Obicetrapib exhibits favorable physiochemical and pharmacokinetic properties compared to previous cholesteryl ester transfer protein inhibitors: An integrated summary of results from non-human primate studies and clinical trials.

IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pharmacology Research & Perspectives Pub Date : 2024-12-01 DOI:10.1002/prp2.70010
Stephen J Nicholls, Adam J Nelson, John J P Kastelein, Marc Ditmarsch, Andrew Hsieh, Judith Johnson, Danielle Curcio, Douglas Kling, Carol F Kirkpatrick, Michael H Davidson
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Abstract

Anacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor previously under development, exhibited an usually extended terminal half-life and large food effect and accumulated in adipose tissue. Other CETP inhibitors have not shown such effects. Obicetrapib, a potent selective CETP inhibitor, is undergoing Phase III clinical development. Dedicated assessments were conducted in pre-clinical and Phase I and II clinical studies of obicetrapib to examine the pharmacokinetic issues observed with anacetrapib. After 9 months of dosing up to 50 mg/kg/day in cynomolgus monkeys, obicetrapib was completely eliminated from systemic circulation and not detected in adipose tissue after a 13-week recovery period. In healthy humans receiving 1-25 mg of obicetrapib, the mean terminal half-life of obicetrapib was 148, 131, and 121 h at 5, 10, and 25 mg, respectively, and food increased plasma levels by ~1.6-fold with a 10 mg dose. At the end of treatment in Phase II trials, mean plasma levels of obicetrapib ranged from 194.5 ng/mL with 2.5 mg to 506.3 ng/mL with 10 mg. Plasma levels of obicetrapib decreased by 92.2% and 98.5% at four and 15 weeks post-treatment, respectively. Obicetrapib shows no clinically relevant accumulation, is minimally affected by food, and has a mean terminal half-life of 131 h for the 10 mg dose. These data support once daily, chronic dosing of obicetrapib in Phase III trials for dyslipidemia management.

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与以往的胆固醇酯转移蛋白抑制剂相比,奥比司他匹具有良好的理化和药代动力学特性:非人灵长类动物研究和临床试验结果的综合总结。
之前正在开发的胆固醇酯转移蛋白(CETP)抑制剂 Anacetrapib 通常具有较长的终末半衰期和较大的食物效应,并在脂肪组织中蓄积。其他 CETP 抑制剂则没有显示出这种效应。Obicetrapib 是一种强效的选择性 CETP 抑制剂,目前正在进行 III 期临床开发。在 Obicetrapib 的临床前研究和 I、II 期临床研究中进行了专门评估,以检查 Anacetrapib 的药代动力学问题。在犬科猴体内进行了为期 9 个月的剂量试验,剂量最高达 50 毫克/千克/天,经过 13 周的恢复期后,obicetrapib 从全身循环中完全排出,在脂肪组织中也未检测到obicetrapib。健康人服用 1-25 毫克奥昔他匹,5、10 和 25 毫克奥昔他匹的平均终末半衰期分别为 148、131 和 121 小时,10 毫克剂量的食物可使血浆水平增加约 1.6 倍。在 II 期试验治疗结束时,2.5 毫克剂量的 obicetrapib 平均血浆水平为 194.5 纳克/毫升,10 毫克剂量为 506.3 纳克/毫升。在治疗后4周和15周,血浆中的奥昔他匹水平分别下降了92.2%和98.5%。奥昔他匹无临床相关蓄积,受食物影响极小,10 毫克剂量的平均终末半衰期为 131 小时。这些数据支持在治疗血脂异常的 III 期试验中每天一次长期服用 obicetrapib。
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来源期刊
Pharmacology Research & Perspectives
Pharmacology Research & Perspectives Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics
CiteScore
5.30
自引率
3.80%
发文量
120
审稿时长
20 weeks
期刊介绍: PR&P is jointly published by the American Society for Pharmacology and Experimental Therapeutics (ASPET), the British Pharmacological Society (BPS), and Wiley. PR&P is a bi-monthly open access journal that publishes a range of article types, including: target validation (preclinical papers that show a hypothesis is incorrect or papers on drugs that have failed in early clinical development); drug discovery reviews (strategy, hypotheses, and data resulting in a successful therapeutic drug); frontiers in translational medicine (drug and target validation for an unmet therapeutic need); pharmacological hypotheses (reviews that are oriented to inform a novel hypothesis); and replication studies (work that refutes key findings [failed replication] and work that validates key findings). PR&P publishes papers submitted directly to the journal and those referred from the journals of ASPET and the BPS
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