Nedosiran population pharmacokinetic and pharmacodynamic modelling and simulation to guide clinical development and dose selection in patients with primary hyperoxaluria type 1.

AIM

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

METHODS

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) Simulations of dosing to achieve clinically meaningful reduction in U in children, adolescents and adults with PH1 were performed.

RESULTS

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 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/1.73m). Following the proposed dosing regimens, the simulated median fold-changes in PK AUC were acceptable (≤1.51 fold-change) and ~71% of PH1 patients across all age groups achieved near-normal U (<0.6 mmol) by week 52.

CONCLUSIONS

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