Early Clinical Development, IMED Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 431 83, Gothenburg, Sweden.
Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
Drugs R D. 2018 Jun;18(2):149-159. doi: 10.1007/s40268-018-0236-x.
The aim of this study was to summarise the pharmacokinetic findings from eight phase I studies in healthy volunteers given oral AZD5069, a selective small-molecule CXCR2 antagonist.
240 healthy volunteers across eight phase I studies received single (0.1-200 mg) or multiple once- or twice-daily (10-120 mg) oral AZD5069 as solution, suspension, capsules or tablets. Pharmacokinetics were evaluated using non-compartmental analysis methods.
AZD5069 was rapidly absorbed (time to maximum concentration ~ 2 h) under fasting conditions. A high-fat, high-calorie meal delayed and reduced the peak plasma AZD5069 concentration (C) by 50%, but total exposure (AUC) was unchanged (fed:fasting geometric mean ratio 90% confidence interval within 0.80-1.25). The plasma concentration of AZD5069 declined with an initial half-life of 4 h and terminal half-life of 11 h. Steady-state plasma concentrations were achieved within 2-3 days and accumulation was ~ 1.1-fold with twice-daily dosing. Systemic exposure was approximately proportional to dose. Intra- and inter-subject variability in AUC was 3-11 and 29-64%, respectively. Less than 5% of the AZD5069 dose was excreted as parent drug in the urine. Elderly subjects had 39% higher AZD5069 AUC and 21% higher C than younger adults. Japanese subjects had similar or slightly higher exposure to AZD5069 than Caucasian subjects. Co-administration with ketoconazole resulted in 2.1-fold higher AUC and 1.6-fold higher C. All formulations had similar bioavailability.
AZD5069 demonstrated predictive linear pharmacokinetics with low intra- and moderate inter-subject variability and no major influences from ethnicity, age, food or formulation. Half-life data indicated suitability for twice-daily dosing. CLINICALTRIALS.
NCT00953888, NCT01051505, NCT01083238, NCT01100047, NCT01332903, NCT01480739, NCT01735240, NCT01989520.
本研究旨在总结在健康志愿者中单次和多次口服选择性小分子 CXCR2 拮抗剂 AZD5069 的 8 项 I 期研究的药代动力学结果。
8 项 I 期研究中，240 名健康志愿者单次或多次口服 AZD5069（0.1-200mg），每日 1 次或 2 次。采用非房室分析方法评估药代动力学。
在禁食条件下，AZD5069 迅速吸收（达峰时间约 2h）。高脂肪、高热量饮食使 AZD5069 的峰血浆浓度（C）延迟且降低 50%，但总暴露量（AUC）不变（fed:fasting 几何均数比值 90%置信区间为 0.80-1.25）。AZD5069 血浆浓度以初始半衰期 4h 和终末半衰期 11h 下降。在 2-3 天内达到稳态血浆浓度，每日 2 次给药时蓄积约 1.1 倍。系统暴露与剂量呈比例。AUC 的个体内和个体间变异性分别为 3-11%和 29-64%。少于 5%的 AZD5069 剂量以原形药物从尿液中排泄。老年受试者的 AZD5069 AUC 比年轻成年人高 39%，C 高 21%。日本受试者的 AZD5069 暴露与白种人受试者相似或略高。酮康唑合用使 AUC 增加 2.1 倍，C 增加 1.6 倍。所有制剂的生物利用度相似。
AZD5069 表现出预测性线性药代动力学特征，个体内和个体间变异性低，种族、年龄、食物或制剂无明显影响。半衰期数据表明适合每日 2 次给药。
临床试验.gov 标识符：NCT00953888、NCT01051505、NCT01083238、NCT01100047、NCT01332903、NCT01480739、NCT01735240、NCT01989520。
