Nedosiran population pharmacokinetic and pharmacodynamic modelling and simulation to guide clinical development and...

To characterize pharmacokinetic and pharmacodynamic profiles of nedosiran in patients with primary hyperoxaluria type 1 (PH1), identify influential covariates and confirm therapeutic doses.

A population pharmacokinetic (PK)/pharmacodynamic (PD) (POP-PKPD) model was developed to characterize the concentration-time course of nedosiran and the corresponding effect on 24-h urinary oxalate (U_ox)_. Simulations of dosing to achieve clinically meaningful reduction in U_ox in children, adolescents and adults with PH1 were performed.

Analyses included PK data from 143 healthy participants and PH1/PH2 patients, and PD data from 46 PH1 patients. Nedosiran PK was described by a two-compartment model with dual n-transit absorption and parallel linear and nonlinear elimination. The relationship between nedosiran exposure and U_ox was described by an indirect response model. Body weight, estimated glomerular filtration rate (eGFR) and disease status were identified as influential covariates for the POP-PK model. The simulation results supported a weight-banded dosing regimen of nedosiran sodium in adolescents and adults (≥12 years) with PH1 of 170 mg (weight ≥50 kg) and 136 mg (weight <50 kg), in children (6-11 years) with PH1 of 3.5 mg/kg, and no dose adjustments for PH1 patients with relatively preserved kidney function (eGFR ≥ 30 mL/min/1.73m²). Following the proposed dosing regimens, the simulated median fold-changes in PK AUC_0-τ,ss were acceptable (≤1.51 fold-change) and ~71% of PH1 patients across all age groups achieved near-normal U_ox (<0.6 mmol) by week 52.

The final POP-PKPD model characterizes observed nedosiran PK and U_ox data. Simulations support nedosiran dosing regimens in PH1 patients aged ≥6 years with relatively preserved kidney function.