AZD3293: Pharmacokinetic and Pharmacodynamic Effects in Healthy Subjects and Patients with Alzheimer's Disease
AZD3293: Pharmacokinetic and Pharmacodynamic Effects in Healthy Subjects and Patients with Alzheimer's Disease
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DOI：
10.3233/jad-160701
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发表时间：
2017-01-01
影响因子：
4
通讯作者：
Kugler, Alan R.
中科院分区：
文献类型：
--
作者：
Cebers, Gvido;Alexander, Robert C.;Kugler, Alan R.
AZD 3293（LY 3314814）是一种有前途的新型潜在疾病修饰BACE 1（β-分泌酶）抑制剂，正在III期临床开发中，用于治疗阿尔茨海默病。这里报告的是前两项I期研究：（1）在老年受试者中进行的一项单次剂量递增研究，评价1-750 mg的剂量（含食物效应组分）（n = 72），和（2）一项2周多次剂量递增研究，评价15或50 mg每日一次（QD）或70 mg每周一次（QW）的剂量（第1部分，n = 31）和15、50或150 mg QD治疗轻度至中度阿尔茨海默病患者（第2部分，n = 16）。AZD 3293在最高给药剂量下通常耐受良好。未观察到明显的食物效应。在15 - 150 mg剂量范围内，多次给药（第2部分）后的PK为t（max）1 - 3 h，平均t（1/2）16 - 21 h。对于≥ 5 mg的单次给药，观察到平均血浆A β（40）和A β（42）浓度降低≥ 70%，在研究的最高剂量水平下，抑制时间延长至3周。多次给药后，观察到血浆（15 mg时>= 64%，>= 50 mg时>= 78%）和脑脊液（15 mg时>= 51%，>= 50 mg时>= 76%）A β肽的显著降低，包括即使采用QW给药方案也会延长抑制。AZD 3293是唯一一种在QW给药方案下可长期抑制血浆A β的BACE 1抑制剂。目前正在进行两项AZD 3293的III期研究（阿马兰斯，NCT 02245737;和DAYBREAK-ALZ，NCT 02783573）。
AZD3293 (LY3314814) is a promising new potentially disease-modifying BACE1 (beta-secretase) inhibitor in Phase III clinical development for the treatment of Alzheimer's disease. Reported here are the first two Phase I studies: (1) a single ascending dose study evaluating doses of 1-750 mg with a food-effect component (n = 72), and (2) a 2-week multiple ascending dose study evaluating doses of 15 or 50 mg once daily (QD) or 70 mg once weekly (QW) in elderly subjects (Part 1, n = 31), and 15, 50, or 150 mg QD in patients with mild to moderate Alzheimer's disease (Part 2, n = 16). AZD3293 was generally well tolerated up to the highest doses given. No notable food effects were observed. PK following multiple doses (Part 2) were t(max) of 1 to 3 h and mean t(1/2) of 16 to 21 h across the 15 to 150 mg dose range. For single doses of >= 5 mg, a >= 70% reduction was observed in mean plasma A beta(40) and A beta(42) concentrations, with prolonged suppression for up to 3 weeks at the highest dose level studied. Following multiple doses, robust reductions in plasma (>= 64% at 15 mg and >= 78% at >= 50 mg) and cerebrospinal fluid (>= 51% at 15 mg and >= 76% at >= 50 mg) A beta peptides were seen, including prolonged suppression even with a QW dosing regimen. AZD3293 is the only BACE1 inhibitor for which prolonged suppression of plasma A beta with a QW dosing schedule has been reported. Two Phase III studies of AZD3293 (AMARANTH, NCT02245737; and DAYBREAK-ALZ, NCT02783573) are now ongoing.