Pharmacokinetic-pharmacodynamic model of urinary δ-aminolevulinic acid reduction after givosiran treatment in patients with acute hepatic porphyria.

ABSTRACT: Givosiran, an RNA interference-based therapeutic, is a recent addition to the limited treatment armamentarium for acute hepatic porphyria (AHP). As a small interfering RNA that is selectively taken up in the liver, both the mechanism and targeted delivery create a complex relationship between givosiran pharmacokinetics (PK) and the pharmacodynamic (PD) response. Using pooled data from phase I-III clinical trials of givosiran, we developed a semimechanistic PK/PD model to describe the relationship between predicted liver and RNA-induced silencing complex concentrations of givosiran and the associated reduction in synthesis of δ-aminolevulinic acid (ALA), a toxic heme intermediate that accumulates in patients with AHP, contributing to disease pathogenesis. Model development included quantifi

SUBMITTER: Lee J 

PROVIDER: S-EPMC10272304 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature