Bempedoic acid

Chemical formula: C₁₉H₃₆O₅  Molecular mass: 344.492 g/mol  PubChem compound: 10472693

Mechanism of action

Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) by inhibition of cholesterol synthesis in the liver. ACL is an enzyme upstream of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase in the cholesterol biosynthesis pathway. Bempedoic acid and its active metabolite, ESP15228, require coenzyme A (CoA) activation by very long-chain acyl-CoA synthetase 1 (ACSVL1) to ETC-1002-CoA and ESP15228-CoA, respectively. ACSVL1 is expressed primarily in the liver. Inhibition of ACL by ETC-1002-CoA results in decreased cholesterol synthesis in the liver and lowers LDL-C in blood via upregulation of low-density lipoprotein receptors.

Pharmacodynamic properties

Administration of bempedoic acid alone and in combination with other lipid modifying medicinal products decreases LDL-C, non-high density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (apo B), and total cholesterol (TC) in patients with hypercholesterolaemia or mixed dyslipidaemia.

Because patients with diabetes are at elevated risk for atherosclerotic cardiovascular disease, the clinical trials of bempedoic acid included patients with diabetes mellitus. Among the subset of patients with diabetes, lower levels of HbA1c were observed as compared to placebo (on average 0.2%). In patients without diabetes, no difference in HbA1c was observed between bempedoic acid and placebo and there were no differences in the rates of hypoglycaemia.

Cardiac Electrophysiology

At a dose of 240 mg (1.3 times the approved recommended dose), bempedoic acid does not prolong the QT interval to any clinically relevant extent.

Pharmacokinetic properties

Bempedoic acid pharmacokinetic parameters are presented as the mean [standard deviation ± (SD)] unless otherwise specified. The steady-state maximum plasma concentration (Cmax) and area under the curve (AUC) following multiple-dose administration of bempedoic acid at 180 mg/day were 20.6 ± 6.1 µg/mL and 289.0 ± 96.4 µg∙h/mL, respectively. Bempedoic acid steady-state pharmacokinetics were generally linear over a range of >60 mg to 220 mg (approximately 33% to 122% of the recommended dosage of 180 mg daily). There were no time-dependent changes in bempedoic acid pharmacokinetics following repeat administration at the recommended dosage, and bempedoic acid steady-state was achieved after 7 days. The mean accumulation ratio was approximately 2.3-fold.

The steady-state Cmax and AUC of the active metabolite (ESP15228) of bempedoic acid were 2.8 ± 0.9 µg/mL and 51.2 ± 17.2 µg∙h/mL, respectively. ESP15228 likely made a minor contribution to the overall clinical activity of bempedoic acid based on systemic exposure, relative potency, and pharmacokinetic properties.

Absorption

Pharmacokinetic data indicate that bempedoic acid is absorbed with a median time to maximum concentration of 3.5 hours when administered as bempedoic acid 180 mg tablets.

Effect of Food

Concomitant food administration had no effect on the oral bioavailability of bempedoic acid.

Distribution

The bempedoic acid apparent volume of distribution (V/F) was 18 L. Plasma protein binding of bempedoic acid, its glucuronide and its active metabolite, ESP15228, were 99.3%, 98.8% and 99.2%, respectively. Bempedoic acid does not partition into blood cells.

Elimination

The steady-state clearance (CL/F) of bempedoic acid was 11.2 mL/min after once-daily dosing; renal clearance of unchanged bempedoic acid represented less than 2% of total clearance. The mean ± SD half-life for bempedoic acid in humans was 21 ± 11 hours at steady-state.

Metabolism

The primary route of elimination for bempedoic acid is through metabolism of the acyl glucuronide. Bempedoic acid is also reversibly converted to an active metabolite (ESP15228) based on aldo-keto reductase activity observed in vitro from human liver. Mean plasma AUC metabolite/parent drug ratio for ESP15228 following repeat-dose administration was 18% and remained constant over time. Both compounds are converted to inactive glucuronide conjugates in vitro by UGT2B7. Bempedoic acid, ESP15228 and their respective conjugated forms were detected in plasma with bempedoic acid accounting for the majority (46%) of the AUC0-48h and its glucuronide being the next most prevalent (30%). ESP15228 and its glucuronide represented 10% and 11% of the plasma AUC0-48h, respectively.

Excretion

Following single oral administration of 240 mg of bempedoic acid (1.3 times the approved recommended dose), approximately 70% of the total dose (bempedoic acid and its metabolites) was recovered in urine, primarily as the acyl glucuronide conjugate of bempedoic acid, and approximately 30% was recovered in feces. Less than 5% of the administered dose was excreted as unchanged bempedoic acid in feces and urine combined.

Specific Populations

Patients with Renal Impairment

Pharmacokinetics of bempedoic acid was evaluated in a single-dose pharmacokinetic study in subjects with varying degrees of renal function. The mean bempedoic acid AUC in subjects with mild renal impairment (n=8) were 1.5-fold higher compared to those with normal renal function (n=6). Relative to those with normal renal function, mean bempedoic acid AUCs were higher in patients with moderate (n=5) or severe (n=5) renal impairment by 2.3-fold and 2.4-fold, respectively.

A population pharmacokinetic analysis was performed on pooled data from all clinical trials (n=2261) to further evaluate the effects of renal function on the steady-state AUC of bempedoic acid. Compared to patients with normal renal function, the mean bempedoic acid exposures were higher in patients with mild or moderate renal impairment by 1.4-fold (90% CI: 1.3, 1.4) and 1.9-fold (90% CI: 1.7, 2.0), respectively. These differences were not clinically significant. Clinical studies of bempedoic acid did not include patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or patients with ESRD on dialysis.

Patients with Hepatic Impairment

The pharmacokinetics of bempedoic acid and its metabolite (ESP15228) was studied in patients with normal hepatic function or mild or moderate hepatic impairment (Child-Pugh A or B) following a single dose (n=8/group). Compared to patients with normal hepatic function, the bempedoic acid mean Cmax and AUC were decreased by 11% and 22%, respectively, in patients with mild hepatic impairment and by 14% and 16%, respectively, in patients with moderate hepatic impairment. Compared to patients with normal hepatic function, the ESP15228 mean Cmax and AUC were decreased by 13% and 23%, respectively, in patients with mild hepatic impairment and by 24% and 36%, respectively, in patients with moderate hepatic impairment. This is not expected to result in lower efficacy.

Bempedoic acid was not studied in patients with severe hepatic impairment (Child Pugh C).

Other Specific Populations

The pharmacokinetics of bempedoic acid were not affected by age, gender, race, or weight.

Drug Interaction Studies

Cytochrome P450 Substrates

In vitro metabolic interaction studies suggest that bempedoic acid, as well as its active metabolite and glucuronide forms are not metabolized by and do not interact with cytochrome P450 enzymes.

Transporter-mediated Drug Interactions

In vitro drug interaction studies suggest bempedoic acid, as well as its active metabolite and glucuronide form, are not substrates of commonly characterized drug transporters with the exception of bempedoic acid glucuronide, which is an OAT3 substrate. Bempedoic acid weakly inhibits OAT3 at high multiples of clinically relevant concentrations, and bempedoic acid and its glucuronide weakly inhibit OATP1B1, and OATP1B3 at clinically relevant concentrations. Bempedoic acid weakly inhibits OAT2 in vitro, which is likely the mechanism responsible for minor elevations in serum creatinine and uric acid.

Probenecid

Administration of bempedoic acid 180 mg with steady-state probenecid resulted in a 1.7- and a 1.2-fold increase in bempedoic acid AUC and Cmax, respectively. AUC and Cmax for bempedoic acid active metabolite (ESP15228) were increased 1.9- and 1.5-fold, respectively. These elevations are not clinically meaningful and do not impact dosing recommendations.

Statins

The pharmacokinetic interactions between bempedoic acid (at systemic exposure relevant to the indicated ASCVD population) and simvastatin 20 mg, atorvastatin 10 mg, pravastatin 40 mg, and rosuvastatin10 mg were evaluated in clinical trials.

Simvastatin: Administration of simvastatin 20 mg with 240 mg of bempedoic acid or 40 mg with 180 mg of bempedoic acid in healthy subjects at steady-state resulted in approximately 2-fold (91% for 20 mg and 96% for 40 mg) and 1.5-fold (54% for 20 mg and 52% for 40 mg) increases in simvastatin acid AUC and Cmax, respectively.

Pravastatin: Administration of pravastatin 40 mg with steady-state bempedoic acid 240 mg in healthy subjects resulted in 99% (2-fold) and 104% (2-fold) increases in pravastatin acid AUC and Cmax, respectively.

Atorvastatin and Rosuvastatin: Elevations of 1.7-fold in AUC of atorvastatin, and rosuvastatin and/or their major metabolites were observed, suggesting a weak interaction. These elevations were generally within the individual statin exposures and do not impact dosing recommendations.

Ezetimibe

Increases in AUC and Cmax for ezetimibe were less than 20% when a single dose of ezetimibe was taken with steady-state bempedoic acid. Total ezetimibe (ezetimibe and its glucuronide form) and ezetimibe glucuronide AUC and Cmax increased approximately 1.6- and 1.8-fold, respectively. These elevations are not clinically meaningful and do not impact dosing recommendations.

Warfarin

In vitro studies indicate that bempedoic acid is not an inhibitor or inducer of CYP2C9. Because warfarin is primarily eliminated through CYP2C9, its pharmacokinetics is not expected to be altered by bempedoic acid.

Other

Bempedoic acid had no effect on the pharmacokinetics of metformin or the oral contraceptive Ortho-Novum 1/35.

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