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

Abstract

ABSTRACT Amoxicillin plasma concentrations ( n = 1,152) obtained from 48 healthy subjects in two bioequivalence studies were used to develop limited-sampling strategy (LSS) models for estimating the area under the concentration-time curve (AUC), the maximum concentration of drug in plasma ( C max ), and the time interval of concentration above MIC susceptibility breakpoints in plasma (T>MIC). Each subject received 500-mg amoxicillin, as reference and test capsules or suspensions, and plasma concentrations were measured by a validated microbiological assay. Linear regression analysis and a “jack-knife” procedure revealed that three-point LSS models accurately estimated ( R 2 , 0.92; precision, <5.8%) the AUC from 0 h to infinity (AUC 0-∞ ) of amoxicillin for the four formulations tested. Validation tests indicated that a three-point LSS model (1, 2, and 5 h) developed for the reference capsule formulation predicts the following accurately ( R 2 , 0.94 to 0.99): (i) the individual AUC 0-∞ for the test capsule formulation in the same subjects, (ii) the individual AUC 0-∞ for both reference and test suspensions in 24 other subjects, and (iii) the average AUC 0-∞ following single oral doses (250 to 1,000 mg) of various amoxicillin formulations in 11 previously published studies. A linear regression equation was derived, using the same sampling time points of the LSS model for the AUC 0-∞ , but using different coefficients and intercept, for estimating C max . Bioequivalence assessments based on LSS-derived AUC 0-∞ 's and C max 's provided results similar to those obtained using the original values for these parameters. Finally, two-point LSS models ( R 2 = 0.86 to 0.95) were developed for T>MICs of 0.25 or 2.0 μg/ml, which are representative of microorganisms susceptible and resistant to amoxicillin.