J Korean Soc Clin Pharmacol Ther JKSCPT Journal of Korean Society for Clinical Pharmacology and Therapeutics 1225-5467 Korean Society for Clinical Pharmacology and Therapeutics 10.0000/jkscpt.2012.20.2.125 Original Article Tolerability and Pharmacokinetics Following a Single Dose of Vardenafil in Healthy Korean Volunteers Kim Seokuee 1 Lee SeungHwan 1 Lim Kyoung Soo 1 Lim Hyeong-Seok 2 Shin Sang-Goo 1 Jang In-Jin 1 Yu Kyung-Sang 1 Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, South Korea. Department of Clinical Pharmacology and Therapeutics, University of Ulsan and Asan Medical Center, Seoul, South Korea. Corresponding author (ksyu@snu.ac.kr) 12 2012 31 12 2012 20 2 125 134 21 06 2012 01 12 2012 05 12 2012 Copyright © 2012 Korean Society for Clinical Pharmacology and Therapeutics 2012 Background

Vardenafil is a phosphodiesterase type 5 inhibitor, used in erectile dysfunction. This study aimed to evaluate the pharmacokinetics and tolerability of vardenafil following a single oral administration in healthy male subjects.

 Methods

A randomized, double-blind, placebo-controlled, single dosing, dose-escalation study was conducted in 30 healthy subjects. A single oral dose of vardenafil or placebo was given to 10 subjects (8 active + 2 placebo) in each dose group of 5, 10 and 20 mg. Serial blood and urine samples were obtained up to 48 hours for pharmacokinetic analysis. Vardenafil and its metabolite were detected by high performance liquid chromatography tandem mass spectrometry assay.

 Results

A total of 45 adverse events (AE) were reported in 22 subjects, including 5 AEs from placebo treatment, and all the AEs were mild, except one case of moderate nasal stuffiness. Vardenafil was absorbed after a single oral dose, with the tmax of 0.5-1.0 hours. The Cmax and AUClast were 10.21 ± 3.68 ug/L(mean ± SD) and 18.08 ± 7.44 ug×h/L in 5 mg dose group, 19.79 ± 12.13 ug/L and 38.61 ± 21.04 ug×h/L in 10 mg dose group and 53.16 ± 37.01 ug/L and 110.05 ± 69.65 ug×h/L in 20 mg dose group. Dose-linearity on AUClast and Cmax of vardenafil were observed in three dose groups. In all dose groups, the fraction excreted in urine was less than 1%.

 Conclusion

The vardenafil was tolerable over a single dose range of 5 - 20 mg. The pharmacokinetics of vardenfil after a single oral dose was explored and linear pharmacokinetic characteristics were observed over the dose range of 5 - 20 mg in healthy subjects.

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Chemical structure of vardenafil andits metabolite N-desethylvardenafil.

Mean (arithmetic mean) - SD plasma concentration-time profiles of (a) vardenafil and (b) N-desethyl vardenafil in log scale after a single oral administration of vardenafil 5 mg, 10 mg and 20 mg. Error bars represent standard deviations.

Dose-normalized Cmax and AUClast after a single oral administration of vardenafil 5 mg, 10 mg and 20 mg. The box defines the upper quartile and lower quartile, and encloses 50% of the data. The median is depicted as a line with in the box. ((a): Dose-normalized Cmax, (b): dose-normalized AUClast).

Metabolic ratio between vardenafil and N-desethyl vardenafil after a single oral administration of vardenafil 5 mg, 10 mg and 20 mg. The box defines the upper quartile and lower quartile, and encloses 50% of the data. The median is depicted as a line with in the box.

Demographic data of subjects

*Data are presented as mean ± standard deviation. *Kruskal-Wallis test.

Pharmacokinetic parameters of vardenafil and N-desethyl vardenafil after oral administratioin of vardenafil

All data presented as arithmetic mean ± standard deviation except tmax. *Data presented as median (range). tmax: Time of maximum observed plasma concentration. Cmax: Maximum observed plasma concentration. AUClast: Areaunder the plasma concentration-time curve from zero time until the last measurable concentration. CL/F: Apparent clearance. t1/2: Termin alelimination half-life. Ae0-48h: Total Amount of unchanged drug excreted into the urine within time span 0 to 48h. fe/Fe: Fraction of the non-intravenously administered drug excreted into the urine. CLR: Renal clearance of the drug from plasma.

Assessment of dose-proportionality for pharmacokinetics of vardenafil

Y = a + b × Dose, Y: parameter (Cmax, AUClast). Ln Y=a + b × ln(Dose), Y: parameter (Cmax, AUClast). ANOVA: Analysis of variance.