Related Experiment Video
Updated: Sep 17, 2025

Use of Ultra-high Field MRI in Small Rodent Models of Polycystic Kidney Disease for In Vivo Phenotyping and Drug Monitoring
Published on: June 23, 2015
Population Pharmacokinetic and Pharmacodynamic Modelling and Simulation for Nedosiran Clinical Development and Dose
Steven Zhang1, Pablo Gamallo2, Verity Rawson3
1Novo Nordisk Inc., 75 Hayden Avenue, Lexington, MA, 02421, USA. xvzn@novonordisk.com.
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).
Related Concept Videos
Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance
A recent model describes pravastatin's hepatobiliary excretion,...
Pharmacokinetic Models: Overview
There are three primary types of models: empirical, compartment, and physiological. Empirical models, with minimal...
Analysis of Population Pharmacokinetic Data
Nonlinear Pharmacokinetics: Overview
Nonlinearity can arise due to the saturation of plasma protein-binding or...
Model-Independent Approaches for Pharmacokinetic Data: Noncompartmental Analysis
One important characteristic of noncompartmental analyses is that drug exposure increases proportionally with increasing doses. This...
Pharmacokinetic Models: Comparison and Selection Criterion
Physiological models take a detailed approach by considering specific molecular processes. They can predict drug distribution, metabolism, and elimination changes, providing a comprehensive understanding of how drugs interact with the body.

