Dogterom Peter, de Greef Rik, Peeters Pierre A M
Early Stage Development, Merck Sharp & Dohme, PO Box 20, 5340 BH, Oss, The Netherlands,
Eur J Clin Pharmacol. 2015 Jan;71(1):65-74. doi: 10.1007/s00228-013-1587-4. Epub 2015 Jan 1.
To determine the effects of food on the pharmacokinetics of sublingual asenapine.
Healthy male volunteers (n=26, age 19-53 years) randomly received a single sublingual dose of asenapine 5 mg after ≥ 10 h fasting (Treatment A, reference), after a high-fat meal (Treatment B) and after ≥ 10 h fasting with a high-fat meal at 4 h post-dose (Treatment C). Blood samples were drawn over 72 h to measure asenapine plasma concentrations. Effects of food intake on asenapine pharmacokinetics were assessed using bioequivalence criteria and evaluated using a compartmental modelling analysis.
Compared with the reference, mean asenapine exposure (AUC0-last and AUC0-∞) was approximately 20 % lower after intake of a high-fat meal prior to dosing, whereas Cmax decreased by only about 10 %. When a high-fat meal was taken 4 h post-dose in the fasting state, asenapine concentrations were similar to the reference during the first 4 h post-dose. After the meal intake, asenapine concentrations decreased quickly for several hours. Compartmental modelling indicated that a transient 2.5-fold increase in asenapine clearance after eating could explain the asenapine concentration-time profiles for both food regimens.
To our knowledge, this is the first study investigating the effect of food upon the sublingual administration of a drug. A high-fat meal taken before or 4 h post-dose of sublingual asenapine indirectly caused a transient increase in liver blood flow that resulted in a temporal increase in asenapine clearance. As the effects on asenapine exposure were small and not clinically relevant, no additional restrictions are required for the timing of food intake in relation to asenapine dosing.
确定食物对舌下含服阿塞那平药代动力学的影响。
健康男性志愿者（n = 26，年龄19 - 53岁）在禁食≥10小时后（治疗A，参照组）、高脂餐后（治疗B）以及给药后4小时高脂餐且禁食≥10小时后（治疗C），随机接受单次舌下含服5毫克阿塞那平。在72小时内采集血样以测量阿塞那平血浆浓度。使用生物等效性标准评估食物摄入对阿塞那平药代动力学的影响，并通过房室模型分析进行评价。
与参照组相比，给药前摄入高脂餐后阿塞那平的平均暴露量（AUC0-last和AUC0-∞）降低约20%，而Cmax仅降低约10%。在禁食状态下给药后4小时摄入高脂餐时，给药后最初4小时内阿塞那平浓度与参照组相似。进食后，阿塞那平浓度在数小时内迅速下降。房室模型表明，进食后阿塞那平清除率短暂增加2.5倍可以解释两种食物摄入方案下阿塞那平的浓度-时间曲线。
据我们所知，这是第一项研究食物对药物舌下给药影响的研究。舌下含服阿塞那平给药前或给药后4小时摄入高脂餐间接导致肝血流量短暂增加，从而使阿塞那平清除率暂时升高。由于对阿塞那平暴露量的影响较小且无临床相关性，因此在阿塞那平给药时间与食物摄入时间方面无需额外限制。
