Abstract
Urinary tract infection (UTI) is one of the most prevalent bacterial infectious diseases worldwide. However, the resistance of urinary pathogens to other UTI antibiotics such as trimethoprim and trimethoprim/sulphamethoxazole increased. Pivmecillinam is a prodrug of mecillinam, which is effective for the treatment of urinary tract infections. The purpose of this study was to assess the safety, and pharmacokinetics of pivmecillinam and mecillinam after single- and multiple-dose oral administration of pivmecillinam tablets in healthy Chinese subjects. The study also investigated the profile of urinary excretion of mecillinam, as well as the effect of food and gender on the pharmacokinetics of pivmecillinam and mecillinam. This study was a single-center, open-label phase I study carried out in three groups. In total, 34 subjects were included in the study: group 1-food effect study with pivmecillinam 200 mg (n = 12); group 2-single- and multiple-dose study with pivmecillinam 400 mg (n = 12); group 3-single dose study with pivmecillinam 600 mg (n = 10). The plasma and urine concentrations of pivmecillinam and mecillinam were measured, and their pharmacokinetics were calculated. Treatment-emergent adverse events were evaluated and recorded in safety assessments for three groups. No severe adverse events were found in this study. After a single dose of pivmecillinam was taken orally, the maximum plasma concentration (Cmax) and the area under the concentration–time curve (AUC) of pivmecillinam increased in a dose-proportional manner, nor did mecillinam. Food had significant effects on Cmax and AUC0−t of pivmecillinam and Cmax of mecillinam. The mean cumulative percentage of urine excretion of mecillinam at 0 to 24 h ranged from 35.5 to 44.0%. Urinary cumulative excretion is relative to the drug dose, but the diet and multiple-dose administration did not affect the urinary cumulative excretion rate. The safety and pharmacokinetics of pivmecillinam and mecillinam after single- (200/400/600 mg) or multiple-dose (400 mg) administration were demonstrated in healthy Chinese subjects. Food affected the pharmacokinetics of pivmecillinam and mecillinam.
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This work was supported by the Outstanding Young and Middle-aged Talents Support Program of the First Affiliated Hospital of Nanjing Medical University, Grant/Award Number: YNRCQN025.
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Y.Q.W. and L.N.S. contributed to the study’s conception and design. L.J.X, C.Z, and J.C supervised the execution of the clinical trial. Material preparation, data collection, and analysis were performed by L.L.Z., Y.L., and Q.Y.H. The first draft of the manuscript was written by Y.L. All authors read and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
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This study was conducted at one site in the First Affiliated Hospital of Nanjing Medical University (Nanjing, China). This study had been approved by the Ethics Committee and met the requirements of the Declaration of Helsinki and Good Clinical Practice in China. Nation Medical Products Administration clinical trial permission numbers of this study were 2018L03010 and 2018L03011.
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Zhang, LL., Liu, Y., Huang, QY. et al. Safety, pharmacokinetics, and food-effect of pivmecillinam after single- and multiple-dose in healthy Chinese subjects: a phase I study. Naunyn-Schmiedeberg's Arch Pharmacol (2024). https://doi.org/10.1007/s00210-024-03118-3
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DOI: https://doi.org/10.1007/s00210-024-03118-3