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

Abstract 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 μg/mL, the time above the MIC (T > MIC) would be approximately ≥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 μg/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 (∼0.05 μg/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 ≤4 μg/mL.