Shire Development Inc., Wayne, Pennsylvania, USA.
Clin Drug Investig. 2011;31(6):357-70. doi: 10.2165/11588190-000000000-00000.
Data on pharmacokinetic parameters of the prodrug stimulant lisdexamfetamine dimesylate via alternate routes of administration are limited. The pharmacokinetics of d-amphetamine derived from lisdexamfetamine dimesylate after single oral (PO) versus intranasal (IN) administration of lisdexamfetamine dimesylate were compared.
In this randomized, two-period, crossover study, healthy men without a history of substance abuse were administered single PO or IN (radiolabelled with ≤100 μCi (99m)Tc-diethylenetriamine-pentaacetic acid and confirmed by scintigraphy) lisdexamfetamine dimesylate 50 mg ≥7 days apart. Serial blood samples were drawn to measure d-amphetamine and intact lisdexamfetamine at 0 (pre-dose), 15, 30 and 45 minutes and at 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 and 72 hours post-dose for PO administration and at 0 (pre-dose), 5, 10, 15, 20, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 and 72 hours post-dose for IN administration. Treatment-emergent adverse events (TEAEs) were assessed.
Eighteen subjects were enrolled and completed the study. The mean ± SD maximum observed plasma concentration (C(max)) and area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUC(last)) of d-amphetamine following PO administration of lisdexamfetamine dimesylate were 37.6 ± 4.54 ng/mL and 719.1 ± 157.05 ng · h/mL, respectively; after IN administration, these parameters were 35.9 ± 6.49 ng/mL and 690.5 ± 157.05 ng · h/mL, respectively. PO and IN administration demonstrated similar median time to reach C(max) (t(max)) for d-amphetamine: 5 hours for PO administration versus 4 hours for IN administration. Mean ± SD elimination half-life (t(1/2)) values were also similar for PO (11.6 ± 2.8 hours) and IN (11.3 ± 1.8 hours) lisdexamfetamine dimesylate. TEAEs after PO and IN administration were reported by 27.8% of subjects (5/18) and 38.9% of subjects (7/18), respectively; all AEs were mild or moderate in severity, and TEAEs such as anorexia, dry mouth, headache and nausea were consistent with known amphetamine effects.
IN administration of lisdexamfetamine dimesylate resulted in d-amphetamine plasma concentrations and systemic exposure to d-amphetamine comparable to those seen with PO administration. Subject variability for d-amphetamine pharmacokinetic parameters was low. Both PO and IN lisdexamfetamine dimesylate demonstrated a tolerability profile similar to that of other long-acting stimulants.
关于前体兴奋剂左苯丙胺二甲酯经不同给药途径的药代动力学参数的数据有限。本研究比较了单口服（PO）与鼻内（IN）给予左苯丙胺二甲酯后，来自左苯丙胺二甲酯的 d-苯丙胺的药代动力学。
在这项随机、双周期、交叉研究中，没有药物滥用史的健康男性在至少 7 天的时间间隔内分别接受单 PO 或 IN（放射性标记 ≤100μCi（99m）Tc-二乙三胺五乙酸，通过闪烁照相术确认）给予 50mg 左苯丙胺二甲酯。在 PO 给药后，在 0（预剂量）、15、30 和 45 分钟以及 1、1.5、2、3、4、5、6、8、12、16、24、36、48 和 72 小时以及 IN 给药后，在 0（预剂量）、5、10、15、20、30、45 分钟以及 1、1.5、2、3、4、5、6、8、12、16、24、36、48 和 72 小时时采集连续血样，以测量 d-苯丙胺和完整的左苯丙胺。在 PO 给药后，d-苯丙胺的最大观测血浆浓度（C（max））和从时间零到最后可测量浓度的时间的血浆浓度-时间曲线下面积（AUC（last））分别为 37.6±4.54ng/mL 和 719.1±157.05ng·h/mL；在 IN 给药后，这些参数分别为 35.9±6.49ng/mL 和 690.5±157.05ng·h/mL。PO 和 IN 给药显示 d-苯丙胺的中位达峰时间（t（max））相似：PO 给药为 5 小时，IN 给药为 4 小时。PO（11.6±2.8 小时）和 IN（11.3±1.8 小时）左苯丙胺二甲酯的平均（±SD）消除半衰期（t（1/2））值也相似。PO 和 IN 给药后分别有 27.8%（5/18）和 38.9%（7/18）的受试者报告了治疗中出现的不良事件（TEAEs）；所有 AE 均为轻度或中度，厌食、口干、头痛和恶心等 TEAEs 与已知的苯丙胺作用一致。
IN 给予左苯丙胺二甲酯导致 d-苯丙胺的血浆浓度和全身暴露于 d-苯丙胺与 PO 给药相当。d-苯丙胺药代动力学参数的个体差异较小。PO 和 IN 左苯丙胺二甲酯均表现出与其他长效兴奋剂相似的耐受性特征。
