Jazz Pharmaceuticals, Palo Alto, CA, United States.
Vince and Associates Clinical Research, Overland Park, KS, United States.
Clin Ther. 2019 Feb;41(2):196-204. doi: 10.1016/j.clinthera.2018.12.001. Epub 2018 Dec 28.
Solriamfetol (JZP-110), a selective dopamine and norepinephrine reuptake inhibitor with robust wake-promoting effects, is currently being evaluated for the reduction of sleepiness and improvement of wakefulness in patients with narcolepsy and obstructive sleep apnea. The purpose of this study was to evaluate the effect of food on the pharmacokinetic (PK) parameters and bioavailability of solriamfetol at the highest intended therapeutic dose in healthy adults and to characterize its renal excretion under fasting conditions.
In this open-label, randomized, crossover study, healthy adult subjects received a single 300-mg dose of solriamfetol in a fasted condition (10 h) and in a fed condition (30 min after the start of a standardized high-fat, high-calorie breakfast), with at least a 7-day washout period between doses. Blood samples for PK analyses were collected during both conditions at prespecified time points. Urine samples were collected up to 48 h postdose in the fasted condition. Samples were analyzed for solriamfetol (plasma and urine) and N-acetyl solriamfetol (urine) by using validated LC-MS/MS bioanalytical methods. The effect of food on solriamfetol relative bioavailability was examined by comparing the 90% confidence intervals (CIs) of the fed/fasted ratios of natural log-transformed PK parameters C, AUC, and AUC with the prespecified range of 80%-125%. Safety and tolerability were also assessed.
A total of 32 subjects were enrolled (50% female; 53.1% black, 46.9% white; mean age, 35.6 years), and 31 were included in the PK analyses. Solriamfetol was rapidly absorbed in both conditions. The 90% CIs for the fed/fasted geometric mean ratios were 89.2-98.8 for C (ratio of 93.9%) and 93.8-101.5 for AUC (ratio of 97.6%), indicating the absence of a food effect. In the fasted condition, 89.8% of solriamfetol was recovered in urine as unchanged drug over 48 h; 1.1% was excreted as a minor metabolite, N-acetyl solriamfetol. A total of 55 adverse events (AEs), all mild, were reported by 18 subjects (56.3%). The frequency and type of AEs were similar in the 2 conditions; the most common AEs (insomnia, headache, hypervigilance, decreased appetite, and nausea) were all mild in severity and resolved without treatment.
Solriamfetol relative bioavailability was bioequivalent in the fed and fasted conditions, showing that solriamfetol can be taken without regard to meals; furthermore, tolerability was similar in both conditions. Renal excretion of unchanged drug is the primary route of elimination.
索里昂伏他酯（JZP-110）是一种选择性的多巴胺和去甲肾上腺素再摄取抑制剂，具有很强的促醒作用，目前正在评估其用于减少嗜睡并改善嗜睡症和阻塞性睡眠呼吸暂停患者的觉醒。本研究的目的是评估食物对健康成年人最高治疗剂量的索里昂伏他酯的药代动力学（PK）参数和生物利用度的影响，并描述其在禁食条件下的肾脏排泄情况。
在这项开放标签、随机、交叉研究中，健康成年受试者在禁食（10 小时）和进食（开始标准化高脂肪、高热量早餐后 30 分钟）条件下接受单次 300mg 索里昂伏他酯治疗，两种条件之间至少有 7 天的洗脱期。在预定时间点采集两种条件下的 PK 分析血样。在禁食条件下，在给药后 48 小时内采集尿液样本。采用经验证的 LC-MS/MS 生物分析方法检测索里昂伏他酯（血浆和尿液）和 N-乙酰索里昂伏他酯（尿液）。通过比较空腹/进食比值的 90%置信区间（CI）与预先设定的 80%-125%范围，评估食物对索里昂伏他酯相对生物利用度的影响。还评估了安全性和耐受性。
共纳入 32 名受试者（50%为女性；53.1%为黑人，46.9%为白人；平均年龄为 35.6 岁），其中 31 名纳入 PK 分析。索里昂伏他酯在两种条件下均迅速吸收。空腹/进食几何均数比值的 90%CI 为 C（93.9%的比值）的 89.2-98.8 和 AUC（97.6%的比值）的 93.8-101.5，表明无食物影响。在禁食条件下，48 小时内 89.8%的索里昂伏他酯以原形药物从尿液中回收；1.1%以次要代谢物 N-乙酰索里昂伏他酯排泄。18 名受试者（56.3%）报告了 55 次不良事件（AE），均为轻度。两种条件下 AE 的频率和类型相似；最常见的 AE（失眠、头痛、警觉性增加、食欲下降和恶心）均为轻度，无需治疗即可缓解。
索里昂伏他酯在进食和禁食条件下的相对生物利用度是生物等效的，这表明索里昂伏他酯可以不考虑进餐时间服用；此外，两种条件下的耐受性相似。未改变的药物的肾脏排泄是主要的消除途径。
