title: Development and validation of limited-sampling strategies for predicting amoxicillin pharmacokinetic and pharmacodynamic parameters.
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-infinity)) 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-infinity) for the test capsule formulation in the same subjects, (ii) the individual AUC(0-infinity) for both reference and test suspensions in 24 other subjects, and (iii) the average AUC(0-infinity) 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-infinity), but using different coefficients and intercept, for estimating C(max). Bioequivalence assessments based on LSS-derived AUC(0-infinity)'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 microg/ml, which are representative of microorganisms susceptible and resistant to amoxicillin.
authors.affiliation: Instituto Nacional de Câncer, Coordenação de Pesquisa, Rio de Janeiro, Brazil. kurtz@inca.org.br
authors.forename: G
authors.initials: G
authors.lastname: Suarez-Kurtz
authors.forename: F M
authors.initials: FM
authors.lastname: Ribeiro
authors.forename: F L
authors.initials: FL
authors.lastname: Vicente
authors.forename: C J
authors.initials: CJ
authors.lastname: Struchiner
mesh_terms: D000328:Adult; D000658:Amoxicillin / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D016982:Micrococcus luteus / Q000187:drug effects; D010406:Penicillins / Q000493:pharmacokinetics*; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D013810:Therapeutic Equivalency
chemical_list: D010406:Penicillins; D000658:Amoxicillin