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 microg/mL, the time above the MIC (T >MIC) would be approximately > or = 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 microg/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 (approximately 0.05 microg/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 < or = 4 microg/mL.
Kaye
C M
CM
Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Welwyn, Hertfordshire, United Kingdom. clive_m_kaye@sbphrd.com
Allen
A
A
Perry
S
S
McDonagh
M
M
Davy
M
M
Storm
K
K
Bird
N
N
Dewit
O
O
D000293:Adolescent; D000328:Adult; D000658:Amoxicillin / Q000493:pharmacokinetics*; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D019818:Clavulanic Acid / Q000493:pharmacokinetics*; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010406:Penicillins / Q000493:pharmacokinetics*
D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D010406:Penicillins; D019818:Clavulanic Acid; D000658:Amoxicillin