Pharmacokinetics of sildenafil citrate after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality
Pharmacokinetics of sildenafil citrate after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality
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DOI：
10.1046/j.0306-5251.2001.00027.x
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发表时间：
2002-01-01
影响因子：
3.4
通讯作者：
Harness, JA
中科院分区：
文献类型：
--
作者：
Nichols, DJ;Muirhead, GJ;Harness, JA
目的 确定单次口服枸橼酸西地那非的绝对生物利用度、剂量比例以及食物对药代动力学的影响。方法在健康男性受试者中进行了三项开放标签、rand、zed 交叉研究。通过比较单次口服和静脉注射 50 mg 西地那非剂量后的药代动力学数据来确定绝对生物利用度（n = 12 名受试者）。通过比较西地那非及其主要循环代谢物 UK-103,320 在禁食和进食状态下单次口服 100 mg 剂量后的药代动力学数据来检查食物效应（n = 34 名受试者）。根据向 32 名受试者施用四种单次口服剂量的西地那非（25、50、100 和 200 mg）后获得的药代动力学数据评估剂量比例。所有这些研究还评估了西地那非的安全性和耐受性。 结果 计算得出的西地那非绝对口服生物利用度为 41% (90%, CI: 36-47)。食物会减慢吸收速率，使平均 t(max) 延迟约 1 小时，并使 C-max 降低 29% (90% CI: 19-38)。根据血浆浓度-时间曲线下平均面积 (AUC) 评估，全身暴露量减少了 11% (90% CI: 6-16)。这些食物影响不被认为具有临床意义。有统计证据表明，在 25-200 mg 剂量范围内，C-max 和 AUC 不成比例。然而，不成比例的程度很小，剂量加倍时，预计 C-max 和 AUC 分别增加 2.2 倍和 2.1 倍，并且被认为在临床上不显着。在这三项研究中，西地那非的耐受性良好；大多数不良事件都是轻微且短暂的。结论西地那非的平均绝对生物利用度为 41%。食物导致全身暴露的速率和程度小幅降低；这些减少不太可能具有临床意义。在 25-200 mg 的剂量范围内，全身暴露量的增加略大于剂量比例。
Aims To determine the absolute bioavailability, dose proportionality and the effects of food on the pharmacokinetics of single oral doses of sildenafil citrate.Methods Three open-label, rand, zed crossover studies were conducted in healthy male subjects. Absolute bioavailability was determined by comparing pharmacokinetic data after administration of single oral and intravenous 50-mg doses of sildenafil (n = 12 subjects). Food effects were examined by comparing pharmacokinetic data for sildenafil and its primary circulating metabolite, UK-103,320, after administration of a single oral 100-mg dose ill the fasted and fed states (n = 34 subjects). Dose proportionality was assessed from pharmacokinetic data obtained after administration Of four single oral doses of sildenafil (25, 50, 100 and 200 mg) to 32 subjects. The safety and tolerability of sildenafil were also assessed in all of these studies.Results The calculated absolute oral bioavailability of sildenafil was 41% (90%, CI: 36-47). Food slowed the rate of absorption, delaying mean t(max) by approximately 1 h and reducing C-max by 29% (90% CI: 19-38). Systemic exposure, as assessed by the mean area under the plasma concentration-time curve (AUC), was reduced by 11% (90% CI: 6-16). These food effects were not considered to be of clinical significance. There was statistical evidence of nonproportionality in C-max and AUC over the dose range 25-200 mg. However the degree of nonproportionality was small, with predicted increases in C-max and AUC of 2.2- and 2.1-fold, respectively, for a doubling in dose, and was thought to be clinically nonsignificant. Sildenafil was well tolerated in the three studies; the majority of adverse events were mild and transient.Conclusions Sildenafil had a mean absolute bioavailability of 41%. Food caused small reductions in the rate and extent of systemic exposure; these reductions are unlikely to be of clinical significance. Across the dose range of 25-200 mg, systemic exposure increased in a slightly greater than dose-proportional manner.