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. 2025 Sep;64(9):1395-1411.
doi: 10.1007/s40262-025-01540-1. Epub 2025 Jul 2.

Population Pharmacokinetic and Pharmacodynamic Modelling and Simulation for Nedosiran Clinical Development and Dose Guidance in Pediatric Patients with Primary Hyperoxaluria Type 1

Steven Zhang  1 , Pablo Gamallo  2 , Verity Rawson  3
Affiliations

Population Pharmacokinetic and Pharmacodynamic Modelling and Simulation for Nedosiran Clinical Development and Dose Guidance in Pediatric Patients with Primary Hyperoxaluria Type 1

Steven Zhang et al. Clin Pharmacokinet. 2025 Sep.

Abstract

Background and objectives: Nedosiran (Rivfloza®) is an RNA interference (RNAi) therapy approved for individuals aged ≥ 2 years with primary hyperoxaluria type 1 (PH1), a rare autosomal-recessive disorder causing renal failure and systemic oxalosis. Nedosiran silences lactate dehydrogenase (LDH) mRNA in hepatocytes, reducing oxalate levels. This study evaluated the model-informed clinical development of nedosiran to support proposed doses in children aged 2 to < 12 years with PH1.

Methods: A population pharmacokinetic/pharmacodynamic (Pop-PK/PD) model characterizing the plasma concentration-time profile of nedosiran and its effect on the spot urine oxalate-to-creatinine ratio (Uox/Cr) was developed using data from six trials. Simulations assessed spot Uox/Cr reduction in children aged 2 to < 12 years for the proposed dosing regimen versus those aged ≥ 12 years weighing ≥ 50 kg with similar renal function.

Results: The datasets included 2087 PK (N = 148) and 668 spot Uox/Cr (N = 41, with PH1) observations. Body weight, estimated glomerular filtration rate (eGFR), and PH type were covariates in the PK model, with body weight in low and high percentiles affecting nedosiran exposures. Moderate renal impairment (eGFR 30-59 mL/min/1.73 m2) increased exposure, while only age was significant for baseline Uox/Cr in the PD model. Simulations showed similar Uox/Cr reduction and times to maximum effect in children aged 2 to < 12 years, treated once-monthly (Q1M) with 3.5 mg/kg, compared to those aged ≥ 12 years treated Q1M with 170 mg.

Conclusions: Simulations based on the final Pop-PK/PD model support the 3.5 mg/kg Q1M dosing regimen in children aged 2 to < 12 years with PH1 and relatively intact kidney function (eGFR ≥30 mL/min/1.73 m2).

Trial registration: Trials are registered at ClinicalTrials.gov with study numbers NCT03392896 (PHYOX1), NCT03847909 (PHYOX2), NCT04042402 (PHYOX3), and NCT05001269 (PHYOX8) and at EudraCT with study numbers 2018-003098-91 (PHYOX2) and 2018-003099-10 (PHYOX3).

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Conflict of interest statement

Declarations. Funding: This study was supported by Dicerna Pharmaceuticals, Inc., a Novo Nordisk Company (Lexington, MA, USA). Conflict of interest: All authors are employees, and SZ and VR are shareholders of Novo Nordisk. Ethics approval: The institutional review board or ethics committee at each participating center approved the final study protocols. Consent to participate: Written informed consent was obtained from all adult participants and participating children’s parents or legal guardians. The safety review committee convened at predefined decision points and the occurrence of any potential dose-limiting toxicities to ensure the acceptability of continued nedosiran administration within each study (and cohort) and of dose escalation to subsequent cohorts (where applicable). Consent for publication: Not applicable. Availability of data and material: Data will be made available, on reasonable request. Code availability: Not applicable. Author contributions: Steven Zhang was responsible for the study conception and design. Model development and simulations were performed by Pablo Gamallo. Verity Rawson ensured medical accuracy. All authors participated in the interpretation of the study data, drafting of the manuscript, critical revision, and approval of the final version of the manuscript.

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