Bulitta JB, Landersdorfer CB, Kinzig M, Holzgrabe U, Sorgel F
A New Semi-Physiological Absorption Model to Assess the Pharmacodynamic Profile of Cefuroxime Axetil using Nonparametric and Parametric Population Pharmacokinetics. [JOURNAL ARTICLE]
Antimicrob Agents Chemother 2009 Jun 15.
Cefuroxime axetil is widely used to treat respiratory tract infections. We are not aware of a population pharmacokinetic (PK) model for cefuroxime axetil. Our objectives were to develop a semi-physiological population PK model and evaluate the pharmacodynamic (PD) profile for cefuroxime axetil. Twenty-four healthy volunteers received 250mg oral cefuroxime as suspension after a standardized breakfast. LC-MS/MS was used for drug analysis, NONMEM and S-ADAPT (results reported) for parametric population PK, and NPAG for nonparametric population PK modeling. Monte Carlo simulations were used to predict the time of non-protein bound concentration above the MIC (fT>MIC). A model with one disposition compartment, a saturable and time-dependent drug release from stomach and fast drug absorption from intestine yielded precise (r>0.992) and unbiased curve fits and an excellent predictive performance. Apparent clearance was 21.7 L/h (19.8% CV) and volume of distribution 38.7 L (18.3%). Robust (>/=90%) probabilities of target attainment (PTA) were achieved by 250 mg Q12h (Q8h) cefuroxime for MICs </=0.375 mg/L (0.5 mg/L) for the bacteriostasis target fT>MIC>/=40% and for MICs </=0.094 mg/L (0.375 mg/L) for the near-maximal killing target fT>MIC>/=65%. For the fT>MIC>/=40% target, PTAs for 250 mg cefuroxime Q12h were >/=97.8% against S. pyogenes and penicillin-susceptible S. pneumoniae. Cefuroxime 250 mg Q12h (Q8h) achieved PTAs below 73% (92%) against H. influenzae, M. catarrhalis, and penicillin-intermediate S. pneumoniae for susceptibility data from various countries. Depending on the MIC distribution, 250 mg oral cefuroxime Q8h instead of Q12h should be considered especially for more severe infections that require near-maximal killing by cefuroxime.
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