Pharmacodynamic effect of bempedoic acid and statin combinations: predictions from a dose–response model

Author:

Jadhav Satyawan B1,Crass Ryan L1,Chapel Sunny1,Kerschnitzki Michael2,Sasiela William J3,Emery Maurice G3,Amore Benny M3,Barrett P Hugh R4,Watts Gerald F5,Catapano Alberico L6ORCID

Affiliation:

1. Ann Arbor Pharmacometrics Group, 900 Victors Way #328, Ann Arbor, MI 48108, USA

2. Daiichi Sankyo Europe GmbH, Zielstattstraße 48, 81379 Munich, Germany

3. Esperion Therapeutics, Inc., 3891 Ranchero Dr, Ann Arbor, MI 48108, USA

4. Faculty of Medicine and Health, University of New England, Armidale, NSW 2351, Australia

5. School of Medicine, University of Western Australia, Medical Research Foundation Building, Rear 50 Murray Street, Perth, WA 6001, Australia

6. Department of Pharmacological and Biomolecular Sciences, University of Milan and IRCCS Multimedica, Via Balzaretti 9, 20133 Milan, Italy

Abstract

Abstract Aims Many patients are unable to achieve guideline-recommended LDL cholesterol (LDL-C) targets, despite taking maximally tolerated lipid-lowering therapy. Bempedoic acid, a competitive inhibitor of ATP citrate lyase, significantly lowers LDL-C with or without background statin therapy in diverse populations. Because pharmacodynamic interaction between statins and bempedoic acid is complex, a dose–response model was developed to predict LDL-C pharmacodynamics following administration of statins combined with bempedoic acid. Methods and results Bempedoic acid and statin dosing and LDL-C data were pooled from 14 phase 1–3 clinical studies. Dose–response models were developed for bempedoic acid monotherapy and bempedoic acid–statin combinations using previously published statin parameters. Simulations were performed using these models to predict change in LDL-C levels following treatment with bempedoic acid combined with clinically relevant doses of atorvastatin, rosuvastatin, simvastatin, and pravastatin. Dose–response models predicted that combining bempedoic acid with the lowest statin dose of commonly used statins would achieve a similar degree of LDL-C lowering as quadrupling that statin dose; for example, the predicted LDL-C lowering was 54% with atorvastatin 80 mg compared with 54% with atorvastatin 20 mg + bempedoic acid 180 mg, and 42% with simvastatin 40 mg compared with 46% with simvastatin 10 mg + bempedoic acid 180 mg. Conclusion These findings suggest bempedoic acid combined with lower statin doses offers similar LDL-C lowering compared with statin monotherapy at higher doses, potentially sparing patients requiring additional lipid-lowering therapies from the adverse events associated with higher statin doses.

Funder

Esperion Therapeutics, Inc.

Publisher

Oxford University Press (OUP)

Subject

Pharmacology (medical),Cardiology and Cardiovascular Medicine

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