Lumasiran is a double-stranded small interfering ribonucleic acid (siRNA) that reduces levels of glycolate oxidase (GO) enzyme by targeting the hydroxyacid oxidase 1 (HAO1) gene messenger ribonucleic acid (mRNA) in hepatocytes through RNA interference. Decreased GO enzyme levels reduce the amount of available glyoxylate, a substrate for oxalate production. This results in reduction of urinary and plasma oxalate levels, the underlying cause of disease manifestations in patients with PH1. As the GO enzyme is upstream of the deficient alanine: glyoxylate aminotransferase (AGT) enzyme that causes PH1, the mechanism of action of lumasiran is independent of the underlying AGXT gene mutation.
Following subcutaneous administration, lumasiran is rapidly absorbed with a median (range) time to reach maximum plasma concentration (tmax) of 4.0 (0.5 to 12.0) hours. In children and adults with PH1 ≥20 kg, the peak plasma concentration of lumasiran (Cmax) and area under the concentration curve from time zero to the last measurable concentration after dosing (AUC0-last) following the recommended lumasiran dose of 3 mg/kg were 529 (205 to 1130) ng/mL and 7400 (2890 to 10700) ng·h/mL, respectively. In children less than 20 kg, Cmax and AUC0-last of lumasiran following the recommended lumasiran dose of 6 mg/kg were 912 (523 to 1760) and 7960 (5920 to 13300). Lumasiran concentrations were measurable, up to 24 to 48 hours post-dose.
In healthy adult plasma samples, the protein binding of lumasiran is moderate to high (77 to 85%) at clinically relevant concentrations. For an adult patient with PH1, the population estimate for the apparent central volume of distribution (Vd/F) for lumasiran is 4.9 L. Lumasiran primarily distributes to the liver after subcutaneous dosing.
Lumasiran is metabolised by endo- and exonucleases to oligonucleotides of shorter lengths. In vitro studies indicate that lumasiran does not undergo metabolism by CYP450 enzymes.
Lumasiran is primarily eliminated from plasma by hepatic uptake, with only 7 to 26% of the administered dose recovered in urine as lumasiran in the pooled data from healthy adult subjects and patients with PH1 >6 years of age. The mean (CV) terminal plasma half-life of lumasiran is 5.2 (47.0) hours. The population estimate for apparent plasma clearance was 26.5 L/h for a typical 70-kg adult. The mean renal clearance of lumasiran was minor and ranged from 2.0 to 3.4 L/h in paediatric and adult patients with PH1.
Lumasiran exhibited linear to slightly nonlinear, time-independent pharmacokinetics in plasma following single subcutaneous doses ranging from 0.3 to 6 mg/kg and multiple doses of 1 and 3 mg/kg once monthly or 3 mg/kg quarterly. There was no accumulation of lumasiran in plasma after repeated once monthly or quarterly dosing.
Plasma concentrations of lumasiran do not reflect the extent or duration of the pharmacodynamic activity of lumasiran. Rapid and targeted uptake of lumasiran by the liver results in rapid decline in plasma concentrations. In the liver, lumasiran exhibits a long half-life leading to maintenance of pharmacodynamic effect over the monthly or quarterly dosing interval.
In vitro studies indicate that lumasiran is not a substrate or an inhibitor of cytochrome P450 (CYP) enzymes. Lumasiran is not expected to inhibit or induce CYP enzymes or modulate the activities of drug transporters.
No studies have been conducted in patients ≥65 years of age. Age was not a significant covariate in the pharmacokinetics of lumasiran.
In clinical studies, there was no difference in the plasma exposure or pharmacodynamics of lumasiran based on gender or race.
No studies have been conducted in patients with hepatic impairment. Limited pharmacokinetic data in patients with mild and transient elevations in total bilirubin (total bilirubin >1.0 to 1.5×ULN) showed comparable plasma exposure of lumasiran and similar pharmacodynamics as patients with normal hepatic function. Published literature show lower expression of the asialoglycoprotein receptors in the liver, i.e. the receptors responsible for lumasiran uptake, in patients with hepatic impairment. Nonclinical data suggest that this may not influence liver uptake or pharmacodynamics at therapeutic doses. The clinical relevance of these data is unknown.
Patients with mild renal impairment (eGFR 60 to <90 mL/min/1.73 m²) had comparable plasma exposure of lumasiran and similar pharmacodynamics as patients with normal renal function (eGFR ≥90 mL/min/1.73 m²). In patients with moderate renal impairment (eGFR 30 to <60 mL/min/1.73 m²) Cmax was similar to that in patients with normal renal function; AUC was 25% higher based on limited data. Limited clinical data are available in patients with severe renal impairment (eGFR 15 to <30 mL/min/1.73 m²), end-stage renal disease (eGFR <15 mL/min/1.73 m²), or who are on dialysis. For ESRD patients on dialysis, within the same body weight category, a transient 3- to 7-fold higher Cmax and 2- to 3.5-fold AUC0-last increase was observed. However, plasma concentrations decline below the level of detection within 24 to 48 hours, similar to patients without renal impairment.
Data in children younger than 1 year of age are limited. In children <20 kg, lumasiran Cmax was 2-fold higher due to the nominally higher 6-mg/kg dose and faster absorption rate. The pharmacodynamics of lumasiran were comparable in paediatric patients (aged 4 months to 17 years) and in adults, despite the transiently higher plasma concentrations in children <20 kg, due to the rapid and predominant distribution of lumasiran to the liver.
The recommended dosing regimens yielded up to 2-fold higher Cmax in children <20 kg while AUC was similar across the body weights studied (6.2 to 110 kg).
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and genotoxicity.
In rats, but not in monkeys, microscopic changes in the liver (e.g. hepatocellular vacuolation, mitosis and karyomegaly) were observed, accompanied by decrease in plasma fibrinogen levels and other laboratory changes. The reason for the apparent rodent-specificity is not understood and the relevance for humans is unclear.
Lumasiran did not show any adverse effects on male and female fertility and pre- and post-natal development in rats. In embryo-foetal development studies in rats and rabbits, skeletal abnormalities were observed, but at high exposure multiples relative to human therapeutic exposures. The NOAELs were approximately 20- to 70-times higher (based on monthly exposures).
A dose-range finding toxicity study in neonate rats did not show increased sensitivity of the developing rat to either the toxicology or pharmacology of lumasiran at exposure multiples of 2 compared to human therapeutic exposures (based on monthly exposures).
Animal studies have not been conducted to evaluate the carcinogenic potential of lumasiran.
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