GlaxoSmithKline, Stevenage, United Kingdom.
GlaxoSmithKline, Uxbridge, United Kingdom.
Clin Ther. 2018 Aug;40(8):1410-1417. doi: 10.1016/j.clinthera.2018.06.011. Epub 2018 Jul 25.
Novel therapies to treat chronic obstructive pulmonary disease are highly desirable. The safety, tolerability, and pharmacokinetic (PK) parameters of nemiralisib, a phosphoinositide 3-kinase δ inhibitor, administered via the Ellipta dry powder inhaler (GlaxoSmithKline, Research Triangle Park, North Carolina) was evaluated, including an assessment of oral bioavailability.
This single-center, 3-part, placebo-controlled trial in 22 healthy subjects evaluated single (100 and 200 μg) and repeat (200 μg for 10 days) doses of inhaled nemiralisib in parts A (n = 12) and B (n = 12) (double-blind) and single doses of inhaled nemiralisib (200 µg) with and without charcoal block in Part C (n = 6) (open-label, 2-period, crossover). There was a minimum 14-day washout period between dosing days.
21 subjects completed the study, mean age was similar in the three parts (A: 49 years; B: 44 years; C: 55 years). After single doses of nemiralisib, observed plasma C dropped rapidly, followed by a slower elimination phase. Near-dose proportionality was observed: mean (95% CI) plasma C and AUC values were 174.3 pg/mL (96.9-313.3) and 694.6 pg·h/mL (503.5-958.2) for 100 μg and 398.9 pg/mL (318.3-500.1) and 1699.6 pg·h/mL (1273.3-2268.7) for 200 μg, respectively. Repeat dosing for 10 days showed exposures ∼2- to 4-fold higher than on the single dose (peak, trough, and AUC levels), achieving steady-state by day 6. Mean AUC was 2193.6 pg·h/mL and 1645.3 pg·h/mL in the absence/presence of charcoal. Two non-drug-related adverse events were observed; neither was serious or resulted in withdrawal.
Inhalation of nemiralisib was well tolerated in these healthy subjects. Plasma pharmacokinetic variables were well defined, and charcoal block data indicate that ∼23% of the total systemic exposure after inhalation from Ellipta was attributable to orally absorbed drug. ClinicalTrials.gov identifier: NCT02691325.
治疗慢性阻塞性肺疾病的新型疗法是非常需要的。本研究评估了磷脂酰肌醇 3-激酶 δ 抑制剂 nemiralisib 通过 Ellipta 干粉吸入器（葛兰素史克，北卡罗来纳州三角研究园）给药的安全性、耐受性和药代动力学（PK）参数，包括口服生物利用度评估。
本研究为单中心、3 部分、安慰剂对照试验，纳入 22 例健康受试者，评估了单剂量（100 和 200μg）和重复剂量（10 天，200μg）吸入 nemiralisib（部分 A，n=12；部分 B，n=12）以及单次剂量吸入 nemiralisib（200μg）伴或不伴活性炭阻断（部分 C，n=6）的安全性、耐受性和 PK 参数（开放标签、2 周期、交叉）。给药日之间至少有 14 天的洗脱期。
21 例受试者完成了研究，3 部分的平均年龄相似（A：49 岁；B：44 岁；C：55 岁）。单次给予 nemiralisib 后，观察到血浆 C 迅速下降，随后进入较慢的消除相。接近剂量比例：100μg 和 200μg 时，平均（95%CI）血浆 C 和 AUC 值分别为 174.3pg/mL（96.9-313.3）和 694.6pg·h/mL（503.5-958.2）和 398.9pg/mL（318.3-500.1）和 1699.6pg·h/mL（1273.3-2268.7）；重复给药 10 天，暴露量约为单次给药的 2-4 倍（峰值、谷值和 AUC 水平），第 6 天达到稳态。无/有活性炭时的平均 AUC 分别为 2193.6pg·h/mL 和 1645.3pg·h/mL。在这些健康受试者中，吸入 nemiralisib 耐受性良好。血浆药代动力学参数定义明确，活性炭数据表明，Ellipta 吸入后系统总暴露量的约 23%归因于口服吸收的药物。临床试验标识符：NCT02691325。
