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

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).

Fig. 1

Schematic representation of the POP-PK/PD model. C_eff effect compartment concentration, CL/F apparent clearance, Eff the inhibitory effect of nedosiran on the zero-order production rate of Uox/Cr, FR1 fraction of the dose absorbed via the slow pathway, γ Hill coefficient, IC₅₀ half maximal inhibitory concentration, I_max maximum inhibitory effect, k_a1 absorption transit rate constant for the slow pathway, k_a2 absorption transit rate constant for the fast pathway, k_e0 first-order equilibrium rate constant of effect compartment, k_in zero-order production rate of spot Uox/Cr, KM Michaelis-Menten constant, k_out first-order elimination rate of spot Uox/Cr, λ equilibration half-life in the effect compartment, Q/F apparent inter-compartmental clearance, SC subcutaneous, Uox/Cr spot urine oxalate-to-creatinine ratio, V_c/F apparent volume of distribution for the central compartment, V_max maximum metabolic rate, V_p/F apparent volume of distribution for the peripheral compartment

Fig. 2

Standard GOF plots of the final Pop-PK/PD model. GOF goodness of fit, PK/PD pharmacokinetics/pharmacodynamics, Pop population, Uox/Cr spot urine oxalate-to-creatinine ratio

Fig. 3

Visual predictive check (VPCs) for the final Pop-PK/PD model stratified by study. Dashed blue lines represent observed 5th and 95th percentiles, solid red line represent observed median, and shaded areas represent 95% CI around the model predicted 5th, median, and 95th percentiles. CI confidence interval, PK/PD pharmacokinetics/pharmacodynamics, Pop population, Uox/Cr spot urine oxalate-to-creatinine ratio

Fig. 4

Covariate effects on relative exposure. Forest plots show data represented as AUC_tau,_ss (a) and C_max,ss (at steady state) (b), respectively, relative to a reference participant profile (PH1 adult of 75 kg body weight with eGFR = 100 mL/min/1.73 m² and 170 mg Q1M dose regimen). Forest plots show medians and 90% CI of relative exposure. Vertical dotted lines represent the bioequivalence limits [0.80, 1.25]. AUC area under the concentration-time curve, AUC_tau,_ss AUC over the dosing interval at steady state, CI confidence intervals, C_max,ss maximum concentration at steady state, PH primary hyperoxaluria, Q1M once-monthly

Fig. 5

Comparison of simulated fold changes in nedosiran (AUC_tau and C_max at steady state) across age ranges for the renal functions PH1 with normal renal function (a), PH1 with mild renal impairment (b), and moderate renal impairment (c), using as reference the group age ≥ 12 and weight ≥ 50 kg with corresponding renal function. The solid black line represents no change from the median of the reference group. Dashed red or orange lines represent the 50–200%, 80–125% or 80–150% range of the reference group. The blue dots and error bars represent the median and 95% PI. AUC area under the concentration-time curve, AUC_tau,_ss AUC over the dosing interval at steady state, CI confidence intervals, C_max,ss maximum concentration at steady state, PH1 primary hyperoxaluria type 1, PI prediction interval

Fig. 6

Simulated change in mean spot Uox/Cr from baseline in patients with PH1 treated with nedosiran, comparing different age groups for various renal functions. Comparison of the age group from 2 to < 6 years (3.5 mg/kg Q1M) versus age ≥ 12 years and weight ≥ 50 kg (170 mg Q1M) for different renal functions for normal renal function (a), mild renal impairment (c), and moderate renal impairment different renal functions (e). Comparison from 6 to < 9 years with weight < 50 kg (3.5 mg/kg Q1M, with max dose of 136 or 170 mg) versus age ≥ 12 years with weight ≥ 50 kg (170 mg Q1M) for normal renal function (b), mild renal impairment (d), and moderate renal impairment different renal functions (f). Solid lines represent medians and dashed lines 90% PI. PH1 primary hyperoxaluria type 1, PI prediction interval, Q1M once-monthly, Uox/Cr spot urine oxalate-to-creatinine ratio

Fig. 7

Simulated change in mean spot Uox/Cr from baseline in patients with PH1 treated with nedosiran, comparing different age and weight combinations for various renal functions. Comparison of the age group from 9 to < 12 years with weight < 50 kg (3.5 mg/kg Q1M) with a max dose of 136 and 170 mg, respectively, versus age ≥ 12 years with weight ≥ 50 kg (170 mg Q1M) for normal renal function (a), mild renal impairment (d), and moderate renal impairment different renal functions (g). Simulated spot Uox/Cr in patients with PH1. Comparison of the age group from 9 to < 12 years with weight ≥ 50 kg (3.5 mg/kg Q1M) and with a max dose of 136 and 170 mg, respectively, versus age ≥ 12 years and weight ≥ 50 kg (170 mg Q1M) for normal renal function (b), mild renal impairment (e), and moderate renal impairment different renal functions (h). Simulated spot Uox/Cr in patients with PH1. Comparison of the age group ≥ 12 years with weight ≥ 50 kg and weight < 50 kg, respectively, and a dose of 170 mg Q1M, versus age ≥ 12 years with weight < 50 kg and a dose of 136 mg Q1M for normal renal function (c), mild renal impairment (f), and moderate renal impairment different renal functions (i) Solid lines represent medians and dashed lines 90% PI. PH1 primary hyperoxaluria type 1, PI prediction interval, Q1M once-monthly, Uox/Cr spot urine oxalate-to-creatinine ratio