A bioequivalence trial is a statistically based comparison of two formulations to demonstrate with a controlled consumer (patient) risk that two formulated drug products are interchangeable. The basic assumption underlying a bioequivalence trial is that essentially the same plasma time-course leads to essentially the same effect allowing two formulations to be interchanged. Bioequivalence is generally assessed using kinetic end points and in practice, two formulations in which bioavailability parameters (rate and extent) differ by 20% or less, with a 90% degree of confidence, are considered to be bioequivalent. In this review, the design and evaluation of bioequivalence studies are presented with special attention given to scientific issues.
Serial blood samples were collected and plasma concentrations of florfenicol (FLO) were measured following the administration of an intravenous bolus of 50 mg/kg FLO to five healthy non-lactating dairy cows. A triexponential equation provided the best fit of the data for four of the five cows. The mean value for beta corresponded to a half-life of 3.2 h. The mean apparent volume of distribution was 0.67 l/kg, and the mean body clearance was 0.15 l/kg/h. The extent of binding of FLO to bovine plasma proteins was determined in vitro at concentrations of 5 micrograms/ml and 50 micrograms/ml by equilibrium dialysis and ultrafiltration. The drug was 18% and 19% bound by equilibrium dialysis, and 23% and 19% bound by ultrafiltration, at 5 micrograms/ml and 50 micrograms/ml, respectively. Phagocytosis of 32phosphorus-labelled Staphylococcus aureus by bovine blood neutrophils was compared in vitro between neutrophils incubated in phosphate-buffered saline alone or in combination with 5, 125, or 1000 micrograms/ml chloramphenicol or FLO. There was no significant effect of chloramphenicol at any concentration. Florfenicol significantly inhibited phagocytosis at all concentrations, but the percentage inhibition was small. The clinical significance, if any, of this effect of FLO remains to be demonstrated.
The pharmacokinetics of lidocaine in dogs were investigated following the intravenous and intramuscular administration of single doses of lidocaine hydrochloride. The mean elimination rate constant and the mean specific clearance determined for the intravenous portion of the study were 0.786 h-1 and 2.40 1/kg/h, respectively. Following intramuscular administration the mean absorption rate constant was 7.74 h-1. Absorption was nearly complete as the percentage of an intramuscular dose absorbed averaged 91.9%. Concentrations of two N-deethylated metabolites, determined following the administration of lidocaine suggest that monoethylglycinexylidide is eliminated rapidly while glycinexylidide is more slowly eliminated. The relative contribution of these metabolites to the therapeutic and toxic effects of lidocaine and the potential for glycinexylidide accumulation during lidocaine administration remain to be investigated.
The pharmacokinetics of theophylline were investigated in dogs following intravenous, single oral, and multiple oral doses of aminophylline. Mean half-life (t1/2) of theophylline following single intravenous administration was 5.7 h and the apparent specific volume of distribution (V'd area) was 0.82 litre/kg. The bioavailability of theophylline was high (91%) following oral administration of aminophylline tablets and the absorption half-life (t1/2ab) was 0.4 h. Theophylline plasma concentrations observed following repeated oral administration of aminophylline tablets were somewhat greater than predicted. This suggests that theophylline plasma concentrations should be monitored and the dosage regimen individually adjusted in critically ill animals.
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