Comparison of Fasting Bioavailability Among 100-mg Commercial, 100-mg Generic, and 50-mg Chewable Generic Sildenafil Tablets in Healthy Male Mexican Volunteers: A Single-Dose, 3-Period, Crossover Study

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• 作者：Gabriel Marcel&iacute ; n-Jimé ; nez ; PhD¹ ; Alionka P. Á ; ngeles-Moreno ; BS¹ ; Leticia Contreras-Zavala ; BS² ; Alberto Garc&iacute ; a-Gonzá ; lez ; PhD¹ ; Eduardo Ram&iacute ; rez-San Juan ; PhD² ; ^{esanjuan@hotmail.com}
• 关键词：CAS no. 171599-83-0 ; sildenafil chewable tablet tolerability ; sildenafil citrate bioavailability ; sildenafil pharmacokinetics ; UPLC-MS/MS sildenafil quantification
• 刊名：Clinical Therapeutics
• 出版年：2012
• 期刊代码：65_01492918
• 类别：med
• 出版时间：March, 2012
• 卷：34
• 期：3
• 页码：689-698
• 文件大小：437 K

摘要

Background

Sildenafil citrate (SIL) was the first oral drug registered in Mexico for the treatment of erectile dysfunction. However, succinct pharmacokinetic data are available in the Mexican population.

Objective

The goals of the present work were: (1) to design a specific method to quantify SIL plasma levels by using UPLC-MS/MS; (2) to compare oral SIL bioavailability in Mexican men with pharmacokinetic data in other populations; (3) to fulfill local regulatory requests; and (4) to describe the relative tolerability of a new 50-mg chewable tablet.

Methods

This was a randomized, single-dose, 3-period, 6-sequence crossover study in healthy male volunteers. In each period, subjects received single oral doses of 100 mg of sildenafil (1 commercial [reference], 1 generic [test 1], or 2 chewable generic tablets [test 2]), with a 4-day washout period between each dose. Serial blood samples were collected for up to 24 hours. SIL was measured in heparinized plasma by using a validated UPLC-MS/MS method. Pharmacokinetic parameters included C_max, T_max, AUC_0-24, and AUC_{0-鈭?/sub>. Bioequivalence was established if 90%CIs for mean test:reference ratios of log-transformed Cmax and AUC fell within the range of 0.80 to 1.25. Tolerability was assessed on the basis of a clinical interview with the subject and monitoring of vital signs.}

Results

Demographic data showed a homogeneous population. Validation of analytical method proved to be linear within the range of 1 to 1000 ng/mL, with selectivity, accuracy, and precision. 90%CIs for test 1:reference ratios were 86.52 to 113.56, 94.75 to 108.84, and 94.97 to 108.82 for the logarithm parameters C_max, AUC_0-24, and AUC_{0-鈭?/sub>, respectively. The 90%CIs for the test 2:reference ratios were 82.14 to 107.24, 98.26 to 112.56, and 99.19 to 113.34 for Cmax, AUC0-24, and AUC0-鈭?/sub>. Regarding relative tolerability, slight cephalea was the most common adverse effect.}

Conclusions

The developed analytical method was validated in compliance with local requirements and was useful for sildenafil measurement. This single-dose study under fasting conditions suggests that both test products met the Mexican regulatory criteria for assuming bioequivalence in these healthy, male Mexican volunteers. The clinical data suggest that the chewable tablets were well tolerated by volunteers. Trial registration code number: DIC/09/407/02/020, Research Direction of Hospital General de M茅xico, Mexico City, Mexico.