title: Systematic comparison of the population pharmacokinetics and pharmacodynamics of piperacillin in cystic fibrosis patients and healthy volunteers.
abstract: Respiratory tract infections cause 90% of premature mortality in patients with cystic fibrosis (CF). Treatment of Pseudomonas aeruginosa infection is often very problematic. Piperacillin-tazobactam has good activity against P. aeruginosa, but its pharmacokinetics (PK) in CF patients has not been compared to the PK in healthy volunteers in a controlled clinical study. Therefore, we compared the population PK and pharmacodynamics (PD) of piperacillin between CF patients and healthy volunteers. We studied 8 adult (median age, 20 years) CF patients (average total body weight [WT], 43.1 +/- 7.8 kg) and 26 healthy volunteers (WT, 71.1 +/- 11.8 kg) who each received 4 g piperacillin as a 5-min intravenous infusion. We determined piperacillin levels by high-performance liquid chromatography, and we used NONMEM for population PK and Monte Carlo simulation. We used a target time of nonprotein-bound concentration above the MIC of 50%, which represents near-maximal bacterial killing. Unscaled total clearance was 25% lower, and the volume of distribution was 31% lower in CF patients. Allometric scaling by lean body mass reduced the unexplained (random) between-subject variability in clearance by 26% compared to the variability of linear scaling by WT. A standard dosage regimen of 3 g/70 kg body WT every 4 h as a 30-min infusion (daily dose, 18 g) achieved a robust (> or =90%) probability-of-target attainment (PTA) for MICs of < or =12 mg/liter in CF patients and < or =16 mg/liter in healthy volunteers. Alternative modes of administration allowed a marked dose reduction to 9 g daily. Prolonged (4-h) infusions of 3 g/70 kg WT every 8 h and continuous infusion (daily dose, 9 g), achieved a robust PTA for MICs of < or =16 mg/liter in both groups. Piperacillin achieved PTA expectation values of 64% and 89% against P. aeruginosa infection in CF patients, based on susceptibility data from two German CF clinics.
authors.affiliation: Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany.
authors.forename: J B
authors.initials: JB
authors.lastname: Bulitta
authors.forename: S B
authors.initials: SB
authors.lastname: Duffull
authors.forename: M
authors.initials: M
authors.lastname: Kinzig-Schippers
authors.forename: U
authors.initials: U
authors.lastname: Holzgrabe
authors.forename: U
authors.initials: U
authors.lastname: Stephan
authors.forename: G L
authors.initials: GL
authors.lastname: Drusano
authors.forename: F
authors.initials: F
authors.lastname: Sörgel
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016022:Case-Control Studies; D003198:Computer Simulation; D003550:Cystic Fibrosis / Q000097:blood / Q000188:drug therapy*; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D010878:Piperacillin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011153:Population; D011552:Pseudomonas Infections / Q000150:complications / Q000188:drug therapy; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000302:isolation & purification
chemical_list: D000900:Anti-Bacterial Agents; D010878:Piperacillin