Pharmacokinetics of bempedoic acid in patients with renal impairment

Abstract

Bempedoic acid is an ATP citrate lyase inhibitor approved for the treatment of hypercholesterolemia. The objective of this phase I study was to assess the pharmacokinetics (PKs) and safety of bempedoic acid in 24 subjects with normal renal function or mild, moderate, or severe renal impairment. All subjects received a single oral bempedoic acid 180-mg dose and PK parameters were monitored for up to 23 days. Resulting estimates of area under the concentration-time curve exposure following bempedoic acid treatment were 1.5-fold, 2.2-fold, and 2.2-fold higher in subjects with mild, moderate, or severe renal impairment, respectively, compared with subjects with normal renal function. With decreases in renal function, plasma free fraction was increased up to 20.1%, whereas total and unbound clearances were decreased by 55.2% and 62.6%, respectively, in subjects with severe renal impairment relative to those with normal renal function. These observed decreases in total and unbound oral clearance in subjects with decreased renal function are not explained by the increases in free fraction and might therefore also be attributable to changes in bioavailability or intrinsic clearance. Bempedoic acid was generally well-tolerated and the incidence and type of adverse events were not affected by the degree of renal impairment. In conclusion, bempedoic acid exposures in subjects with renal impairment were increased up to approximately two-fold with no safety signals identified, consistent with findings in phase III patients with mild or moderate renal impairment. No dose adjustments are necessary for patients with mild or moderate renal impairment.

FIGURE 1

Arithmetic mean (±SD) bempedoic acid plasma concentration‐time profiles in subjects with normal renal function and mild, moderate, and severe renal impairment after single bempedoic acid 180‐mg dose administration. Insert depicts linear profiles on a 0–24 h time scale. Assay lower limit of quantitation, 20 ng/ml; inter‐run precision, 1.5 to 4.4% CV; accuracy, −3.3% to 1.6% mean bias

FIGURE 2

Arithmetic mean (±SD) ESP15228 plasma concentration‐time profiles in subjects with normal renal function and mild, moderate, and severe renal impairment after single bempedoic acid 180‐mg dose administration. Insert depicts linear profiles on a 0–24 h time scale. Assay lower limit of quantitation, 10 ng/ml; inter‐run precision, 2.6% to 5.7% CV; accuracy, −1.5% to 2.9% mean bias

FIGURE 3

Bempedoic acid plasma concentration‐time profiles from individual subjects with (a) normal renal function (n = 6) and (b) severe renal impairment (n = 5) after single bempedoic acid 180‐mg dose administration. Insert depicts linear profiles of subjects with (a) normal renal function and (b) severe renal impairment on a 0–24 h time scale