porphyria (AHP), is the first subcutaneously administered RNAi therapeutic. This analysis was undertaken to describe the plasma pharmacokinetics (PK) of givosiran and its active metabolite, AS(N-1)3′ givosiran, and to identify factors that contribute to intersubject PK variability. Methods A population PK model was developed using data from givosiran clinical trials that enrolled patients with AHP or who were asymptomatic chronic high excreters (CHEs) of toxic heme intermediates. Givosiran and AS(N-1)3′ givosiran PK were modeled simultaneously using non-linear mixed-effects modeling. Results Plasma PK of givosiran was best described by a two-compartment model. Givosiran absorption after subcutaneous administration and conversion of givosiran to AS(N-1)3′ givosiran were incorporated as first-order processes. Hepatic clearance was the major route of elimination from the central compartment, with renal clearance accounting for < 20% of the total clearance. Body weight, East Asian ethnicity, and renal impairment were significant covariates in the model; however, none of the covariates evaluated resulted in clinically meaningful differences in plasma exposures of givosiran and AS(N-1)3′ givosiran. The model adequately described observed concentrations and variability across a wide range of dose levels. Model-derived simulations showed similar exposures for givosiran and its active metabolite in adults and adolescents. Conclusions The PK of givosiran and its active metabolite were not significantly affected by demographic or clinical parameters that would require adjustment from the approved body weight-based dose of givosiran 2.5 mg/kg once monthly.