Pharmacokinetics of current and emerging treatments for hypercholesterolemia

ABSTRACT

Introduction: Reduction of low-density-lipoprotein cholesterol (LDL-C) and other apolipoprotein B (apoB)-containing lipoproteins reduces cardiovascular (CV) events and greater reductions have greater benefits. Current lipid treatments cannot always achieve desirable LDL-C targets and additional or alternative treatments are often needed.

Areas covered: In this article, we review the pharmacokinetics of the available and emerging treatments for hypercholesterolemia and focus on recently approved drugs and those at a late stage of development.

Expert opinion: Statin pharmacokinetics are well known and appropriate drugs and doses can usually be chosen for individual patients to achieve LDL-C targets and avoid adverse effects and drug-drug interactions. Ezetimibe, icosapent ethyl and the monoclonal antibodies evolocumab and alirocumab have established efficacy and safety. Newer oral agents including pemafibrate and bempedoic acid have generally favorable pharmacokinetics supporting use in a wide range of patients. RNA-based therapies with antisense oligonucleotides are highly specific for their targets and those inhibiting apoB, apoCIII, angiopoietin-like protein 3 and lipoprotein(a) have shown promising results. The small-interfering RNA inclisiran has the notable advantage that a single subcutaneous administration may be effective for up to 6 months. The CV outcome trial results and long term safety data are eagerly awaited for these new agents.

KEYWORDS:

• LDL-C-lowering
• bempedoic acid
• ezetimibe
• gemcabene
• inclisiran
• pemafibrate
• pradigastat
• proprotein convertase subtilisin/kexin type 9 inhibitors
• statins
• volanesorsen

Article highlights

• The pharmacokinetics of statins, ezetimibe and the monoclonal antibody PCSK9 inhibitors, alirocumab and evolocumab, are well established and these drugs are generally safe apart from some drug-drug interactions and muscle problems with statins.

• Omega-3 fatty acids formulations, such as icosapent ethyl, and fibrates, particularly fenofibrate, can be combined safely with statins to reduce residual risk related to elevated triglycerides.

• The novel potent SPPARM-α agonist pemafibrate may prove to have advantages over other fibrates whereas bempedoic acid may avoid some of the systemic adverse effects of statins because of selective drug activation in the liver.

• RNA-based therapies provide highly specific targets with the ASOs mipomersen, volanesorsen, IONIS-ANGPTL3-L_Rx and IONIS-APO(a)-L_Rx and the GalNac-modified products show liver selectivity and increased potency.

• The small-interfering RNA inclisiran with the GalNac conjugation provides very long acting liver-selective intracellular PCSK9 inhibition at the target site allowing dosing every 6 months.

• Long term safety data and cardiovascular outcome studies are required with these new drugs.

This box summarizes key points contained in the article.

Declaration of interest

Brian Tomlinson has acted as consultant or speaker for Amgen Inc, Kowa, and Merck Serono for which he received honoraria. The other authors have no conflicts to disclose.