Femke de Velde (1,2), Brenda de Winter (2), Birgit Koch (2), Teun van Gelder (2,3), Johan Mouton (1). on behalf of COMBACTE consortium.
(1) Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands; (2) Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands; (3) Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
Objectives: Amoxicillin is an aminopenicillin that has been in clinical use for decades. Yet, the pharmacokinetic profile has been poorly described. Some small pharmacokinetic studies have shown nonlinearity in the absorption [1-3]. The aim of this study was to describe the population pharmacokinetics of oral amoxicillin with a focus on absorption and consequences for exposure.
Methods: 28 healthy volunteers received on 2 separate occasions either 2 (b.i.d. 875/125 mg or 500/125 mg) or 3 (t.i.d. 500/125 mg or 250/125 mg) single oral doses of amoxicillin/clavulanic acid at the start of a meal. Blood samples were collected just before administration and after 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h (t.i.d. until 8 h). 140 amoxicillin concentration-time profiles with 1428 samples were available. The data were analyzed with nonlinear mixed effect modeling (NONMEM, version 7.2). Different absorption models (first-order, zero-order, Michaelis-Menten) with and without lag-time were evaluated in combination with one- and two-compartment disposition models. Model selection criteria were decrease in objective function, diagnostic plots and visual predictive checks.
Results: The increase in mean AUC0-24h was proportional to the dose for 250/125 mg t.i.d., 500/125 mg b.i.d. and 500/125 mg t.i.d. (750, 1000 and 1500 mg/day amoxicillin, respectively). However, the mean AUC0-24h of 875/125 mg b.i.d. (1750 mg/day) was equal to 500/125 mg t.i.d. (1500 mg/day), thus nonlinear absorption was to be assumed. As expected, a first-order absorption model did not fit the data. Nonlinear (zero-order or Michaelis-Menten) absorption models showed a significant improvement in diagnostic plots. Pharmacokinetics of amoxicillin was best described by a two-compartment model with time-lagged nonlinear (zero-order or Michaelis-Menten) absorption and first-order elimination. Mean central volume of distribution was 28,1 L and mean clearance was 21,2 L/h. With each concentration-time profile analyzed separately, variability was included for central volume of distribution, clearance, lag-time and the model-specific absorption parameters (duration of the zero-order absorption process and the Michaelis-Menten parameters Km and Vmax).
Conclusions: Absorption pharmacokinetics of amoxicillin is dose-dependent and best described by a zero-order or Michaelis-Menten absorption model. These findings may have consequences for the dosing regimen of amoxicillin.
COMBACTE is supported by IMI/EU and EFPIA.
References:
[1] Sjövall J, Alván G, Westerlund D. Dose-dependent absorption of amoxicillin and bacampicillin. Clin Pharmacol Ther (1985) 38(3): 241-50.
[2] Westphal JF, Deslandes A, Brogard JM, Carbon C. Reappraisal of amoxicillin absorption kinetics. J Antimicrob Chemother (1991) 27(5): 647-54.
[3] Piotrovskij VK, Paintaud G, Alván G, Trnovec T. Modeling of the saturable time-constrained amoxicillin absorption in humans. Pharm Res (1994) 11(9): 1346-51.
Reference: PAGE 24 (2015) Abstr 3533 [www.page-meeting.org/?abstract=3533]
Poster: Drug/Disease modeling - Infection