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 quantification of variability and evaluation of covariate effects. The final model was used to assess the adequacy of the recommended givosiran dosing regimen across demographic and clinical subgroups. The population PK/PD model adequately described the time course of urinary ALA reduction with various dosing regimens of givosiran, the interindividual variability across a wide range of givosiran doses (0.035–5 mg/kg), and the influence of patient characteristics. None of the covariates tested had a clinically relevant effect on PD response that would necessitate dose adjustment. For patients with AHP, including adults, adolescents, and patients with mild to moderate renal impairment or mild hepatic impairment, the 2.5-mg/kg once monthly dosing regimen of givosiran results in clinically meaningful ALA lowering, reducing the risk for AHP attacks.