title: Population pharmacokinetic comparison and pharmacodynamic breakpoints of ceftazidime in cystic fibrosis patients and healthy volunteers.
abstract: Despite the promising activity of ceftazidime against Pseudomonas aeruginosa and Burkholderia cepacia, there has not yet been a study that directly compared the pharmacokinetics (PK) of ceftazidime in cystic fibrosis (CF) patients and healthy volunteers by population PK methodology. We assessed the population PK and PK/pharmacodynamic (PD) breakpoints of ceftazidime in CF patients and healthy volunteers. Eight CF patients (total body weight [WT] [average +/- standard deviation] = 42.9 +/- 18.4 kg) and seven healthy volunteers (WT = 66.2 +/- 4.9 kg) received 2 g ceftazidime as a 5-min intravenous infusion. High-performance liquid chromatography (HPLC) was used for drug analysis, and NONMEM (results reported), S-ADAPT, and NPAG were used for parametric and nonparametric population PK modeling. We considered linear and allometric body size models to scale clearance and volume of distribution. Monte Carlo simulations were based on a target time of non-protein-bound plasma concentration of ceftazidime above MIC of > or =65%, which represents near-maximal killing. Unscaled total clearance was 19% lower in CF patients, and volume of distribution was 36% lower. Total clearance was 7.82 liters/h for CF patients and 6.68 liters/h for healthy volunteers with 53 kg fat-free mass. Allometric scaling by fat-free mass reduced the between-subject variability by 32% for clearance and by 18 to 26% for volume of both peripheral compartments compared to linear scaling by WT. A 30-min ceftazidime infusion of 2 g/70 kg WT every 8 h (q8h) achieved robust (> or =90%) probabilities of target attainment (PTAs) for MICs of < or =1 mg/liter in CF patients and < or =3 mg/liter in healthy volunteers. Alternative modes of administration achieved robust PTAs up to markedly higher MICs of < or =8 to 12 mg/liter in CF patients for 5-h infusions of 2 g/70 kg WT q8h and < or =12 mg/liter for continuous infusion of 6 g/70 kg WT daily.
authors.affiliation: IBMP Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany.
authors.forename: J B
authors.initials: JB
authors.lastname: Bulitta
authors.forename: C B
authors.initials: CB
authors.lastname: Landersdorfer
authors.forename: S J
authors.initials: SJ
authors.lastname: Hüttner
authors.forename: G L
authors.initials: GL
authors.lastname: Drusano
authors.forename: M
authors.initials: M
authors.lastname: Kinzig
authors.forename: U
authors.initials: U
authors.lastname: Holzgrabe
authors.forename: U
authors.initials: U
authors.lastname: Stephan
authors.forename: F
authors.initials: F
authors.lastname: Sörgel
mesh_terms: D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002442:Ceftazidime / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002648:Child; D002851:Chromatography, High Pressure Liquid; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008826:Microbial Sensitivity Tests / Q000592:standards; D008875:Middle Aged; D009010:Monte Carlo Method; D011153:Population; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D002442:Ceftazidime