Generic Vardenafil Tablets Prove Bioequivalent to Levitra in Rigorous Clinical Trial

A single-center, randomized, open-label, two-formulation, single-dose, four-period, fully replicated crossover trial has confirmed that generic vardenafil hydrochloride tablets are bioequivalent to the branded reference formulation Levitra in healthy Chinese male volunteers. Conducted under both fasting and fed clinical conditions, the research demonstrated that the test formulation manufactured by Jiangsu Wangao Pharmaceutical Co., Ltd. matched the reference product marketed by Bayer AG across all primary pharmacokinetic parameters, covering both the rate and extent of systemic absorption. The study team collected venous blood samples across rigorous multi-period dosing sequences to measure plasma concentrations of the active agent through liquid chromatography-tandem mass spectrometry, confirming that geometric mean ratios for peak concentration and systemic drug exposure remained securely within standard regulatory bioequivalence limits.

Vardenafil hydrochloride functions as a phosphodiesterase type 5 inhibitor widely prescribed as a first-line treatment for male erectile dysfunction. Clinical literature defines erectile dysfunction as the persistent inability to achieve and maintain a penile erection sufficient for satisfactory sexual intercourse for at least six months, representing a prevalent sexual disorder. Epidemiological studies demonstrate that the prevalence of erectile dysfunction is approximately forty percent among men aged forty years and increases to seventy percent in men aged seventy years, with projections estimating nearly 320 million men affected worldwide by 2025. Mechanistically, the compound acts as a novel, highly selective inhibitor of phosphodiesterase type 5, preventing enzyme-mediated degradation of cyclic guanosine monophosphate in the penile corpus cavernosum. By potentiating the effect of endogenous nitric oxide released upon sexual stimulation, the drug induces cavernosal smooth muscle relaxation, ultimately increasing blood perfusion in penile erectile tissues.

In accordance with national generic consistency guidelines, the clinical protocol was approved by the Xianning Municipal Ethics Committee and registered on the China Drug Trials platform under numbers CTR20244010 and CTR20250019. The trial recruited healthy adult male volunteers aged between eighteen and sixty-five years, with a body weight of at least fifty kilograms and a body mass index strictly between nineteen and twenty-six kilograms per square meter. The upper age boundary was intentionally established at sixty-five years to balance population representativeness against physiological variability, especially considering that reference product labeling notes reduced vardenafil clearance in elderly individuals and recommends a lower starting dose of five milligrams. Volunteer candidates were excluded if they had participated in other investigational drug trials within three months, had penile anatomical malformations or unresolved erections, took medications altering hepatic metabolizing enzymes within thirty days, or tested positive during alcohol or substance abuse screening.

The investigation enrolled twenty-four volunteers in the fasting trial and thirty in the fed cohort, using block randomization in a 1:1 ratio to establish groups A and B. Group A received formulations in the sequence T-R-T-R, whereas Group B received R-T-R-T across four periods. Between adjacent dosing periods, a three-day washout interval was scheduled, ensuring complete drug elimination based on vardenafil’s terminal half-life of 4 to 5 hours. In the fasting trial, after an overnight fast of at least ten hours, each volunteer swallowed a single 20 mg tablet with 240 mL of warm water. In the fed trial, subjects fasted overnight and consumed a standardized high-fat breakfast within thirty minutes before dosing, consisting of fried eggs, butter toast, whole milk, and pork sausage totaling approximately 800 kcal (52% fat, 18% protein, 30% carbohydrates). Water intake was prohibited from one hour before to one hour after dosing, with standard meals provided at four and ten hours post-dose.

Venous blood sampling schedules were tailored to reflect the differing absorption kinetics of fasting and fed states without compromising terminal elimination profiles. At each time point, approximately 4 mL of venous blood was drawn into vacuum tubes containing EDTA-K2 anticoagulant. Samples were centrifuged within 60 minutes at 1700g at 4 °C for 10 minutes, yielding 1.6 to 1.8 mL of plasma that was divided equally into two cryotubes and stored at −80 °C until liquid chromatography-tandem mass spectrometry pharmacokinetic analysis.

Quantification of vardenafil concentrations in harvested plasma was accomplished using a validated bioanalytical liquid chromatography-tandem mass spectrometry method developed in accordance with the Chinese Pharmacopoeia and ICH M10 guidelines. Chromatographic separation utilized a YMC-Triart C18 column measuring 2.1 by 100 millimeters with three-micrometer particle size, maintained at 45 °C with a gradient mobile phase of water and methanol containing 0.1% formic acid and 5 mM ammonium acetate. Detection operated via positive electrospray ionization under multiple reaction monitoring mode, tracking ion transitions of m/z 489.2 to 151.0 for vardenafil and m/z 494.2 to 151.0 for the internal standard vardenafil-d5. Sample preparation involved protein precipitation using acetonitrile, where 100 µL of plasma was combined with internal standard and precipitant, vortexed, centrifuged, and reconstituted in ten percent methanol. The assay demonstrated robust linearity across 0.20 to 60.00 ng/mL with a determination coefficient of 0.9992, establishing a lower limit of quantification of 0.20 ng/mL alongside validated precision, accuracy, extraction recovery, and autosampler stability.

Pharmacokinetic parameters were determined through non-compartmental analysis using Phoenix WinNonlin software, followed by linear mixed-effects modeling in SAS software to calculate geometric mean ratios and ninety percent confidence intervals. Among the fasting participants, twenty-three of twenty-four subjects completed all four crossover periods, with one subject withdrawing during the initial washout interval. For the test and reference formulations under fasting conditions, measured maximum plasma concentrations were 37.10 ± 16.62 ng/mL and 34.76 ± 16.21 ng/mL, with identical median peak times of 0.67 hours. The area under the plasma concentration-time curve from zero to the last quantifiable concentration reached 78.66 ± 44.29 ng·h/mL for the test tablet and 75.61 ± 40.81 ng·h/mL for the reference drug, while total area extrapolated to infinity reached 81.44 ± 45.59 and 78.30 ± 41.51 ng·h/mL. The resulting 90% confidence intervals for maximum concentration, area to last point, and total area were 96.52–115.47%, 96.70–108.45%, and 96.60–108.32%, falling entirely within the 80.00–125.00% acceptance range.

In the fed trial cohort, twenty-nine of thirty enrolled volunteers completed the full four-period clinical protocol, with data from one subject excluded from fourth-period bioequivalence analysis due to vomiting within twice the median peak time. High-fat breakfast consumption delayed absorption and altered peak levels, producing maximum concentrations of 25.02 ± 14.54 ng/mL for the test tablet and 26.52 ± 14.23 ng/mL for the reference tablet, while shifting median peak times to 1.34 hours and 1.50 hours. The area under the curve to last quantifiable concentration reached 98.81 ± 47.50 ng·h/mL for test versus 91.20 ± 45.67 ng·h/mL for reference, with infinite areas of 101.68 ± 48.28 and 94.08 ± 46.26 ng·h/mL. Because fed intra-subject peak variability increased to a standard deviation of 0.330, reference-scaled average bioequivalence was applied for peak concentration. Statistical analysis confirmed that the reference-scaled acceptance criterion upper bound was non-positive, satisfying regulatory standards, while ninety percent confidence intervals for systemic exposure metrics remained completely within 80.00–125.00%.

Clinical safety evaluations revealed that both formulations were well tolerated, with all adverse events presenting as mild. In the fasting trial, sixteen adverse events occurred in ten subjects (41.7%), while five adverse drug reactions occurred in three subjects (12.5%). In the fed cohort, thirty-three adverse events were recorded in twelve participants, yielding an incidence rate of 40.0 percent, alongside five adverse drug reactions in three subjects reflecting a 10.0 percent incidence rate. From a broader pharmacological perspective, vardenafil belongs to Biopharmaceutics Classification System Class 2 agents characterized by low aqueous solubility, exhibiting an oral bioavailability of approximately 15 percent. The drug undergoes extensive hepatic oxidation via cytochrome P450 3A4 enzymes, with its primary metabolite retaining 13 percent of parent inhibitory activity, while terminal elimination occurs predominantly via feces with measured half-lives ranging from 3.41 to 3.92 hours.

Comparing these findings to published clinical trials highlights important population characteristics regarding food interactions and comparative pharmacokinetics. While previous pharmacokinetic studies in Caucasian volunteers demonstrated simultaneous reductions in both peak concentration and total exposure following high-fat meals, this study observed delayed absorption and reduced peak concentration without altering total systemic exposure in Chinese subjects, a divergence likely attributable to population variations in hepatic cytochrome P450 3A4 activity. When compared to sildenafil and tadalafil, vardenafil displays faster fasting absorption, with a median peak time of 0.67 hours compared to one to two hours for comparator agents. Additionally, because the trial evaluated single-dose administration rather than chronic or on-demand therapeutic regimens, the researchers recommended further real-world investigations to confirm pharmacokinetic consistency and long-term safety across prolonged clinical usage.

Subject of Research: Bioequivalence evaluation of generic vardenafil hydrochloride tablets in healthy Chinese volunteers

Article Title: Bioequivalence Study of Vardenafil Hydrochloride Tablets in Healthy Chinese Subjects

Article References: Li, H., Hua, M., Zhang, Y., Chen, L., He, B., Xu, M., Li, T., Wang, L., Gan, F., & Liu, Q. (2026). Bioequivalence Study of Vardenafil Hydrochloride Tablets in Healthy Chinese Subjects. Drugs in R&D. https://doi.org/10.1007/s40268-026-00554-9

Image Credits: AI Generated

DOI: 10.1007/s40268-026-00554-9

Keywords: vardenafil hydrochloride, bioequivalence, pharmacokinetics, erectile dysfunction, clinical trial, crossover study, food effect, LC-MS/MS, Vardenafil, Hydrochloride, Tablets, Healthy