Bioequivalence between two furosemide-spironolactone formulations: A pharmacokinetic and pharmacodynamic approach

Summary

Two formulations of the drug combination furosemide (20 mg)-spironolactone (100 mg) were tested for bioequivalence in a randomized crossover trial in 12 healthy volunteers. By comparing the A UC values derived from drug serum concentrations, bioequivalence was only achieved for canrenone, the main metabolite of spironolactone, but not for furosemide. A significant difference in the t_max values indicates sustained release of furosemide from one of the formulations. By contrast, bioequivalence was achieved if pharmacodynamic criteria, such as urine volume and Na⁺ and Cl⁻ excretion over a period of 12 hours, were used. Fractional measurements of urinary volume and electrolyte excretion (0 to 3 h, 3 to 6 h, 6 to 12 h) correlated with the different t_max values for both formulations. These data indicate that bioequivalence is more conclusively verified on the basis of pharmacodynamic parameters than on the basis of pharmacokinetic parameters. These considerations are applicable in particular to drugs displaying large inter-individual variations in serum levels and/or a poor correlation between serum levels and effect.

Key Words::

• Furosemide
• Spironolactone
• drug combinations
• bioavailability
• bioequivalence
• canrenone