Nonlinearity of amoxicillin absorption kinetics in human

Abstract

Specialised gastrointestinal absorption of amoxicillin has been suggested in man and has been demonstrated in animals. In order to study the rate and extent of amoxicillin absorption, six healthy subjects were given 500 mg IV and two oral doses (500 mg and 3 g as a suspension). Absorption kinetics was analysed by compartmental modelling, noncompartmental methods and by calculation of absorption rates using deconvolution. Dose-dependency of the extent of amoxicillin absorption was observed, with a lower than expected mean maximum plasma concentration (49%), and fraction of the dose absorbed (39%) after the 3 g dose calculated from the 500 mg dose, assuming kinetic linearity. Zero-order kinetics of absorption was apparent in some subjects after the 500 mg dose, both from model fitting and absorption rate profile. However, no pattern consistent with pure first-order or zero-order absorption was observed after both oral doses in any individual. The dose-dependency of amoxicillin absorption was confirmed by a trend to an increased time of absorption for the high dose. The results show the variable nature and nonlinearity of the gastrointestinal absorption of amoxicillin and indicate the involvement of a number of factors, in addition to simple diffusion.

Development and Validation of Limited-Sampling Strategies for Predicting Amoxicillin Pharmacokinetic and Pharmacodynamic Parameters

“…A large number of plasma samples (n ϭ 1,152) collected from 48 closely monitored, healthy volunteers in two bioequivalence studies allowed the development and subsequent validation of LSS models by using several different procedures. The results show that the AUC 0-ϱ of amoxicillin, following administration of single oral doses (500 ) for amoxicillin in 11 previously published studies (1,3,7,10,13,14,(17)(18)(19)(20)26), and the corresponding AUC 0-ϱ derived from the three-point LSS model developed for the reference capsule formulation in the present study (Table 3, (Table 2). The statistical principle of parsimony advises in favor of models with fewer parameters; thus, we settled for three-sample regressions for independent estimation of amoxicillin's AUC 0-ϱ .…”

“…The robustness of the three-point LSS regression equation derived from the capsule formulation data set as a predictor of the plasma amoxicillin AUC 0-ϱ was confirmed when tested on data from 11 published studies (1,3,7,10,13,14,(17)(18)(19)(20)26), encompassing a large range of amoxicillin single doses (250 to 1,000 mg) and AUC 0-ϱ 's (9 to 55 g ⅐ h ⅐ ml Ϫ1 ). This result not only validates our proposed three-point LSS model but also extends its applicability to a variety of experimental conditions, both clinical and analytical, which prevailed in the 11 studies examined.…”

“…As a third test of the validity of the LSS models developed for estimating amoxicillin's AUC 0-ϱ , the most informative three-point LSS equation derived for the training data set (reference capsule formulation) was used to estimate the AUC 0-ϱ of subjects enrolled in 11 previously published studies after administration of single oral doses (250 to 1,000 mg) of various amoxicillin formulations (1,3,7,10,13,14,(17)(18)(19)(20)26). Scanned plots of the published AUCs were used to obtain the data points employed for the LSS-derived AUC 0-ϱ 's and to obtain the best estimated AUC 0-ϱ 's by means of the trapezoidal method.…”

Pharmacokinetics of a new oral formulation of amoxicillin

“…This can also reflect the wide interindividual variability encountered with this type of antibiotic, due to an irregular absorption process. Amoxicillin absorption appears to be a non linear, capacity-limited and dose-dependent process, the largest fall in absorption being observed with a 3 g single dose (18)(19)(20)(21). The dispersible tablet and the reference form were bioequivalent, with respect to the extent of absorption (AVC) and the rate of absorption (C max ).…”

Hollow-Fiber Pharmacodynamic Studies and Mathematical Modeling To Predict the Efficacy of Amoxicillin for Anthrax Postexposure Prophylaxis in Pregnant Women and Children

“…We did not consider the known reduction in the absorption of orally administered amoxicillin that occurred in people as the dosage was increased, because the doses simulated within the HF systems extended above the highest dosage (3,000 mg) that has been reported in clinical investigations (30,37). Also, the clinical studies examined the oral absorption of single doses of amoxicillin, while the current project used multidose regimens.…”