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Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin
Open accessAbstract
Aims The primary aims of these two single‐centre, randomized, evaluator‐blind, placebo/positive‐controlled, parallel‐group studies were to evaluate the potential for pharmacodynamic and pharmacokinetic interaction between ezetimibe 0.25, 1, or 10 mg and simvastatin 10 mg (Study 1), and a pharmacodynamic interaction between ezetimibe 10 mg and simvastatin 20 mg (Study 2). Evaluation of the tolerance of the coadministration of ezetimibe and simvastatin was a secondary objective. Methods Eighty‐two healthy men with low‐density lipoprotein cholesterol (LDL‐C) ≥130 mg dl−1 received study drug once daily in the morning for 14 days. In Study 1 (n=58), five groups of 11–12 subjects received simvastatin 10 mg alone, or with ezetimibe 0.25, 1, or 10 mg or placebo. In Study 2 (n=24), three groups of eight subjects received simvastatin 20 mg alone, ezetimibe 10 mg alone, or the combination. Blood samples were collected to measure serum lipids in both studies. Steady‐state pharmacokinetics of simvastatin and its β‐hydroxy metabolite were evaluated in Study 1 only. Results In both studies, reported side‐effects were generally mild, nonspecific, and similar among treatment groups. In Study 1, there were no indications of pharmacokinetic interactions between simvastatin and ezetimibe. All active treatments caused statistically significant (P<0.01) decreases in LDL‐C concentration vs placebo from baseline to day 14. The coadministration of ezetimibe and simvastatin caused a dose‐dependent reduction in LDL‐C and total cholesterol, with no apparent effect on high‐density lipoprotein cholesterol (HDL‐C) or triglycerides. The coadministration of ezetimibe 10 mg and simvastatin 10 mg or 20 mg caused a statistically (P<0.01) greater percentage reduction (mean −17%, 95% CI −27.7, −6.2, and −18%, −28.4, −7.4, respectively) in LDL‐C than simvastatin alone. Conclusions The coadministration of ezetimibe at doses up to 10 mg with simvastatin 10 or 20 mg daily was well tolerated and caused a significant additive reduction in LDL‐C compared with simvastatin alone. Additional clinical studies to assess the efficacy and safety of coadministration of ezetimibe and simvastatin are warranted.
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“Ezetimibe selectively inhibits the absorption of cholesterol in the small intestine [by interfering with the Niemann-Pick C1-like 1 protein (NPC1L1)] without modifying uptake of other nutrients and vitamins [56, 57].”
From Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention (2023) · cites this paper as [56]
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“Ezetimibe targets the Niemann-Pick C1-like 1 (NPC1L1) protein, thereby reducing absorption of cholesterol from the intestine.15,16”
From Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes (2015) · cites this paper as [16]
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Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes
Cannon, C. P., Blazing, M. A., Giugliano, R. P., McCagg, A., White, J. A., Theroux, P., Darius, H., Lewis, B. S., Ophuis, T. O., Jukema, J. W., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1410489 · Cited by 4,487
Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia
Davidson, M. H., Mcgarry, T. F., Bettis, R. B., Melani, L., Lipka, L., LeBeaut, A., Suresh, R., Sun, S. H., & Veltri, E. P. (2002) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(02)02610-4 · Cited by 557
Self-citationGagné, C., Gaudet, D., & Bruckert, É. (2002) · Circulation · doi:10.1161/01.cir.0000018744.58460.62 · Cited by 480
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Self-citationSoppert, J., Lehrke, M., Marx, N., Jankowski, J., & Noels, H. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.07.019 · Cited by 440
Metadata
- Authors
- Kosoglou, T., Meyer, I., Veltri, E. P., Statkevich, P., Yang, B., Zhu, Y., Mellars, L., Maxwell, S. E., Patrick, J. E., Cutler, D. L., Batra, V. K., & Affrime, M. B.
- Affiliations
- IQVIA (United States) (US)
- Corresponding author
- Kosoglou, Teddy
- Venue
- British Journal of Clinical Pharmacology
- Publisher
- Wiley
- Published
- 2002-09
- Volume
- 54
- Issue
- 3
- Pages
- 309-319
- ISSN
- 0306-5251 (ISSN-L)
- 1365-2125
- PMC
- PMC1874429
- OpenAlex
- W1498903994
- Semantic Scholar
- 72c4048e09bae02d9558d6f422ca2effd4944f2f
- Cited by
- 117
- References
- 52
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 3 · 2022: 1 · 2020: 3 · 2019: 6 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 4 · 2014: 5 · 2013: 6 · 2012: 4
- FWCI
- 14.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Clinical Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- ezetimibe, simvastatin, drug-drug interactions, pharmacodynamic interactions, pharmacokinetic interactions, LDL cholesterol, total cholesterol, statins, cholesterol absorption inhibitors, serum lipids, hypercholesterolemia, dose dependence, healthy men, healthy women, healthy children, healthy older adults, healthy pregnant women
- MeSH terms
- Ezetimibe, Administration, Oral, Adult, Anticholesteremic Agents, Azetidines, Biological Availability, Dose-Response Relationship, Drug, Drug Combinations, Drug Interactions, Humans, Cholesterol, LDL, Male, Middle Aged, Body Mass Index, Simvastatin
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