Javelin Pharmaceuticals (now Hospira, Inc.), Cambridge, Massachusetts; The Leviathan Biopharma Group, Inc., Oncolupta, Inc., Newton, Massachusetts.
Pharmacotherapy. 2013 Oct;33(10):1012-21. doi: 10.1002/phar.1304. Epub 2013 Jun 6.
To evaluate single- and repeated-dose pharmacokinetics (PK) and dose proportionality of hydroxypropyl-β-cyclodextrin (HPβCD)-diclofenac compared with Voltarol after intravenous (IV) and intramuscular (IM) administration.
Study 1: Single-dose randomized four-way crossover study. Study 2: Multiple-dose randomized three-way crossover study.
Clinical research center.
Healthy adult volunteers.
Study 1: Subjects received HPβCD-diclofenac and Voltarol, IV and IM, with a 5-day washout between treatment periods. Study 2: Subjects received two doses of IV HPβCD-diclofenac and oral Cataflam once every 6 hours for four doses with a 48-hour washout period between treatment periods.
Study 1: IV HPβCD-diclofenac had a higher peak plasma concentration (Cmax ) and earlier time to reach maximum plasma concentration (Tmax ), but equivalent plasma exposure (area under the curve from time zero to t [AUC0-t ]) to IV Voltarol. The geometric mean ratio of HPβCD-diclofenac (IV) to Voltarol (IV) for AUC0-t was 106.27%. The geometric mean ratio of HPβCD-diclofenac (IM) to Voltarol (IM) for AUC0-t was 110.91%. The geometric mean ratio of HPβCD-diclofenac (IV) to HPβCD-diclofenac (IM) for AUC0-t was 101.25%. The geometric mean ratio of HPβCD-diclofenac (IM) to Voltarol (IV) for AUC0-t was 104.96%. Study 2: Cmax for diclofenac was 2904 and 6031 ng/ml after the first IV dose of 18.75 and 37.5 mg HPβCD-diclofenac, respectively, and was 3090 and 5617 ng/ml after the fourth dose, indicating no accumulation. Plasma exposures to 18.75 mg (866 ng·hour/ml) and 37.5 mg (1843 ng·hour/ml) IV HPβCD-diclofenac bracketed that of oral Cataflam 50 mg (1473 ng·hour/ml).
Study 1: Bioavailability in terms of AUC after IV administration was equivalent for HPβCD-diclofenac compared with Voltarol and after IM administration of HPβCD-diclofenac and Voltarol. Bioavailability in terms of AUC after IM administration of HPβCD-diclofenac was equivalent to IV administration of HPβCD-diclofenac and IV administration of Voltarol. Study 2: HPβCD-diclofenac showed dose proportionality after single- and multiple-dose administration and no accumulation of HPβCD-diclofenac. HPβCD-diclofenac was safe and well tolerated following IV and IM administration.
评估羟丙基-β-环糊精（HPβCD）-双氯芬酸单次和多次给药的药代动力学（PK）和剂量比例性，与静脉（IV）和肌肉内（IM）给予的扶他林相比。
研究 1：单剂量随机四交叉研究。研究 2：多剂量随机三交叉研究。
临床研究中心。
健康成年志愿者。
研究 1：受试者接受 HPβCD-双氯芬酸和扶他林，IV 和 IM，每个治疗期之间有 5 天的洗脱期。研究 2：受试者每 6 小时接受两次 IV HPβCD-双氯芬酸和口服 Cataflam，共 4 次，每个治疗期之间有 48 小时的洗脱期。
研究 1：IV HPβCD-双氯芬酸具有更高的峰血浆浓度（Cmax）和更早达到最大血浆浓度的时间（Tmax），但与 IV 扶他林的血浆暴露（从时间零到 t 的曲线下面积[AUC0-t]）相当。AUC0-t 的 HPβCD-双氯芬酸（IV）与扶他林（IV）的几何均数比值为 106.27%。AUC0-t 的 HPβCD-双氯芬酸（IM）与扶他林（IM）的几何均数比值为 110.91%。AUC0-t 的 HPβCD-双氯芬酸（IV）与 HPβCD-双氯芬酸（IM）的几何均数比值为 101.25%。AUC0-t 的 HPβCD-双氯芬酸（IM）与扶他林（IV）的几何均数比值为 104.96%。研究 2：首次给予 18.75 和 37.5mg HPβCD-双氯芬酸的 IV 剂量后，双氯芬酸的 Cmax 分别为 2904 和 6031ng/ml，第四次剂量后分别为 3090 和 5617ng/ml，表明无蓄积。18.75mg（866ng·小时/ml）和 37.5mg（1843ng·小时/ml）IV HPβCD-双氯芬酸的血浆暴露量与口服 Cataflam 50mg（1473ng·小时/ml）相当。
研究 1：IV 给予 HPβCD-双氯芬酸的 AUC 生物利用度与扶他林相当，IM 给予 HPβCD-双氯芬酸和扶他林的 AUC 生物利用度也相当。IM 给予 HPβCD-双氯芬酸的 AUC 生物利用度与 IV 给予 HPβCD-双氯芬酸和 IV 给予扶他林相当。研究 2：单次和多次给药后，HPβCD-双氯芬酸显示出剂量比例性，且无 HPβCD-双氯芬酸蓄积。IV 和 IM 给予 HPβCD-双氯芬酸均安全且耐受良好。
