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

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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.


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.


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.


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.

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Medical writing support, funded by Alnylam Pharmaceuticals, was provided by Crystal Murcia, PhD, of Inkwell Medical Communications LLC.

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Correspondence to Gabriel J. Robbie.

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This work was sponsored by Alnylam Pharmaceuticals.

Conflicts of interest

Megan Melch, Jongtae Lee, and Gabriel Robbie are Alnylam Pharmaceutical employees and may hold Alnylam stocks or options. Claudia Jomphe is an employee of Certara Strategic Consulting.

Ethics approval

All study protocols received Institutional Review Board or Ethics Committee approval and were conducted in accordance with the principles of the International Conference on Harmonisation Good Clinical Practice guidelines, the World Health Organization Declaration of Helsinki, and the 1996 Health Insurance Portability and Accountability Act.

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All study participants provided written informed consent.

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Not applicable.

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De-identified individual participant data access will be provided contingent upon the approval of a research proposal and execution of a data sharing agreement. Requests for access to data can be submitted via the website

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Author contributions

Gabriel J. Robbie was involved in the conception and design of the study. All authors were involved in the analysis and interpretation of the data, critical review of manuscript drafts, and approval of the submitted manuscript.

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Melch, M., Lee, J., Jomphe, C. et al. Population Pharmacokinetic Analysis of the RNAi Therapeutic Givosiran in Patients with Acute Hepatic Porphyria. Clin Pharmacokinet 62, 89–99 (2023).

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