Pharmacokinetics and pharmacodynamics of inclisiran, a small interfering RNA therapy, in patients with hepatic impairment

Abstract

Inclisiran, a small interfering RNA molecule, reduces low-density lipoprotein cholesterol (LDL-C) by inhibiting production of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the liver. To investigate the pharmacokinetics, pharmacodynamics, and safety of inclisiran in patients with mild or moderate hepatic impairment (HI) vs participants with normal hepatic function (NHF). In this single-center, open-label, parallel-group study, patients with mild (Child-Pugh A) or moderate (Child-Pugh B) HI and with NHF, matched by age, body mass index, sex, and race (if possible), received a single subcutaneous therapeutic dose of inclisiran (300 mg). Pharmacokinetic profiles, pharmacodynamic endpoints (PCSK9 and LDL-C), and safety were assessed. Twenty-eight participants completed the study (mild HI: n = 10; moderate HI: n = 6; NHF: n = 12). Inclisiran achieved maximum plasma concentration at 4-6h and was undetectable in plasma at 48h in most participants, irrespective of liver function. Inclisiran exposure was 1.24-fold higher in the mild HI vs NHF groups (90% confidence interval [CI] 1.01-1.53) and 2.03-fold higher in the moderate HI vs NHF groups (90% CI 1.60-2.58). LDL-C and PCSK9 plasma levels decreased from baseline up to the last assessment on Day60 in all groups, with a similar response in NHF and mild HI groups but a less pronounced and more varied decrease in the moderate HI group. Inclisiran was generally safe and well tolerated. The pharmacokinetic exposure of inclisiran increased by up to two fold in patients with moderate HI compared with those with NHF, while pharmacodynamic effects remained relatively unchanged. Inclisiran is generally safe and well tolerated in patients with mild or moderate HI, with no dose adjustment needed. However, a larger, long-term clinical trial would help to further evaluate the long-term safety profile of inclisiran in patients with liver disease.