Nedosiran is a double-stranded siRNA, conjugated to GalNAc aminosugar residues. After subcutaneous administration, the GalNAc-conjugated sugars bind to asialoglycoprotein receptors (ASGPR) to deliver nedosiran to hepatocytes.
Nedosiran reduces levels of hepatic lactate dehydrogenase (LDH) via the degradation of LDHA messenger ribonucleic acid (mRNA) in hepatocytes through RNA interference. The reduction of hepatic LDH by nedosiran reduces the production of oxalate by the liver, thereby reducing subsequent oxalate burden.
The pharmacodynamic effects of nedosiran were evaluated after single-dose and monthly-dose administration in patients with PH1. Dose-dependent reductions in urinary oxalate were observed in the single-dose range of 1.5 mg/kg to 6.0 mg/kg. With the recommended monthly dose regimen of nedosiran, onset of effect was observed at the first measurement (30 days after the first dose) and the effect persisted with continued monthly dosing.
At the recommended dose, nedosiran does not lead to clinically relevant QT interval prolongation.
The pharmacokinetic (PK) properties of nedosiran were evaluated following administration of single and multiple dosages in patients with PH1 or PH2 as summarized in Table 1.
Table 1. Pharmacokinetic Parameters of Nedosiran:
| Nedosiran | ||
|---|---|---|
| General Information | ||
| Steady State Exposure | Cmax [Mean (%CV)] | 844 (44) ng/mL |
| AUC0-last [Mean (%CV)] | 13600 (36) ng*h/mL | |
| Dose Proportionality | Nedosiran exhibited a dose-proportional increase in plasma exposure following single subcutaneous doses from 1.5 to 6.0 mg/kg. Nedosiran exhibited time-independent pharmacokinetics with multiple doses of 160 mg once monthly (body weight ≥50 kg), 128 mg once monthly (body weight <50 kg), or 3.3 mg/kg once monthly in the age range of 6 to 11 years. | |
| Accumulation | No accumulation of nedosiran was observed in plasma following repeated monthly dosing. | |
| Absorption | ||
| Tmax [Median (Range)] | 6 (2 to 12) hours | |
| Distributiona | ||
| Estimated Vz/F | 126 L | |
| Protein Binding | 85.6% | |
| Elimination | ||
| Half-Life (Mean (%CV)]) | 15 (68) hours | |
| Estimated CL/F | 5.7 L/hr | |
| Metabolism | ||
| Primary Pathway | Nedosiran is metabolized by endo- and exonucleases to shorter oligonucleotides. | |
| Excretion | ||
| Primary Pathway | Approximately 27% of the administered nedosiran dose is excreted unchanged into the urine within 24 hours of dosing. | |
a Nedosiran distributes primarily to the liver after subcutaneous administration.
Cmax = maximum plasma concentration; AUC0-last = area under the plasma concentration-time curve from time of administration (0) to the last measurable time point (last); Tmax = time to maximum concentration; Vd/F = apparent volume of distribution; CV = coefficient of variation; CL/F = apparent clearance.
No clinically significant differences in the pharmacokinetics or pharmacodynamics of nedosiran were observed based on age (9 to 73 years old), sex, race/ethnicity, mild-to-moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m²]) or mild hepatic impairment as assessed using the National Cancer Institute Organ Dysfunction Working Group criteria (total bilirubin ≤ ULN and AST > ULN; or total bilirubin >1 to 1.5 × ULN and any AST).
At the recommended clinical dose, PK exposure of nedosiran is similar in adult and pediatric patients 9 years of age and older.
Concomitant use of pyridoxine (vitamin B6) did not have a significant impact on the PK of nedosiran.
In vitro studies demonstrated that nedosiran was not an inhibitor or inducer of cytochrome P450 (CYP) enzymes and was neither a substrate nor an inhibitor of efflux and uptake transporters.
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