Pharmacokinetics of Amoxicillin and Clavulanate Potassium for Suspension (200 mg/28.5 mg) in Healthy Subjects: Sample Add Stabilizer Study and Food Effects.

Abstract

The present study compares the pharmacokinetics of amoxicillin and clavulanate potassium suspension (200 mg/28.5mg) during fasting and postprandial conditions, and the sample adds a stabilizer study. Two randomized, crossover trials were conducted in an open-label, single-center study (a fasting trial and a postprandial trial). In each part of the study, the subjects were randomly assigned to receive either test or reference products (200 mg/28.5 mg) in a 1:1:1 ratio, followed by the alternative products after a 7-day washout period. Plasma amoxicillin and clavulanic acid concentrations were analyzed by liquid chromatography-tandem mass spectrometry. WinNonlin software was used to evaluate the pharmacokinetic parameters (noncompartmental model). The formulations were considered bioequivalent if the geometric means of area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax ) of amoxicillin and clavulanic acid were within the predetermined bioequivalence range established by average bioequivalence (ABE) or reference-scaled ABE. Tolerability was assessed throughout the study. The postprandial trial and the fasting study each had 12 volunteers. Under fasting and postprandial conditions, the 90%CI for the ratio of geometric means of amoxicillin of Cmax , AUC from time 0 to the last measurable concentration, and AUC from time 0 to infinity were within the ABE acceptance limits (80%-125%); the geometric means of clavulanic acid of Cmax (critbound, -0.03; point estimate, 1.07) were within the reference-scaled ABE acceptance limits, and the AUC from time 0 to the last measurable concentration and AUC from time 0 to infinity were within the ABE acceptance limits (80%-125%). Time to maximum concentration of amoxicillin was delayed 1.0 hour with high-fat meals compared to fasting conditions. Meantime, high-fat meals decreased the exposure of clavulanic acid by nearly 40%. No serious adverse events were found among the subjects. The bioequivalence of test and reference amoxicillin and clavulanate potassium for suspension was validated in this study under fasting and postprandial conditions.