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.Electronic supplementary materialThe online version of this article (10.1007/s40262-017-0620-7) contains supplementary material, which is available to authorized users.

Population pharmacokinetics and exposure–response modeling and simulation for evolocumab in healthy volunteers and patients with hypercholesterolemia

“…The precision of the body weight covariate effects on CL and V max may have been influenced by the high correlation between individual random effects on CL and V max (Table 4 ). Baseline PCSK9 concentrations (~ 400 ng/mL) were small relative to mean observed unbound evolocumab C max of 18.6 or 59 µg/mL after 140 mg SC Q2W or 420 mg SC QM, respectively [ 34 ]. In the MM TMDD model approximation, k m represented the ratio of the sum of the complex internalization rate and dissociation rate constant to the drug-target dissociation rate constant.…”

“…There was no evidence that anti-drug binding antibodies affected the PK profile, clinical response, or safety of evolocumab. Therefore, the incidence of anti-evolocumab binding antibodies is low, and not deemed necessary to evaluate in this analysis [ 34 ]. In addition, various analyses showed that evolocumab produced similar lipid-lowering effects in patients with and without diabetes, and hence not deemed a clinically relevant covariate in this analysis [ 35 – 37 ].…”

Hypolipidemic Roles of Casein-Derived Peptides by Regulation of Trans-Intestinal Cholesterol Excretion and Bile Acid Synthesis

“…Recently, a combination therapy comprised of statins and ezetimibe has demonstrated the potential to overcome limitations of statin monotherapy via the inhibition of intestinal cholesterol absorption and the increase of cholesterol excretion [ 6 ]. In addition, a PSCK9 inhibitor, a suppresser of hepatic LDLR expression, has also indicated potential in non-statin hypolipidemic therapy [ 7 ]. Nevertheless, further improvement in therapeutic strategies is imperative for the fundamental regulation of hyperlipidemia.…”

Effect of Evolocumab on Vulnerable Coronary Plaques: A Serial Coronary Computed Tomography Angiography Study

“…PCSK9 also inhibited ATP-binding cassette transporter A1 expression in macrophages by depleting LDL receptors, which reduced cholesterol efflux from lipid-laden foam cells [ 36 ]. Evolocumab was reported to facilitate the uptake of serum LDL-cholesterol by hepatocytes by inhibiting LDL-cholesterol receptor clearance [ 37 ], and promote ATP-binding cassette transporter A1 expression in macrophages by upregulating LDL receptor expression [ 36 ]. These findings suggest that evolocumab shrinks atherosclerotic plaques by reducing serum LDL-cholesterol concentrations and increasing cholesterol efflux from lipid-laden foam cells.…”