Non-linear absorption pharmacokinetics of amoxicillin: consequences for dosing regimens and clinical breakpoints

• Published in: Journal of antimicrobial chemotherapy 2016-10, Vol.71 (10), p.2909-2917
• Main Authors: de Velde, Femke, de Winter, Brenda C M, Koch, Birgit C P, van Gelder, Teun, Mouton, Johan W
• Format: Article
• Language: English
• Subjects: Absorption, Physiological; Administration, Oral; Adolescent; Adult; Amoxicillin-Potassium Clavulanate Combination - administration & dosage; Amoxicillin-Potassium Clavulanate Combination - blood; Amoxicillin-Potassium Clavulanate Combination - pharmacokinetics; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - blood; Anti-Bacterial Agents - pharmacokinetics; Area Under Curve; Dose-Response Relationship, Drug; Healthy Volunteers; Humans; Male; Middle Aged; Models, Biological; Monte Carlo Method; Young Adult
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkw226

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.