Influence of Renal Function on Evolocumab Exposure, Pharmacodynamics, and Safety

Abstract

We evaluated the pharmacokinetics, pharmacodynamics, and safety of evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), in an open-label, parallel-design study in participants with normal renal function (n = 6), severe renal impairment (RI; n = 6), or end-stage renal disease (ESRD) receiving hemodialysis (n = 6) who received a single 140-mg dose of evolocumab. The effects of evolocumab treatment on low-density lipoprotein cholesterol (LDL-C) lowering and unbound PCSK9 concentrations were similar in the normal renal function group and the renally impaired groups. Geometric mean Cmax and AUClast values in the severe RI and ESRD hemodialysis groups compared with the normal renal function group were lower but within 37% of the normal renal function group (Jonckheere-Terpstra trend test; Cmax , P = .23; AUClast , P = .22) and within 26% after adjusting for body weight (mean body weight was approximately 9% higher in the renally impaired groups compared with the normal renal function group). No correlations were observed between exposure and baseline creatinine clearance. No adverse event was determined by the investigators to be related to evolocumab, and there were no trends indicative of clinically important effects on laboratory variables or vital signs. Overall, there were no meaningful differences in evolocumab exposure, as assessed by Cmax and AUClast , in patients with severe RI and ESRD hemodialysis compared with patients with normal renal function, and LDL-C-lowering effects were similar across groups. These results support the use of evolocumab without dose adjustment in patients who have severe RI or ESRD.

Keywords: LDL-C; PCSK9; evolocumab; human monoclonal antibody; pharmacokinetics and pharmacodynamics; renal impairment.

© 2019 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Figures

Figure 1

Mean ± standard deviation serum unbound evolocumab concentration‐time profiles from normal renal function, severe renal impairment, or ESRD receiving hemodialysis patients after a single 140‐mg subcutaneous dose of evolocumab, depicted as a log‐linear plot. The lower limit of quantification was 0.8 μg/mL. ESRD, end‐stage renal disease; SD, standard deviation.

Figure 2

Scatterplots of individual values for (A) Cmax, (B) AUClast, and (C) AUCinf. AUClast, area under the drug concentration‐time curve from time zero to time of last quantifiable concentration; AUCinf, area under the drug concentration‐time curve from time zero to infinity; Cmax, maximum observed drug concentration; ESRD, end‐stage renal disease.

Figure 3

Scatterplots of individual log‐transformed values for (A) Cmax, (B) AUClast, and (C) AUECday1‐57 for LDL‐C versus baseline CrCl with regression line. AUClast, area under the drug concentration‐time curve from time zero to time of last quantifiable concentration; AUECday1‐57, area under the effect‐time curve from day 1 to 57; Cmax, maximum observed drug concentration; CrCl, creatinine clearance; ESRD, end‐stage renal disease; LDL‐C, low‐density lipoprotein cholesterol.

Figure 4

Mean percent change ± standard error from baseline of UC LDL‐C (mg/dL) over time by degree of renal impairment. ESRD, end‐stage renal disease; LDL‐C, low‐density lipoprotein cholesterol; UC, ultracentrifugation.

Figure 5

Mean percent change ± standard error from baseline of PCSK9 over time by degree of renal impairment. ESRD, end‐stage renal disease; PCSK9, proprotein convertase subtilisin kexin type 9.