Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Pharmacol Res Perspect. 2020 Aug;8(4):e00633. doi: 10.1002/prp2.633.
Oral administration of docetaxel in combination with the CYP3A4 inhibitor ritonavir is used in clinical trials to improve oral bioavailability of docetaxel. Diarrhea was the most commonly observed and dose-limiting toxicity. This study combined preclinical and clinical data and investigated incidence, severity and cause of oral docetaxel-induced diarrhea. In this study, incidence and severity of diarrhea in patients were compared to exposure to orally administered docetaxel. Intestinal toxicity after oral or intraperitoneal administration of docetaxel was further explored in mice lacking Cyp3a and mice lacking both Cyp3a and P-glycoprotein. In patients, severity of diarrhea increased significantly with an increase in AUC and C (P = .035 and P = .025, respectively), but not with an increase in the orally administered dose (P = .11). Furthermore, incidence of grade 3/4 diarrhea after oral docetaxel administration was similar as reported after intravenous docetaxel administration. Intestinal toxicity in mice was only observed at high systemic exposure to docetaxel and was similar after oral and intraperitoneal administration of docetaxel. In conclusion, our data show that the onset of severe diarrhea after oral administration of docetaxel in humans is similar after oral and intravenous administration of docetaxel and is caused by the concentration of docetaxel in the systemic blood circulation. Mouse experiments confirmed that intestinal toxicity is caused by a high systemic exposure and not by local intestinal exposure. Severe diarrhea in patients after oral docetaxel is reversible and is not related to the route of administration of docetaxel.
口服多西他赛联合 CYP3A4 抑制剂利托那韦用于临床试验，以提高多西他赛的口服生物利用度。腹泻是最常见的观察到的剂量限制毒性。本研究结合了临床前和临床数据，研究了口服多西他赛引起腹泻的发生率、严重程度和原因。在这项研究中，将患者腹泻的发生率和严重程度与口服多西他赛的暴露情况进行了比较。进一步在缺乏 Cyp3a 和同时缺乏 Cyp3a 和 P-糖蛋白的小鼠中研究了口服和腹腔内给予多西他赛后的肠道毒性。在患者中，腹泻的严重程度随着 AUC 和 C 的增加而显著增加（P = 0.035 和 P = 0.025），但与口服剂量的增加无关（P = 0.11）。此外，口服多西他赛后 3/4 级腹泻的发生率与静脉注射多西他赛后报道的相似。仅在高全身暴露于多西他赛时才观察到小鼠的肠道毒性，并且在口服和腹腔内给予多西他赛后观察到的毒性相似。总之，我们的数据表明，人类口服多西他赛后严重腹泻的发作与静脉注射多西他赛后相似，并且是由多西他赛在全身血液循环中的浓度引起的。小鼠实验证实，肠道毒性是由全身高暴露引起的，而不是由局部肠道暴露引起的。口服多西他赛后患者出现严重腹泻是可逆的，与多西他赛的给药途径无关。
