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Cited by 117Lipoproteins and Cardiovascular HealthCholesterol and Lipid MetabolismPharmacogenetics and Drug Metabolism

Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin

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Kosoglou, Teddy, Meyer, Ingo, Veltri, Enrico P., Statkevich, Paul, Yang, Bo, Zhu, Yali, Mellars, Lillian, Maxwell, Stephen E. +4 more·2002·British Journal of Clinical Pharmacology
DOI 10.1046/j.1365-2125.2002.01633.xPMC PMC1874429
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Abstract

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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Crossref · 10.1046/j.1365-2125.2002.01633.x

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  • Ezetimibe selectively inhibits the absorption of cholesterol in the small intestine by interfering with NPC1L1 without modifying uptake of other nutrients and vitamins.

    “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]

    The Introduction (page not specified) describes ezetimibe as a selective cholesterol absorption inhibitor that blocks passage of dietary and biliary cholesterol across the intestinal wall. Our copy does not identify NPC1L1 as its target or say that uptake of other nutrients and vitamins is unaffected; searches for those terms found no supporting passage. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Ezetimibe targets the Niemann-Pick C1-like 1 (NPC1L1) protein, thereby reducing absorption of cholesterol from the intestine.

    “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]

    The Introduction says ezetimibe prevents absorption of dietary and biliary cholesterol across the intestinal wall. It does not identify NPC1L1 as ezetimibe’s target; searches for NPC1L1 and the molecular target found no supporting passage in our copy. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

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Cites

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2 of the 52 references couldn’t be matched to a known paper.

Research works printed but not linked: 5

  1. [31]31. Davis HR Jr, Pula KK, Alton KB, Burrier RE, Watkins RW. The synergistic hypocholesterolemic activity of the potent cholesterol absorption inhibitor ezetimibe in combination with HMG-CoA reductase inhibitors in dogs. Metabolism 2001; 50: 1234-1241.
  2. [34]34. Plosker GL, McTavish D, Simvastatin. A reappraisal of its pharmacology and therapeutic efficacy in hypercholesterolemia. Drugs 1995; 50: 334-363.
  3. [40]40. Zhu Y, Statkevich P, Kosoglou T, et al. Effect of ezetimibe (SCH 58235) on the activity of drug metabolizing enzymes in vivo. Clin Pharmacol Ther 2000; 67: 152 (Abstract).
  4. [43]43. Zhu Y, Statkevich P, Schuessler D, et al. Pharmacokinetics of ezetimibe in rats, dogs, and humans. AAPS Pharm Sci Supplement 2000; 2: 2660 (Abstract).
  5. [44]44. Kosoglou T, Kakkar T, Statkevich P, et al. Multiple-dose safety and pharmacokinetics of ezetimibe in adolescent children. Clin Pharmacol Ther 2001; 69: P52 (Abstract).

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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
ORCID
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
DOI
10.1046/j.1365-2125.2002.01633.x
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
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 17 d)
Locations
  • British Journal of Clinical Pharmacology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Surgery › 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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