Pharmacokinetic/Pharmacodynamic (PK/PD) indices of antibiotics predicted by a semi-mechanistic PKPD model: a step toward model-based dose optimization
2011 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 55, no 10, 4619-4630 p.Article in journal (Refereed) Published
A pharmacokinetic-pharmacodynamic (PKPD) model that characterizes the full time course of in vitro time-kill curve experiments of antibacterial drugs was here evaluated in its capacity to predict the previously determined PK/PD indices. Six drugs (benzylpenicillin, cefuroxime, erythromycin, gentamicin, moxifloxacin, and vancomycin), representing a broad selection of mechanisms of action and PK and PD characteristics, were investigated. For each drug, adose fractionation study was simulated, using a wide range of total daily doses given as intermittent doses (dosing intervals of 4, 8, 12, or 24 h) or as a constant drug exposure. The time course of the drug concentration (PK model) as well as the bacterial response to drug exposure (in vitro PKPD model) was predicted. Nonlinear least-squares regression analyses determined the PK/PD index (the maximal unbound drug concentration [fCmax]/MIC, the area under the unbound drug concentration-time curve [fAUC]/MIC, or the percentage of a 24-h time period that the unbound drug concentration exceeds the MIC [fT>MIC]) that was most predictive of the effect. The in silico predictions based on the in vitro PKPD model identified the previously determined PK/PD indices,with fT>MIC being the best predictor of the effect for β-lactams and fAUC/MIC being the best predictor for the four remaining evaluated drugs. The selection and magnitude of the PK/PD index were, however, shown to be sensitive to differences in PK in subpopulations, uncertainty in MICs, and investigated dosing intervals. In comparison with the use of the PK/PD indices, a model-based approach, where the full time course of effect can be predicted, has a lower sensitivity to study design and allows for PK differences in subpopulations to be considered directly. This study supports the use of PKPD models built from in vitro time-kill curves in the development of optimal dosing regimens for antibacterial drugs.
Place, publisher, year, edition, pages
2011. Vol. 55, no 10, 4619-4630 p.
Research subject Pharmacokinetics and Drug Therapy
IdentifiersURN: urn:nbn:se:uu:diva-144792DOI: 10.1128/AAC.00182-11ISI: 000294952600019OAI: oai:DiVA.org:uu-144792DiVA: diva2:394664