Tellone Valeria, Dragone Patrizia, Picollo Rossella, Rosignoli Maria Teresa, Garofolo Fabio, Del Vecchio Alessandra, Calisti Fabrizio, Comandini Alessandro, Donath Frank, Schug Barbara, Wedemeyer Ralph-Steven
Int J Clin Pharmacol Ther. 2020 Oct;58(10):583-594. doi: 10.5414/CP203652.
To establish the relative bioavailability between a newly developed oral gel and a marketed oral lyophilisate-containing rizatriptan benzoate.
A total of 47 out of 48 healthy subjects, aged 34 ± 10 (SD) years and body mass index 24.7 ± 3.3 (SD) kg/m completed this single-center, open-label, randomized, 2-period cross-over trial with single-dose fasted administrations. Intake of both investigational products was separated by a washout period of at least 6 days. For pharmacokinetic evaluation, blood samples were withdrawn until 24 hours post dose. A validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS) was applied for the determination of rizatriptan in plasma. The lower limit of quantitation (LLOQ) was 0.100 ng/mL. Adverse events (AEs) were descriptively analyzed in the study population. Palatability of the new product was investigated based on a questionnaire.
The geometric means of the parameters related with the extent of total exposure, i.e., AUC and AUC, were 60.285 ng × h/mL and 60.865 ng × h/mL for test and 62.729 ng × h/mL and 63.312 ng × h/mL for reference, respectively. The geometric means of the peak exposure, i.e., C, were 21.262 ng/mL for test and 21.447 ng/mL for reference. The point estimates (PEs) of the test/reference (T/R) adjusted geometric mean ratios of AUC, C, and AUC (secondary parameter) were 96.11%, 99.12%, and 96.15%, respectively, and all of them showed 90% confidence intervals (CIs) within the range of 80.00 - 125.00% as suggested by regulatory requirements for bioequivalence assessment. In total, 13 subjects experienced 20 AEs during the trial; the most frequently reported AEs were headache (5 cases) and dizziness (3 cases). No AEs of severe intensity were reported. Palatability assessment of the new product provided sufficient data to discuss its acceptability.
Bioequivalence was demonstrated in terms of rate and extent of absorption after administration of test and reference products. Concerning the safety evaluation, no negative implications on the possible use of the test formulation could be determined. Based on ratings by the subjects no relevant problem concerning acceptability of the new formulation in particular regarding taste and smell is to be expected.
确定新开发的口服凝胶与市售含苯甲酸利扎曲普坦口服冻干制剂之间的相对生物利用度。
48名健康受试者中，共有47名年龄为34±10（标准差）岁、体重指数为24.7±3.3（标准差）kg/m²的受试者完成了这项单中心、开放标签、随机、两周期交叉试验，试验采用单剂量空腹给药。两种研究产品的服用间隔至少为6天的洗脱期。为进行药代动力学评估，在给药后24小时内采集血样。采用经过验证的液相色谱 - 串联质谱法（LC-MS/MS）测定血浆中的利扎曲普坦。定量下限（LLOQ）为0.100 ng/mL。对研究人群中的不良事件（AE）进行描述性分析。基于问卷对新产品的口感进行了调查。
与总暴露程度相关参数的几何均值，即AUC和AUC，试验制剂分别为60.285 ng×h/mL和60.865 ng×h/mL，参比制剂分别为62.729 ng×h/mL和63.312 ng×h/mL。峰值暴露的几何均值，即Cmax，试验制剂为21.262 ng/mL，参比制剂为21.447 ng/mL。AUC、Cmax和AUC（次要参数）的试验/参比（T/R）调整几何均值比的点估计值（PE）分别为96.11%、99.12%和96.15%，并且所有这些值的90%置信区间（CI）均在生物等效性评估监管要求所建议的80.00 - 125.00%范围内。在试验期间，共有13名受试者经历了20次不良事件；最常报告的不良事件是头痛（5例）和头晕（3例）。未报告严重程度的不良事件。对新产品的口感评估提供了足够数据来讨论其可接受性。
在服用试验制剂和参比制剂后，在吸收速率和程度方面证明了生物等效性。关于安全性评估，未确定对试验制剂可能使用的负面影响。根据受试者的评分，预计新制剂在可接受性方面，特别是在味道和气味方面不存在相关问题。
