Guittet Catherine, Manso Maria, Burton Ingrid, Granier Luc-André, Marçon Frédéric
Advicenne Pharma, Nîmes, France.
ClinBay, Baisy-Thy, Belgium.
Pharm Res. 2017 Sep;34(9):1840-1848. doi: 10.1007/s11095-017-2193-4. Epub 2017 Jun 2.
The objective of this study was to assess the bioavailability and the sedative effect of a single-dose administration of an innovative oral solution of midazolam containing γ-cyclodextrins (ADV6209).
A bioavailability study with a standard two-sequences, two-periods, and crossover design was conducted. Subjects randomly received 15 mg of ADV6209 by oral route followed by 5 mg of the reference drug (midazolam hydrochloride intravenous solution (Hypnovel®, Roche) by intravenous route or vice versa. Blood samples were drawn at different time points to measure midazolam and its metabolite α-hydroxymidazolam concentrations. Non-compartmental pharmacokinetic methods were used to calculate main pharmacokinetic parameters and absolute bioavailability.
Caucasian healthy subjects (n = 12) were included in the study. ADV6209 had a bioavailability of 39.6%. The oral elimination half-life with ADV6209 was slightly shorter than with the reference i.v. form (2.66 h versus 2.99 h). The sedative effect was observed 27.5 ± 15.5 min after oral administration for a duration of 48.5 ± 35.4 min. Double peak phenomenon was observed in 5 patients.
Cyclodextrins have little impact on midazolam oral bioavailability and the pharmacokinetics parameters of midazolam formulation ADV6209 are close to those reported previously.
本研究的目的是评估单剂量给予含γ-环糊精的咪达唑仑创新口服溶液（ADV6209）的生物利用度和镇静效果。
进行了一项采用标准的两序列、两周期交叉设计的生物利用度研究。受试者随机口服15mg的ADV6209，随后静脉注射5mg的参比药物（盐酸咪达唑仑静脉溶液（Hypnovel®，罗氏公司）），或反之亦然。在不同时间点采集血样，以测定咪达唑仑及其代谢物α-羟基咪达唑仑的浓度。采用非房室药代动力学方法计算主要药代动力学参数和绝对生物利用度。
本研究纳入了12名白种健康受试者。ADV6209的生物利用度为39.6%。ADV6209的口服消除半衰期略短于参比静脉注射剂型（分别为2.66小时和2.99小时）。口服给药后27.5±15.5分钟观察到镇静效果，持续时间为48.5±35.4分钟。5名患者出现双峰现象。
环糊精对咪达唑仑的口服生物利用度影响较小，咪达唑仑制剂ADV6209的药代动力学参数与先前报道的相近。
