Development and validation of limited-sampling strategies for predicting amoxicillin pharmacokinetic and pharmacodynamic parameters

Amoxicillin plasma concentrations (n = 1,152) obtained from 48 healthy subj ects in two bioequivalence studies were used to develop limited-sampling st rategy (LSS) models for estimating the area under the concentration-time cu rve (AUC), the maximum concentration of drug in plasma (C-max), and the tim e 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 valid ated microbiological assay. Linear regression analysis and a "jack-knife" p rocedure revealed that three-point LSS models accurately estimated (R-2, 0. 92; precision, <5.8%) the AUC from 0 h to infinity (AUCO-(0-infinity)) of a moxicillin for the four formulations tested. Validation tests indicated tha t a three-point LSS model (1, 2, and 5 h) developed for the reference capsu le formulation predicts the following accurately (R-2, 0.94 to 0.99): (i) t he individual AUCO(0-infinity). for the test capsule formulation in the sam e subjects, (ii) the individual AUC(0-infinity) for both reference and test suspensions in 24 other subjects, and (iii) the average AUC(0-infinity). f ollowing single oral doses (250 to 1,000 mg) of various amoxicillin formula tions 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 -infinity), but using different coefficients and intercept, for estimating C-max. Bioequivalence assessments based on LSS-derived AUC(0-infinity)'s an d C-max's provided results similar to those obtained using the original val ues 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 mug/ml, which are representati ve of microorganisms susceptible and resistant to amoxicillin.