title: Non-linear absorption pharmacokinetics of amoxicillin: consequences for dosing regimens and clinical breakpoints.
abstract: To describe the population pharmacokinetics of oral amoxicillin and to compare the PTA of current dosing regimens.
  
  
  
  Two groups, each with 14 healthy male volunteers, received oral amoxicillin/clavulanic acid tablets on two separate days 1 week apart. One group received 875/125 mg twice daily and 500/125 mg three times daily and the other group 500/125 mg twice daily and 250/125 mg three times daily. A total of 1428 amoxicillin blood samples were collected before and after administration. We analysed the concentration-time profiles using a non-compartmental pharmacokinetic method (PKSolver) and a population pharmacokinetic method (NONMEM). The PTA was computed using Monte Carlo simulations for several dosing regimens.
  
  
  
  AUC0-24 and Cmax increased non-linearly with dose. The final model included the following components: Savic's transit compartment model, Michaelis-Menten absorption, two distribution compartments and first-order elimination. The mean central volume of distribution was 27.7 L and mean clearance was 21.3 L/h. We included variability for the central volume of distribution (34.4%), clearance (25.8%), transit compartment model parameters and Michaelis-Menten absorption parameters. For 40% fT>MIC and >97.5% PTA, the breakpoints were 0.125 mg/L (500 mg twice daily), 0.25 mg/L (250 mg three times daily and 875 mg twice daily), 0.5 mg/L (500 mg three times daily) and 1 mg/L (750, 875 or 1000 mg three times daily and 500 mg four times daily).
  
  
  
  The amoxicillin absorption rate appears to be saturable. The PTAs of high-dose as well as twice-daily regimens are less favourable than regimens with lower doses and higher frequency.
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands f.develde@erasmusmc.nl.
authors.forename: Femke
authors.initials: F
authors.lastname: de Velde
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Brenda C M
authors.initials: BC
authors.lastname: de Winter
authors.affiliation: Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Birgit C P
authors.initials: BC
authors.lastname: Koch
authors.affiliation: Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Teun
authors.initials: T
authors.lastname: van Gelder
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Johan W
authors.initials: JW
authors.lastname: Mouton
mesh_terms: D065567:Absorption, Physiological; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019980:Amoxicillin-Potassium Clavulanate Combination / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009010:Monte Carlo Method; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D019980:Amoxicillin-Potassium Clavulanate Combination