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 threepoint LSS models accurately estimated ( Amoxicillin, a well-known amino-substituted penicillin, enjoys widespread clinical use, not only because of its broad antibacterial spectrum but also because of its high oral bioavailability (Ͼ90%), which makes it relatively unaffected by food or by other concomitantly administered drugs. The pharmacokinetics of amoxicillin has been extensively investigated (reviewed in reference 15) , and the compounded data indicate that an oral dose of 500 mg produces peak concentrations in plasma of about 10 g/ml within 1 to 1.5 h, reaches adequate therapeutic concentrations in pleural, synovial, and ocular fluids, and accumulates in the amniotic fluid, but penetrates poorly into the central nervous system unless inflammation is present. Excretion of amoxicillin is predominantly renal, and Ͼ80% of an intravenous dose is recoverable in the urine, leading to very high urinary concentrations. The drug's terminal half-life (t 1/2 ) of elimination is 1 to 1.5 h.Amoxicillin is the single active principle of at least 26 formulations marketed in Brazil (4), the vast majority of which were not subjected to bioavailability studies prior to registration. Recently, however, the Brazilian agency for drug control, Agência Nacional da Vigilância Sanitária, decreed that bioequivalence studies are mandatory for the registration of generic products and issued guidelines for such studies, which can be performed only at accredited centers (2). This prompted an immediate increase in the demand for such studies, two of which, carried out by our group, assessed the bioequivalence of generic formulations of amoxicillin. The concentration-inplasma data points (n ϭ 1,152 samples) obtained from 48 subjects enrolled in these studies were then used to develop and validate limited-sampling strategy (LSS) models (21, 22) to estimate the major bioequivalence metrics, namely, the area under the concentration-time curve (AUC) and the maximum concentration of drug in plasma (C max ) of amoxicillin. In addition, a similar linear regression approach was carried out in order to develop an LSS for predicting the time interval that amoxicillin concentrations in plasma exceed MIC susceptibility breakpoints (TϾMIC), chosen as a dynamically linked variable. The results indicate that three-point LSS models, based on the same sampling times, provide accurate estimates of both AUC from 0 h to infinity (AUC 0-ϱ ) a...

Evaluation of partial area under the concentration time curve to estimate midazolam apparent oral clearance for cytochrome P450 3A phenotyping

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