Chemical formula: C520H679F21N175O309P43S6
Inclisiran is a cholesterol-lowering, double-stranded, small interfering ribonucleic acid (siRNA), conjugated on the sense strand with triantennary N-acetylgalactosamine (GalNAc) to facilitate uptake by hepatocytes. In hepatocytes, inclisiran utilises the RNA interference mechanism and directs catalytic breakdown of mRNA for proprotein convertase subtilisin kexin type 9. This increases LDL-C receptor recycling and expression on the hepatocyte cell surface, which increases LDL-C uptake and lowers LDL-C levels in the circulation.
Following a single subcutaneous administration of 284 mg inclisiran, LDL-C reduction was apparent within 14 days post-dose. Mean reductions of 48-51% for LDL-C were observed 30 to 60 days post-dose. At day 180, LDL-C levels were still reduced by approximately 53%.
Following single subcutaneous administration, systemic exposure to inclisiran increased approximately dose-proportionally over a range from 24 mg to 756 mg. At the recommended dosing regimen of 284 mg plasma concentrations reached peak in approximately 4 hours post dose, with a mean Cmax of 509 ng/ml. Concentrations reached undetectable levels within 48 hours post dosing. The mean area under the plasma concentration-time curve from dosing extrapolated to infinity was 7980 ng*h/ml. Pharmacokinetic findings following multiple subcutaneous administrations of inclisiran were similar to single-dose administration.
Inclisiran is 87% protein bound in vitro at the relevant clinical plasma concentrations. Following a single subcutaneous 284 mg dose of inclisiran to healthy adults, the apparent volume of distribution is approximately 500 litres. Based on non-clinical data inclisiran has been shown to have high uptake into and selectivity for the liver, the target organ for cholesterol lowering.
Inclisiran is primarily metabolised by nucleases to shorter inactive nucleotides of varying length. Inclisiran is not a substrate for common drug transporters and, although in vitro studies were not conducted, it is not anticipated to be a substrate for cytochrome P450.
The terminal elimination half-life of inclisiran is approximately 9 hours and no accumulation occurs with multiple dosing. Sixteen percent (16%) of inclisiran is cleared through the kidney.
In the phase I clinical study, an approximately dose proportional increase in inclisiran exposure was observed after administration of subcutaneous doses of inclisiran ranging from 24 mg to 756 mg. No accumulation and no time-dependent changes were observed after multiple subcutaneous doses of inclisiran.
In the phase I clinical study, a dissociation was observed between inclisiran pharmacokinetic parameters and LDL-C pharmacodynamic effects. Selective delivery of inclisiran to hepatocytes, where it is incorporated into the RNA-induced silencing complex (RISC), results in a long duration of action, beyond that anticipated based on the plasma elimination half-life of 9 hours. The maximal effects of reducing LDL-C were observed with a 284 mg dose, with higher doses not producing greater effects.
Pharmacokinetic analysis of data from a dedicated renal impairment study reported an increase in inclisiran Cmax of approximately 2.3, 2.0 and 3.3-fold and an increase in inclisiran AUC of approximately 1.6, 1.8 and 2.3-fold, in patients with mild (creatinine clearance [CrCL] of 60 ml/min to 89 ml/min), moderate (CrCL of 30 ml/min to 59 ml/min) and severe (CrCL of 15 ml/min to 29 ml/min) renal impairment, respectively, relative to patients with normal renal function. Despite the higher transient plasma exposures over 48 hours, the reduction in LDL-C was similar across all groups of renal function. Based on population pharmacodynamic modelling, no dose adjustment is recommended in patients with end-stage renal disease. Based on pharmacokinetic, pharmacodynamic and safety assessments, no dose adjustment is necessary in patients with mild, moderate or severe renal impairment. The effect of haemodialysis on inclisiran pharmacokinetics has not been studied. Considering that inclisiran is eliminated renally, haemodialysis should not be performed for at least 72 hours after inclisiran dosing.
Pharmacokinetic analysis of data from a dedicated hepatic impairment study reported an increase in inclisiran Cmax of approximately 1.1 and 2.1-fold, and an increase in inclisiran AUC of approximately 1.3 and 2.0-fold, respectively, in patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment relative to patients with normal hepatic function. Despite the higher transient inclisiran plasma exposures, the reductions in LDL-C were similar between the groups of patients administered inclisiran with normal hepatic function and mild hepatic impairment. In patients with moderate hepatic impairment baseline PCSK9 levels were markedly lower and the reduction in LDL-C was less than that observed in patients with normal hepatic function. No dose adjustment is necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A and B). Inclisiran has not been studied in patients with severe hepatic impairment (Child-Pugh class C).
A population pharmacodynamic analysis was conducted on data from 4,328 patients. Age, body weight, gender, race, and creatinine clearance were not found to significantly influence inclisiran pharmacodynamics. No dose adjustments are recommended for patients with these demographics.
In repeated dose toxicology studies conducted in rats and monkeys the no observed adverse effect levels (NOAEL) were identified as the highest doses administered subcutaneously which produced exposures considerably in excess of the maximum human exposure. Microscopic observations from toxicology studies included vacuolation in hepatocytes of rats and lymph node macrophages of monkeys, and the presence of basophilic granules in hepatocytes of monkeys and kidneys of rats and monkeys. These observations were not associated with changes in clinical laboratory parameters and are not considered adverse.
Inclisiran was not carcinogenic in Sprague-Dawley rats or in TgRasH2 mice administered inclisiran at doses sufficiently in excess of clinical doses.
No mutagenic or clastogenic potential of inclisiran was found in a battery of tests, including a bacterial mutagenicity assay, in vitro chromosomal aberration assay in human peripheral blood lymphocytes and an in vivo rat bone marrow micronucleus assay.
Reproduction studies performed in rats and rabbits have revealed no evidence of harm to the foetus due to inclisiran at the highest doses administered, which produced exposure considerably in excess of the maximum human exposure.
Inclisiran did not affect the fertility or reproductive performance of male rats and female rats exposed to inclisiran prior to gestation and during gestation. The doses were associated with systemic exposures many times greater than the human exposure at clinical doses.
Inclisiran has been observed in the milk of lactating rats; however, there is no evidence of systemic absorption in suckling rat neonates.
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