Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib in Japanese patients with heterozygous familial hypercholesterolemia

Arai, Hidenori; Teramoto, Tamio; Daida, Hiroyuki; Ikewaki, Katsunori; Maeda, Yuko; Nakagomi, Mariko; Shirakawa, Masayoshi; Kakikawa, Taro; Numaguchi, Hirotaka; Johnson‐Levonas, Amy O.; Vaidya, Sanskruti; Blaustein, Robert O.

doi:10.1016/j.atherosclerosis.2016.03.017

Cited by 11 publications

(8 citation statements)

References 38 publications

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“…Given the range of lipid‐altering efficacy and safety, none of the findings from the present study suggest any differences between Japanese and non‐Japanese responses to anacetrapib that would be of clinical consequence. In support of this, the safety and efficacy of anacetrapib in Japanese patients are comparable to in the global studies …”

Section: Discussionsupporting

confidence: 77%

“…In support of this, the safety and efficacy of anacetrapib in Japanese patients are comparable to in the global studies. 5,6 Anacetrapib induces its lipid-altering efficacy through inhibition of CETP activity. The present findings suggest that CETP inhibition can be sustained to a meaningful extent in young, healthy Japanese men, as has previously been found in non-Japanese young, healthy men and other demographic groups.…”

Section: Discussionmentioning

confidence: 99%

“…Anacetrapib, as monotherapy or coadministered with atorvastatin, produced significant reductions in LDL‐C and increases in HDL‐C in Japanese patients with dyslipidemia . More recently, Arai et al (2016) reported on a multicenter, randomized, double‐blind, placebo‐controlled study that assessed the lipid‐modifying efficacy/safety profile of anacetrapib 100 mg added to ongoing statin ± other lipid‐modifying therapies in Japanese patients with heterozygous familial hypercholesterolemia and showed that treatment with anacetrapib 100 mg for 12 weeks resulted in substantial reductions in LDL‐C and increases in HDL‐C and was well tolerated.…”

mentioning

confidence: 99%

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Pharmacokinetics and Pharmacodynamics of Anacetrapib Following Single Doses in Healthy, Young Japanese and White Male Subjects

Krishna

Gheyas

Liu

et al. 2017

The Journal of Clinical Pharma

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Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of mixed dyslipidemia. The aim of the study was to evaluate the pharmacokinetic, pharmacodynamic, and safety characteristics of anacetrapib following single doses in healthy, young Japanese men. In a double-blind, randomized, placebo-controlled, 3-panel, single-rising-dose study, 6 healthy young Japanese male or white male subjects (aged 19 to 44 years) received single oral doses of 5 to 500 mg anacetrapib, and 2 received placebo. Plasma and urine drug concentrations were measured 0-168 hours postdose, and plasma CETP inhibition was measured 0-24 hours postdose. Urinary anacetrapib levels were all below quantitation limits. Plasma concentrations of anacetrapib increased approximately less than dose-proportionally. Consumption of a traditional Japanese breakfast prior to dosing increased the plasma pharmacokinetics of anacetrapib in Japanese subjects compared with fasted conditions, to a similar extent as in white subjects. CETP activity measured over 0-24 hours postdose resulted in significant inhibition. Anacetrapib was generally well tolerated, and there were no serious adverse experiences. No clinically meaningful differences in PK and CETP inhibition parameters were found between Japanese and white subjects.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Pharmacokinetics and Pharmacodynamics of Anacetrapib Following Single Doses in Healthy, Young Japanese and White Male Subjects

Krishna

Gheyas

Liu

et al. 2017

The Journal of Clinical Pharma

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“…This was likely a chance occurrence as previous studies have not documented elevations in serum sodium levels after anacetrapib treatment. 3,10,11 The safety findings during the 12-week reversal phase were similar to that seen in the treatment phase. There were 3 deaths in the placebo group and none in the anacetrapib group during the reversal period.…”

Section: Discussionsupporting

confidence: 61%

“…Similar magnitude effects on LDL-C (BQ) and HDL-C have been previously reported after 24 weeks of anacetrapib treatment and its subsequent cessation over 12 weeks. 8,10 Anacetrapib was well tolerated during the 24-week treatment period, with no notable imbalances in AEs observed between the treatment groups including those that were serious, drug-related, or led to discontinuation of study drug. Serious AEs were infrequent across both groups.…”

Section: Discussionmentioning

confidence: 97%

A Multiregional, Randomized Evaluation of the Lipid-Modifying Efficacy and Tolerability of Anacetrapib Added to Ongoing Statin Therapy in Patients With Hypercholesterolemia or Low High-Density Lipoprotein Cholesterol

Ballantyne

Shah

Sapre

et al. 2017

The American Journal of Cardiology

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This phase 3, multiregional, randomized, double-blind, placebo-controlled study assessed the efficacy/safety profile of anacetrapib added to ongoing therapy with statin ± other lipid-modifying therapies in patients with hypercholesterolemia who were not at their low-density lipoprotein (LDL-C) goal (as per the National Cholesterol Education Program Adult Treatment Panel III guidelines) and in those with low high-density lipoprotein cholesterol (HDL-C). Patients on a stable dose of statin ± other lipid-modifying therapies and with LDL-C ≥70 to <115, ≥100 to <145, ≥130, or ≥160 mg/dl for very high, high, moderate, or low CHD risk or at LDL-C goal (per CHD risk category) with HDL-C ≤40 mg/dl were randomized in a ratio of 1:1 to anacetrapib 100 mg (n = 290) or placebo (n = 293) for 24 weeks, followed by a 12-week off-drug phase. The co-primary end points were % change from baseline in LDL-C and HDL-C and the safety profile of anacetrapib. Treatment with anacetrapib reduced LDL-C (BQ) by 37% (95% confidence interval -42.5, -31.0) and increased HDL-C by 118% (95% confidence interval 110.6, 125.7) relative to placebo (p <0.001 for both). Anacetrapib also reduced non-HDL-C, apolipoprotein B, and lipoprotein a and increased apolipoprotein AI versus placebo (p <0.001 for all). There were no clinically meaningful differences between the anacetrapib and placebo groups in the % patients who discontinued drug due to an adverse event or in abnormalities in liver enzymes, creatine kinase, blood pressure, electrolytes, or adjudicated cardiovascular events. Treatment with anacetrapib substantially reduced LDL-C and also increased HDL-C and was well tolerated over 24 weeks in statin-treated patients with hypercholesterolemia or low HDL-C.

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Study of effect modifiers of genetically predicted CETP reduction

Legault

Barhdadi

Gamache

et al. 2023

Genetic Epidemiology

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Genetic variants in drug targets can be used to predict the effect of drugs. Here, we extend this principle to assess how sex and body mass index may modify the effect of a genetically predicted lower CETP levels on biomarkers and cardiovascular outcomes.We found sex and BMI to be modi ers of the association between genetically predicted lower CETP and lipid biomarkers in UK Biobank participants. Female sex and lower BMI were associated with higher HDLcholesterol and lower LDL-cholesterol for a same genetically predicted reduction in CETP concentration. We found that sex also modulated the effect of genetically lower CETP on cholesterol e ux capacity in samples from the Montreal Heart Institute Biobank. However, these modifying effects did not extend to sex-differences in cardiovascular outcomes in our data.Our results provide insight on the clinical effects of CETP inhibitors in the presence of effect modi cation based on observational genetic data. The approach can support precision medicine applications and help assess the external validity of clinical trials.

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Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib in Japanese patients with heterozygous familial hypercholesterolemia

Cited by 11 publications

References 38 publications

Pharmacokinetics and Pharmacodynamics of Anacetrapib Following Single Doses in Healthy, Young Japanese and White Male Subjects

Pharmacokinetics and Pharmacodynamics of Anacetrapib Following Single Doses in Healthy, Young Japanese and White Male Subjects

A Multiregional, Randomized Evaluation of the Lipid-Modifying Efficacy and Tolerability of Anacetrapib Added to Ongoing Statin Therapy in Patients With Hypercholesterolemia or Low High-Density Lipoprotein Cholesterol

Study of effect modifiers of genetically predicted CETP reduction

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