Safety, Pharmacokinetics, and Exposure –Response Modeling of Nedosiran in Participants With Severe Chronic Kidney Disease

AbstractNedosiran is an investigational RNA-interference therapeutic in development for primary hyperoxaluria (PH). Because nedosiran undergoes renal clearance, we assessed its pharmacokinetic profile in non-PH participants with normal kidney function and Stages 4/5 chronic kidney disease (CKD), the latter with/without dialysis. Nedosiran exposure –response modeling in patients with PH Subtype 1 (PH1) with different renal function level was performed to recommend a nedosiran dose for this subpatient population. In this open-label, single-dose, Phase 1 study, 24 participants with estimated glomerular filtration rate<30  mL/min/1.73 m2 (CKD Stages 4/5; on hemodialysis [Groups 1a, 1b] and not on hemodialysis [Group 2]) and 10  participants with normal kidney function (estimated glomerular filtration rate ≥90 mL/min/1.73 m2; Group 3) received a single dose of subcutaneous nedosiran sodium 170  mg. Group 1a received nedosiran 8 hoursbefore beginning hemodialysis, Group 1b received nedosiran 2  hoursafter completing hemodialysis; Group 2 was not on hemodialysis. Nedosiran population pharmacokinetic –pharmacodynamic analyses were conducted using pooled data from this study and 4 others. Nedosiran pharmacokinetic exposure in non-PH participants with CKD Stages 4/5 was approximately 2-fold higher versus participants with normal kidney function. Hemodialysis timing relative to nedosiran administ ration had no clinically significant impact on pharmacokinetics (Group 1a ...
Source: Clinical Pharmacology in Drug Development - Category: Drugs & Pharmacology Authors: Tags: Original Article Source Type: research