Drug Delivery and Disposition, KU Leuven, Gasthuisberg O&N II, Herestraat 49 - Box 921, 3000 Leuven, Belgium.
Translational Research Center for Gastrointestinal Disorders, TARGID, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
Eur J Pharm Sci. 2020 Jan 15;142:105117. doi: 10.1016/j.ejps.2019.105117. Epub 2019 Nov 1.
In fasting conditions, the gastrointestinal system contracts according to the interdigestive migrating motor complex (MMC), in which phases of quiescence (MMC phase I) alternate with phases of medium (MMC phase II) to very strong (MMC phase III) contractions. The time of drug intake relative to this cyclic motility pattern may cause variations in formulation behavior. To explore this hypothesis, a cross-over study was performed in healthy volunteers with an immediate release tablet of fosamprenavir (Telzir) which was administered in either MMC phase I or MMC phase II, as determined by high-resolution manometry. In the intestinal tract, fosamprenavir is rapidly hydrolyzed to the active compound amprenavir by alkaline phosphatases. Drug concentrations of both prodrug and drug were determined in the stomach and duodenum and linked to simultaneously assessed systemic concentrations. In 5 out of 6 healthy volunteers, the gastric release of fosamprenavir and the systemic uptake of amprenavir were affected by the MMC phase in which the tablet was administered. The intragastric disintegration of the tablet was faster and less variable after administration in MMC phase II, resulting in faster and less variable uptake of amprenavir in the systemic circulation. Mean plasma t values were 157 (±72.0) and 73.3 (±27.3) min after administration in MMC phase I and MMC phase II, respectively. The study clearly identified the time of oral drug intake relative to the interdigestive motility pattern as a possible source of variation in gastrointestinal drug behavior and absorption.
在禁食状态下，胃肠道按照消化间期移行性运动复合波（MMC）收缩，其中静息期（MMC 相 I）与中强度（MMC 相 II）至高强度（MMC 相 III）收缩期交替出现。药物摄入时间与这种周期性运动模式的关系可能会导致制剂行为的变化。为了探索这一假说，我们在健康志愿者中进行了一项交叉研究，给予他们福沙那韦（Telzir）的即刻释放片剂，该片剂通过高分辨率测压法确定在 MMC 相 I 或 MMC 相 II 中给药。在肠道中，福沙那韦被碱性磷酸酶迅速水解为活性化合物安普那韦。在胃和十二指肠中测定了前药和药物的药物浓度，并与同时评估的系统浓度相关联。在 6 名健康志愿者中的 5 名中，片剂给药时的 MMC 相影响了福沙那韦的胃释放和安普那韦的全身摄取。与 MMC 相 I 相比，MMC 相 II 给药后片剂在胃内的崩解更快且变异性更小，导致安普那韦在全身循环中的吸收更快且变异性更小。分别在 MMC 相 I 和 MMC 相 II 后，平均血浆 t 值为 157（±72.0）和 73.3（±27.3）分钟。该研究清楚地确定了口服药物摄入时间与消化间期运动模式之间的关系，这可能是胃肠道药物行为和吸收变化的一个来源。
