Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases plasma low-density lipoprotein cholesterol (LDL-C) by decreasing expression of the LDL receptor on hepatic cells. Evolocumab is a human monoclonal immunoglobulin G2 that binds specifically to human PCSK9 to reduce LDL-C. Evolocumab exhibits nonlinear kinetics as a result of binding to PCSK9. Elimination is predominantly through saturable binding to PCSK9 at lower concentrations and a nonsaturable proteolytic pathway at higher concentrations. The effective half-life of evolocumab is 11-17 days. The pharmacodynamic effects of evolocumab on PCSK9 are rapid, with maximum suppression within 4 h. At steady state, peak reduction of LDL-C occurs approximately 1 week after a subcutaneous dose of 140 mg every 2 weeks (Q2W) and 2 weeks after a subcutaneous dose 420 mg once monthly (QM), and returns towards baseline over the dosing interval. In several clinical studies, these doses of evolocumab reduced LDL-C by approximately 55-75% compared with placebo. Evolocumab also reduced lipoprotein(a) [Lp(a)] levels and improved those of other lipids in clinical studies. No clinically meaningful differences in pharmacodynamic effects on LDL-C were observed in adult subjects regardless of mild/moderate hepatic impairment, renal impairment or renal failure, body weight, race, sex, or age. No clinically meaningful differences were observed for the pharmacodynamic effects of evolocumab on LDL-C between patients who received evolocumab alone or in combination with a statin, resulting in additional lowering of LDL-C when evolocumab was combined with a statin. No dose adjustment is necessary based on patient-specific factors or concomitant medication use.

Fig. 1

Mechanism of action: PCSK9 inhibition with evolocumab increases LDL-R and decreases serum concentrations of LDL-C [, , , , –55]. a The liver is responsible for catabolism of plasma LDL. Hepatocytes express LDL-R that bind LDL and remove it from the plasma. Upon internalization, vesicles containing the LDL–LDL-R complex fuse with endosomes. LDL-R cycles back to the hepatocyte surface to bind additional LDL. Free LDL in endosomes is degraded into lipids, free fatty acids, and amino acids. b PCSK9 is a protein that regulates the expression of LDL-R in the liver. Hepatocytes produce a precursor of PCSK9 that undergoes self-cleavage in the endoplasmic reticulum and ultimately is secreted into plasma as functional PCSK9. Extracellular PCSK9 binds to LDL-Rs on the surface of the hepatocyte and is internalized with the LDL–LDL-R complex. The LDL-R–PCSK9 complex is routed to the lysosome for degradation, thereby preventing the cycling of LDL-R back to the hepatocyte surface. The reduced concentration of LDL-R on the surface of hepatocytes results in a lower rate of plasma LDL elimination. c A monoclonal antibody directed against PCSK9 could lower LDL if binding to circulating PCSK9 blocks the interaction of PCSK9 with cell surface LDL-R. Internalized LDL-R could cycle back to the cell surface instead of being degraded in lysosomes, leading to increased concentrations of LDL-R on the cell surface. This could result in a higher LDL elimination rate by hepatocytes and an overall reduction in plasma LDL. LDL-C low-density lipoprotein cholesterol, LDL-R low-density lipoprotein receptor, PCSK9 proprotein convertase subtilisin/kexin type 9

Fig. 2

Mean unbound evolocumab serum concentrations and geometric mean percent change from baseline in ultracentrifugation LDL-C and unbound PCSK9 in healthy subjects. a Single-dose SC evolocumab 140 mg. b Single-dose SC evolocumab 420 mg. LDL-C low-density lipoprotein cholesterol, PCSK9 proprotein convertase subtilisin/kexin type 9, SC subcutaneous. Amgen data on file

Fig. 3

Percent change (mean and 95% confidence interval) from baseline for lipid parameters: time-averaged effect, mean of weeks 10 and 12, and week 12. ApoA1 apolipoprotein A1, ApoB apolipoprotein B, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, Q2W once every 2 weeks