Population Pharmacokinetic Modeling of Subcutaneous Plozasiran in Healthy Volunteers and Patients with Familial Chylomicronemia Syndrome, Severe Hypertriglyceridemia, and Mixed Hyperlipidemia.

Abstract

Plozasiran, a novel small interfering RNA therapeutic targeting the hepatic biosynthesis of apolipoprotein C-III, has successfully completed the pivotal Phase 3 trial for treatment of familial chylomicronemia syndrome. The Phase 3 trials of plozasiran conducted in patients with severe hypertriglyceridemia (SHTG) are currently ongoing. An integrated population pharmacokinetic (PPK) model was developed by combining plozasiran pharmacokinetic (PK) data from healthy volunteers and patients with varying severities of hypertriglyceridemia (HTG) enrolled in five clinical studies. Plozasiran plasma PK were described by dual first-order absorption kinetics following subcutaneous administration, a one-compartment model of systemic distribution, and a dose-linear, time-independent rate of clearance. Evaluation of covariates identified body weight (BW) and body mass index (BMI) as the only independent intrinsic factors to influence plozasiran PK with statistical significance, although without clinical importance. The PPK analysis supports a fixed dosage of plozasiran for all patients regardless of BW, BMI, sex, age, race (including the Asian population), differing severity of HTG, mild to moderate degrees of renal impairment, or a mild degree of hepatic impairment. As plozasiran PK were not differentiated by patient population, a substantially reduced schedule of PK sampling was justified for the ongoing Phase 3 studies to confirm the safety and efficacy of plozasiran in patients with SHTG. Model-based extrapolation of plozasiran concentrations in plasma and liver suggests that the plozasiran dosing regimen of 25 mg every 3 months recommended for adult patients is likely safe and effective in adolescent patients aged 12 to 17 years old.