TY - JOUR
T1 - Comparison of fasting bioavailability among 100-mg commercial, 100-mg generic, and 50-mg chewable generic sildenafil tablets in healthy male mexican volunteers
T2 - A single-dose, 3-period, crossover study
AU - Marcelín-Jiménez, Gabriel
AU - Ángeles-Moreno, Alionka P.
AU - Contreras-Zavala, Leticia
AU - García-González, Alberto
AU - Ramírez-San Juan, Eduardo
PY - 2012/3
Y1 - 2012/3
N2 - 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 **Trademark: Viagra ® (Pfizer, S.A. de C.V., Mexico City, Mexico).], 1 generic [test 1 ††Trademark: Vimax 100 ® (Siegfried Rhein, S.A. de C.V., Mexico City, Mexico).], or 2 chewable generic tablets [test 2 ‡‡Trademark: Vimax 50 ® (Siegfried Rhein, S.A. de C.V., Mexico City, Mexico).]), 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-∞. Bioequivalence was established if 90% CIs for mean test:reference ratios of log-transformed C max 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-∞, 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 C max, AUC 0-24, and AUC 0-∞. 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 México, Mexico City, Mexico.
AB - 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 **Trademark: Viagra ® (Pfizer, S.A. de C.V., Mexico City, Mexico).], 1 generic [test 1 ††Trademark: Vimax 100 ® (Siegfried Rhein, S.A. de C.V., Mexico City, Mexico).], or 2 chewable generic tablets [test 2 ‡‡Trademark: Vimax 50 ® (Siegfried Rhein, S.A. de C.V., Mexico City, Mexico).]), 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-∞. Bioequivalence was established if 90% CIs for mean test:reference ratios of log-transformed C max 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-∞, 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 C max, AUC 0-24, and AUC 0-∞. 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 México, Mexico City, Mexico.
KW - CAS no. 171599-83-0
KW - Sildenafil chewable tablet tolerability
KW - Sildenafil citrate bioavailability
KW - Sildenafil pharmacokinetics
KW - UPLC-MS/MS sildenafil quantification
UR - http://www.scopus.com/inward/record.url?scp=84858593179&partnerID=8YFLogxK
U2 - 10.1016/j.clinthera.2012.01.021
DO - 10.1016/j.clinthera.2012.01.021
M3 - Artículo
C2 - 22386826
SN - 0149-2918
VL - 34
SP - 689
EP - 698
JO - Clinical Therapeutics
JF - Clinical Therapeutics
IS - 3
ER -