The clinical pharmacokinetics of a new pharmacokinetically enhanced formulation of amoxicillin/clavulanate

Background: A new oral pharmacokinetically enhanced formulation of the broad-spectrum antibiotic amoxicillin/clavulanate has been developed to provide more effective therapy against resistant pathogens than is provided by currently available formulations by maintaining therapeutically useful plasma amoxicillin concentrations for a longer period after dosing. Objective: This study explored the pharmacokinetics of the new oral formulation of amoxicillin/clavulanate in healthy male and female subjects. Methods: A single oral dose of pharmacokinetically enhanced amoxicillin/clavulanate (2000/125 mg: 16:1 ratio) was administered to subjects at the start of a meal. After dosing, blood samples were collected at frequent intervals up to 12 hours, and plasma was assayed for amoxicillin and clavulanate concentrations using validated procedures. The new formulation consisted of 1 layer of immediate-release amoxicillin and clavulanate and another of sustained-release amoxicillin in a proportion such that for an amoxicillin minimum inhibitory concentration (MIC) of 4 mug/mL. the time above the MIC (T > MIC) would be approximately greater than or equal to 40% over a 12-hour dosing interval. Results: The study enrolled 24 and 31 healthy male and female subjects, respectively. Their mean age was 35 years (range, 18-58 years) and mean body weight was 69 kg (range, 51-86 kg). After the expected sharp peak in plasma amoxicillin concentration, there appeared to be a slower decline with the pharmacokinetically enhanced formulation than is usually seen with conventional formulations, and there was evidence of a second amoxicillin absorption phase. The mean T >MIC for an amoxicillin MIC of 4 mug/mL was 49.4% of a 12-hour dosing interval, a value that cannot be achieved with existing approved doses and formulations of amoxicillin/clavulanate. By 12 hours, plasma amoxicillin concentrations were very low (similar to0.05 mug/mL). suggesting no expectation of notable dose-to-dose accumulation on repeat dosing with a BID regimen. The terminal half-lives of amoxicillin (1.27 hours) and clavulanate (1.03 hours) with the new formulation were similar to those of existing formulations of amoxicillin/clavulanate. No deaths or serious adverse events were reported. Conclusions: The enhanced pharmacokinetic profile of amoxicillin/clavulanate seen in this study suggests that this formulation is likely to be highly effective for the oral treatment of infections caused by bacteria-including beta-lactamase-producing organisms-and strains with amoxicillin MICs less than or equal to4 mug/mL.