The Disposition and Metabolism of Bempedoic Acid, a Potent Inhibitor of ATP Citrate Lyase, in Healthy Human Subjects

Abstract

The disposition and metabolism of bempedoic acid, a selective inhibitor of ATP citrate lyase, were examined in healthy male subjects. After a single administration of [ 14 C] bempedoic acid (240 mg, 113 lCi) oral solution, mean concentrations of total radioactivity in plasma as a function of time indicated absorption was rapid with peak concentrations achieved at 1 hour after dose administration. Radioactivity was decreased in a multiexponential fashion with an estimated elimination halflife of 26.0 hours. Radiolabeled dose was predominantly recovered in urine (62.1% of dose) and a smaller amount in feces (25.4% of dose). Bempedoic acid was extensively metabolized with 1.6%-3.7% of dose excreted unchanged in urine and feces combined. Overall, the major clearance route of bempedoic acid is metabolism by uridine 5 0 -diphosphate glucuronosyltransferases. Metabolism in hepatocyte cultures of human and nonclinical species were generally in agreement with clinical metabolite profiles. Pooled plasma samples were characterized by the presence of bempedoic acid (ETC-1002), which accounted for 59.3% of total plasma radioactivity, ESP15228 (M7; a reversible keto metabolite of bempedoic acid), and their respective glucuronide conjugates. The acyl glucuronide of bempedoic acid (M6) represented 23%-36% of radioactivity in plasma and accounted for approximately 37% of dose excreted in urine. In feces, the majority of radioactivity was associated with a co-eluting mixture of a carboxylic acid metabolite of bempedoic acid (M2a), a taurine conjugate of bempedoic acid (M2c), and hydroxymethyl-ESP15228 (M2b), which collectively accounted for 3.1%-22.9% of bempedoic acid dose across subjects. SIGNIFICANCE STATEMENTThis study characterizes the disposition and metabolism of bempedoic acid, an inhibitor of ATP citrate lyase for hypercholesterolemia. This work provides further understanding of bempedoic acid clinical pharmacokinetics and clearance pathways in adult subjects.

Low-Density Lipoprotein Cholesterol-Lowering Drugs: A Narrative Review

“…To manifest its direct and competitive inhibitory effect on cholesterol synthesis, bempedoic acid requires its transformation from a prodrug (8-hydroxy-2,2,4,14tetramethyl-pentadecanedioic acid) to an active metabolite catalyzed by enzyme "very long-chain acyl-CoA synthetase-1 (ACSVL1)" which occurs in hepatocytes and leads to the genesis of the powerful direct and competitive inhibitor, bempedoic acid-CoA [118]. Bempedoic acid is thus activated when acetyl-Coenzyme A is added to the molecule and its reversible conversion to ESP15228, also an active metabolite, is obtained by oxidation of bempedoic acid [119]. ESP15228 contributes minimally to the overall clinical activity of bempedoic acid due to its low systemic exposure and pharmacokinetic properties [118,119].…”

“…Bempedoic acid is thus activated when acetyl-Coenzyme A is added to the molecule and its reversible conversion to ESP15228, also an active metabolite, is obtained by oxidation of bempedoic acid [119]. ESP15228 contributes minimally to the overall clinical activity of bempedoic acid due to its low systemic exposure and pharmacokinetic properties [118,119].…”

Physiologically Based Pharmacokinetic Model Development and Verification for Bioequivalence Testing of Bempedoic Acid Oral Suspension and Reference Tablet Formulation

“…Although these physicochemical properties align with BCS class two (low solubility, high permeability) drugs [ 3 ], bempedoic acid is much more soluble at pH conditions of the small intestine and is readily absorbed as evidenced by a median time to peak plasma concentration observed at 3.5 h after oral administration [ 4 ]. In addition, human mass balance results indicated that a high fraction of the bempedoic acid oral dose was absorbed after a single [ 14 C] bempedoic acid 240 mg dose administration, where approximately 95% of the dose was absorbed and <5% of the dose was excreted as unchanged drug [ 5 ]. Collectively, these in vitro data and clinical observations suggest that neither bempedoic acid solubility nor permeability are rate-limiting factors in terms of the rate and extent of oral absorption.…”

“…Hepatic metabolism represents the main pathway of elimination, where bempedoic acid is primarily metabolized by uridine 5′ diphospho-glucuronosyltransferase (UGT) 2B7 to form an inactive acyl glucuronide metabolite. Bempedoic acid also undergoes reversible metabolism to form a keto metabolite, ESP15228, that becomes activated to a coenzyme A thioester by ACSVL1 and inhibits ATP citrate lyase with similar potency to ETC-1002-CoA [ 5 ].…”

Prodrugs as empowering tools in drug discovery and development: recent strategic applications of drug delivery solutions to mitigate challenges associated with lead compounds and drug candidates

“…After oral administration of a single 240 mg dose of radiolabeled 8f , ∼70% of the total dose was recovered in the urine, primarily, as the acyl glucuronide of 8f , with ∼30% being recovered in the feces and the recovery of unchanged parent drug in the urine and the feces amounting to less than 5% of the administered dose. 321 Approximately 20% of 8f is reversibly converted by an aldo-keto reductase enzyme into ESP15228 ( 8g ) as a metabolite that is also pharmacologically active in the form of its CoA–thioester. In 2020, the FDA approved 8f as a once-daily oral therapy to be used as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease who require additional lowering of LDL-cholesterol.…”