title: Pharmacokinetics-pharmacodynamics of tigecycline in patients with community-acquired pneumonia.
abstract: Exposure-response analyses for efficacy and safety were performed for tigecycline-treated patients suffering from community-acquired pneumonia. Data were collected from two randomized, controlled clinical trials in which patients were administered a 100-mg loading dose followed by 50 mg of tigecycline every 12 h. A categorical endpoint, success or failure, 7 to 23 days after the end of therapy (test of cure) and a continuous endpoint, time to fever resolution, were evaluated for exposure-response analyses for efficacy. Nausea/vomiting, diarrhea, headache, and changes in blood urea nitrogen concentration (BUN) and total bilirubin were evaluated for exposure-response analyses for safety. For efficacy, ratios of the free-drug area under the concentration-time curve at 24 h to the MIC of the pathogen (fAUC(0-24):MIC) of ≥12.8 were associated with a faster time to fever resolution; patients with lower drug exposures had a slower time to fever resolution (P = 0.05). For safety, a multivariable logistic regression model demonstrated that a tigecycline AUC above a threshold of 6.87 mg · hr/liter (P = 0.004) and female sex were predictive of the occurrence of nausea and/or vomiting (P = 0.004). Although statistically significant, the linear relationship between tigecycline exposure and maximum change from baseline in total bilirubin is unlikely to be clinically significant.
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Rubino
authors.forename: Sujata M
authors.initials: SM
authors.lastname: Bhavnani
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
authors.forename: Gary
authors.initials: G
authors.lastname: Dukart
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dartois
authors.forename: Angel
authors.initials: A
authors.lastname: Cooper
authors.forename: Joan
authors.initials: J
authors.lastname: Korth-Bradley
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ambrose
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001663:Bilirubin / Q000097:blood; D001806:Blood Urea Nitrogen; D017714:Community-Acquired Infections / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008911:Minocycline / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D018410:Pneumonia, Bacterial / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D012044:Regression Analysis; D012737:Sex Factors; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000254:growth & development; D000078304:Tigecycline; D016896:Treatment Outcome; D014481:United States
chemical_list: D000900:Anti-Bacterial Agents; D000078304:Tigecycline; D008911:Minocycline; D001663:Bilirubin