title: 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 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.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Welwyn, Hertfordshire, United Kingdom. clive_m_kaye@sbphrd.com
authors.forename: C M
authors.initials: CM
authors.lastname: Kaye
authors.forename: A
authors.initials: A
authors.lastname: Allen
authors.forename: S
authors.initials: S
authors.lastname: Perry
authors.forename: M
authors.initials: M
authors.lastname: McDonagh
authors.forename: M
authors.initials: M
authors.lastname: Davy
authors.forename: K
authors.initials: K
authors.lastname: Storm
authors.forename: N
authors.initials: N
authors.lastname: Bird
authors.forename: O
authors.initials: O
authors.lastname: Dewit
mesh_terms: 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*
chemical_list: D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D010406:Penicillins; D019818:Clavulanic Acid; D000658:Amoxicillin