New Semiphysiological Absorption Model To Assess the Pharmacodynamic Profile of Cefuroxime Axetil Using Nonparametric and Parametric Population Pharmacokinetics

Abstract

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 semiphysiological population PK model and evaluate the pharmacodynamic profile for cefuroxime axetil. Twenty-four healthy volunteers received 250 mg oral cefuroxime as a suspension after a standardized breakfast. Liquid chromatographytandem mass spectrometry was used for drug analysis, NONMEM and S-ADAPT (results reported) were used for parametric population PK modeling, and NPAG was used for nonparametric population PK modeling. Monte Carlo simulations were used to predict the duration for which the non-protein-bound-plasma concentration was above the MIC (fT >MIC ). A model with one disposition compartment, a saturable and timedependent drug release from the stomach, and fast drug absorption from the intestine yielded precise (r > 0.992) and unbiased curve fits and an excellent predictive performance. The apparent clearance was 21.7 liters/h (19.8% coefficient of variation [CV]) and the volume of distribution 38.7 liters (18.3% CV). Robust (>90%) probabilities of target attainment (PTAs) were achieved by 250 mg cefuroxime given every 12 h (q12h) or q8h for MICs of <0.375 mg/liter or <0.5 mg/liter, respectively, for the bacteriostasis target fT >MIC of >40% and for MICs of <0.094 mg/liter or <0.375 mg/liter, respectively, for the near-maximal-killing target fT >MIC of >65%. For the >40% fT >MIC target, the PTAs for 250 mg cefuroxime q12h were >97.8% for Streptococcus pyogenes and penicillin-susceptible Streptococcus pneumoniae. Cefuroxime at 250 mg q12h or q8h achieved PTAs below 73% or 92%, respectively, for Haemophilus influenzae, Moraxella 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.Cefuroxime axetil is the acetoxyethyl-ester prodrug of cefuroxime. Cefuroxime axetil is reliably absorbed and can be taken with or without a meal, although its extent of bioavailability is enhanced under the influence of food (20, 54). Cefuroxime has been successfully used in the treatment of upper and lower respiratory tract infections as well as genitourinary tract infections (45) and is active against Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pyogenes, Klebsiella pneumoniae, Neisseria gonorrhoeae, penicillin-susceptible Streptococcus pneumoniae, and some isolates of penicillin-intermediate S. pneumoniae (6, 7, 25-27, 34, 35, 37, 38, 41, 55).A susceptibility breakpoint of Յ1 mg/liter has been determined for cefuroxime by national organizations in Britain (BSAC) (8) and Germany (DIN) (17). The susceptibility breakpoints from the Clinical and Laboratory Standards Institute (CLSI) (11) are Յ1 mg/liter for S. pneumoniae and Յ4 mg/liter for Haemophilus spp., Enterobacteriaceae, and Staphyl...

Pharmacokinetics ofpara-Aminosalicylic Acid in HIV-Uninfected and HIV-Coinfected Tuberculosis Patients Receiving Antiretroviral Therapy, Managed for Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis

“…The nonlinear mixed-effects modeling of PAS disposition in M. tuberculosis-HIV-coinfected patients was performed using NONMEM (version 7.2) with first-order conditional estimation and with interaction. The one-compartment model with first-order absorption with lag time or transit compartment followed by first-order absorption (15,16) or mixed Michaelis-Menten and first-order absorption (17) was explored for the steady-state concentration-time profiles of patients who were administered 8 g PAS once daily or 4 g PAS twice daily. The final structural model was parameterized on the PK parameters: transit rate constant (K tr ) with 3 transit compartments, apparent oral clearance (CL/F), and the apparent volume of distribution (V/F).…”

Comparable Population Pharmacokinetics and Pharmacodynamic Breakpoints of Cefpirome in Cystic Fibrosis Patients and Healthy Volunteers

“…The residual unidentified variability was modeled by a combined additive and proportional error model for plasma concentrations and amounts in urine. We applied first-order conditional estimation using the interaction option in NONMEM VI level 1.2 software (8) and the importance sampling Monte-Carlo Parametric Expectation-Maximization method (pmethod ϭ 4) in S-ADAPT software (version 1.57 beta) (6) for population PK modeling as reported previously (16,18,19). The SADAPT-TRAN translator tool (14) was used to facilitate S-ADAPT analyses.…”

“…Linear one-, two-, and threecompartment models with a time-delimited zero order input into the central compartment were considered. Models were discriminated based on their predictive performance determined by visual predictive checks (VPCs) (16) and normalized prediction distribution errors (NPDE) (11), their objective function value, and standard diagnostic plots as previously described (19). Renal clearance (CL R ) and nonrenal clearance (CL NR ) were estimated by simultaneously fitting plasma concentrations and amounts excreted unchanged into urine.…”

Population Pharmacokinetic Comparison and Pharmacodynamic Breakpoints of Ceftazidime in Cystic Fibrosis Patients and Healthy Volunteers

“…(i) Structural model. We tested one-, two-, and three-compartment models with linear disposition and evaluated competing models using their predictive performance assessed via visual predictive checks (VPCs), the objective function, and standard diagnostic plots as described previously (16,18).…”

“…An exponential model was used to describe the BSV of PK parameters, and a combined additive and proportional error model was used to describe the residual unidentified variability as reported previously (16,18). We used the first-order conditional estimation with the interaction option (FOCEϩI) in NONMEM V release 1.1 (10), the importance sampling Monte-Carlo parametric expectation maximization method (pmethod ϭ 8) in S-ADAPT (version 1.56) (9), and the nonparametric adaptive grid (NPAG) algorithm of the USC*PACK (version 12.00) (43) for population PK modeling as described previously (16,18). WinNonlin Professional (version 4.0.1; Pharsight Corp., Mountain View, CA) was used for noncompartmental analysis and statistics.…”