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Hereditary angioedema (HAE) is a rare disorder linked to kallikrein-kinin system dysregulation, which leads to uncontrolled activation of plasma prekallikrein. Donidalorsen is an antisense oligonucleotide designed to selectively degrade prekallikrein messenger RNA and thereby reduce prekallikrein production. We aimed to develop population pharmacokinetic and pharmacokinetic/pharmacodynamic models of donidalorsen and evaluate the impact of potential intrinsic/extrinsic covariates on exposure and prekallikrein response. Plasma donidalorsen and prekallikrein data were obtained from phase 1 to 3 studies in healthy volunteers (NCT03263507, 721744-CS9) and adult and adolescent patients with HAE (NCT04030598, NCT05139810). The evaluated doses were 20, 40, 60, and 80 mg every 4 weeks (Q4W) and 80 mg every 8 weeks (Q8W), administered subcutaneously over 13-21 weeks. Donidalorsen pharmacokinetics were well described by a linear 2-compartment model with first-order absorption. The population terminal elimination half-life was 31.4 days. Prekallikrein was well described by an indirect response model with inhibition of prekallikrein production by donidalorsen. Covariate analysis identified body weight as the main factor affecting pharmacokinetic exposure; however, this effect was not considered clinically significant. The developed population pharmacokinetic/pharmacodynamic model well characterized the donidalorsen exposure-prekallikrein response relationship. Modeling analyses support that no dose adjustment is needed with respect to intrinsic/extrinsic factors in adults and adolescents with HAE. The nearly identical simulated pharmacokinetic or prekallikrein time courses for Q4W versus monthly dosing and for Q8W versus every-2-month dosing regimens support switching to more convenient regimens for patients.