A crossover pharmacokinetic study of misoprostol by the oral, sublingual and buccal routes

Abstract

Objectives: The aim of the study was to compare the pharmacokinetic parameters of 800 μg oral, sublingual and buccal misoprostol in healthy non-pregnant women. Methods: This was an open-label, randomised study with a three-way crossover design. Eighteen participants were randomly assigned to treatment sequences of 800 μg oral, sublingual and buccal misoprostol administered under fasting conditions, with a 7-day washout period. Ten participants completed all routes. The primary pharmacokinetic parameters measured were the area under the plasma misoprostol acid concentration–time curve (AUC) from dosing to last quantifiable concentration (AUC0–t), the AUC from 0 to infinity (AUC0–∞) and the maximum plasma concentration (Cmax). Secondary parameters included the plasma elimination rate constant (k_e), the half-life and the mean residence time (MRT). Results: There were statistically significant differences in AUC0–∞, AUC0–t and Cmax at the p < 0.05 level for the three routes of administration. The sublingual route achieved the highest bioavailability, and the buccal route achieved the lowest peak concentration. The oral and buccal routes had a similar AUC0–∞ and the buccal route had the highest MRT and k_e. There were no differences in half-lives, and no serious adverse events were reported. Conclusions: This study shows variability in Cmax and AUC by three by-mouth routes of misoprostol administration. The dose in this study was 800 μg, which is among the highest doses seen in current guidelines. These data contribute to the understanding of efficacy and safety of different routes and could provide a basis for deciding whether certain routes are preferable for particular indications.

Chinese abstract

目的：此项研究的目的是比较健康未孕妇女分别经口服, 舌下, 含化给药800 µg的米索前列醇后的药代动力学参数。方法：这是一项具备三种途径交叉设计的开放式、随机性的研究。18名参与者经过一个7天的洗脱期后, 在空腹状态下被随机分配到口服, 舌下, 含化给药三种途径的治疗序列中给米索前列醇。其中10名参与者完成所有给药途径。测量的主要药代动力学参数是测定从定量到最后一个量化浓度(AUC0–t)给药后血浆中米索前列醇酸浓度时间曲线下的面积（AUC）, 这个AUC是从0到无穷大的曲线下面积(AUC 0–∞)和最大血浆浓度（Cmax）。第二个参数包括血浆消除率常数(k_e), 半衰期和平均滞留时间（MRT）。结果：在P＜0.05的水准下, 三种给药途径 AUC 0–∞, AUC0–t和Cmax具有明显的统计学差异。舌下途径达到最高的生物利用率, 含化途径达到最低峰值浓度。口服和含化给药途径有一个类似的AUC0–∞, 含化途径有最高的MRT和k_e。半衰期没有差异统计学差异, 且无严重不良事件的报告。结论：此项研究显示出经口给药米索前列醇的三种途径在Cmax和AUC的可变性。在这项研究中的剂量为800 µg, 处于目前指南看到的最高剂量之间。这些数据有助于对药物不同途径给药有效性和安全性的理解, 并为某些特定适应证的用药途径优化提供依据。

Keywords:

• Buccal
• misoprostol
• oral
• pharmacokinetics
• sublingual

Disclosure statement

The authors declare no conflicts of interest.

Funding information

The interpretation of data and manuscript preparation were conducted independently with funding from an anonymous donor. The anonymous donor had no role in the data analysis, interpretation of results or drafting of the manuscript. This study was sponsored by Linepharma International Ltd (London, UK).

ORCID details

Laura J. Frye http://orcid.org/0000-0001-7280-1171