Krishna Gopal, Moton Allen, Ma Lei, Medlock Matthew M, McLeod James
Early Clinical Research and Experimental Medicine, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
Antimicrob Agents Chemother. 2009 Mar;53(3):958-66. doi: 10.1128/AAC.01034-08. Epub 2008 Dec 15.
A four-part, randomized, crossover study with healthy subjects evaluated the effects of gastric pH, the dosing frequency and prandial state, food consumption timing, and gastric motility on the absorption of posaconazole. In part 1, a single dose (SD) of posaconazole (400 mg) was administered alone or with an acidic beverage or a proton pump inhibitor (PPI), or both. In part 2, posaconazole (400 mg twice daily and 200 mg four times daily) was administered for 7 days with and without a nutritional supplement (Boost). In part 3, an SD of posaconazole (400 mg) was administered while the subjects were fasting and before, during, and after a high-fat meal. In part 4, an SD of posaconazole (400 mg) and the nutritional supplement were administered alone, with metoclopramide, and with loperamide. Compared to the results obtained with posaconazole alone, administration with an acidic beverage increased the posaconazole maximum concentration in plasma (C(max)) and the area under the concentration-time curve (AUC) by 92% and 70%, respectively, whereas a higher gastric pH decreased the posaconazole C(max) and AUC by 46% and 32%, respectively. Compared to the results obtained with posaconazole alone, posaconazole at 400 mg or at 200 mg plus the nutritional supplement increased the posaconazole C(max) and AUC by 65% and 66%, respectively, and by up to 137% and 161%, respectively. Administration before a high-fat meal increased the C(max) and the AUC by 96% and 111%, respectively, while administration during and after the meal increased the C(max) and the AUC by up to 339% and 387%, respectively. Increased gastric motility decreased the C(max) and the AUC by 21% and 19%, respectively. Strategies to maximize posaconazole exposure in patients with absorption difficulties include administration with or after a high-fat meal, with any meal or nutritional supplement, with an acidic beverage, or in divided doses and the avoidance of proton pump inhibitors.
一项针对健康受试者的四部分随机交叉研究评估了胃内pH值、给药频率与用餐状态、进食时间以及胃动力对泊沙康唑吸收的影响。在第1部分中，单独给予单剂量（SD）泊沙康唑（400mg），或与酸性饮料或质子泵抑制剂（PPI）联合使用，或两者同时使用。在第2部分中，给予泊沙康唑（400mg每日两次和200mg每日四次），持续7天，同时给予或不给予营养补充剂（Boost）。在第3部分中，在受试者空腹时以及高脂餐前、餐中及餐后给予单剂量泊沙康唑（400mg）。在第4部分中，单独给予单剂量泊沙康唑（400mg）和营养补充剂，以及与甲氧氯普胺和洛哌丁胺联合使用。与单独使用泊沙康唑的结果相比，与酸性饮料联合给药使血浆中泊沙康唑的最大浓度（C(max)）和浓度-时间曲线下面积（AUC）分别增加了92%和70%，而较高的胃内pH值使泊沙康唑的C(max)和AUC分别降低了46%和32%。与单独使用泊沙康唑的结果相比，400mg或200mg泊沙康唑加营养补充剂使泊沙康唑的C(max)和AUC分别增加了65%和66%，最高分别增加了137%和161%。高脂餐前给药使C(max)和AUC分别增加了96%和111%，而餐中及餐后给药使C(max)和AUC分别最高增加了339%和387%。胃动力增加使C(max)和AUC分别降低了21%和19%。在吸收困难的患者中使泊沙康唑暴露最大化的策略包括与高脂餐同时或餐后给药、与任何餐食或营养补充剂同时给药、与酸性饮料同时给药、分剂量给药以及避免使用质子泵抑制剂。
