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

David Kallend; Robert Stoekenbroek; YanLing He; Patrick F Smith; Peter Wijngaard

doi:10.1016/j.jacl.2022.01.001

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

J Clin Lipidol. 2022 Mar-Apr;16(2):208-219. doi: 10.1016/j.jacl.2022.01.001. Epub 2022 Jan 10.

Authors

David Kallend¹, Robert Stoekenbroek², YanLing He³, Patrick F Smith⁴, Peter Wijngaard¹

Affiliations

¹ Former employees of The Medicines Company, Europaallee 41, 8004 Zurich, Switzerland (Drs. Kallend and Wijngaard).
² Novartis Pharmaceuticals Corporation, 1 Health Plaza, East Hanover, NJ 07936, USA (Dr. Stoekenbroek).
³ Novartis Institutes for BioMedical Research, 250 Massachusetts Ave, Cambridge, MA 02139, USA (Dr. He). Electronic address: yanling.he@novartis.com.
⁴ Certara, Inc., 6 Campus Drive, Parsippany, NJ 07054, USA (Dr. Smith).

PMID: 35168913
DOI: 10.1016/j.jacl.2022.01.001

Abstract

Background: 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.

Objective: 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).

Methods: 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.

Results: Twenty-eight participants completed the study (mild HI: n = 10; moderate HI: n = 6; NHF: n = 12). Inclisiran achieved maximum plasma concentration at 4-6 h and was undetectable in plasma at 48 h 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 Day 60 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.

Conclusion: 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.

Keywords: Hepatic impairment; Hyperlipidemia; Inclisiran; Pharmacodynamics; Pharmacokinetics.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Cholesterol, LDL
Humans
Liver Diseases* / drug therapy
Proprotein Convertase 9 / genetics
RNA, Small Interfering* / adverse effects
RNA, Small Interfering* / pharmacokinetics
RNA, Small Interfering* / pharmacology

Substances

ALN-PCS
Cholesterol, LDL
RNA, Small Interfering
PCSK9 protein, human
Proprotein Convertase 9