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Antimicrobial Agents and Chemotherapy, November 2006, p. 3701-3707, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.01636-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Population Pharmacokinetics of Tigecycline in Patients with Complicated Intra-Abdominal or Skin and Skin Structure Infections{triangledown}

S. A. Van Wart,1* J. S. Owen,1,2 E. A. Ludwig,1 A. K. Meagher,1 J. M. Korth-Bradley,3 and B. B. Cirincione1

Cognigen Corporation, Buffalo, New York,1 Auburn University, Auburn, Alabama,2 Wyeth Research, Collegeville, Pennsylvania3

Received 23 December 2005/ Returned for modification 28 March 2006/ Accepted 21 August 2006

Tigecycline, a first-in-class expanded glycylcycline antimicrobial agent, has demonstrated efficacy in the treatment of complicated skin and skin structure infections (cSSSI) and complicated intra-abdominal (cIAI) infections. A population pharmacokinetic (PK) model for tigecycline was developed for patients with cSSSI or cIAI enrolled in two phase 2 clinical trials, and the influence of selected demographic factors and clinical laboratory measures was investigated. Tigecycline was administered as an intravenous loading dose followed by a 0.5- or 1-h infusion every 12 h for up to 14 days. Blood samples were collected the day before or the day of hospital discharge for the determination of serum tigecycline concentrations. Patient covariates were evaluated using stepwise forward ({alpha} = 0.05) and backward ({alpha} = 0.001) procedures. The predictive performance of the model was assessed separately using pooled data from either two phase 3 studies for patients with cSSSI or two phase 3 studies for patients with cIAI. A two-compartment model with zero-order input and first-order elimination adequately described the steady-state tigecycline concentration-time data. Tigecycline clearance was shown to increase with increasing weight, increasing creatinine clearance, and male gender (P < 0.001). The final model provided a relatively unbiased fit to each data set. Individual predicted values of the area under the concentration-time curve from 0 to 12 h (AUC0-12) were generally unbiased (median prediction error, –1.60% to –3.78%) and were similarly precise (median absolute prediction error, <4%) when compared across data sets. The population PK model provided the basis to obtain individual estimates of steady-state AUC0-12 in later exposure-response analyses of tigecycline safety and efficacy in patients with cSSSI or cIAI.

* Corresponding author. Mailing address: Cognigen Corporation, 395 Youngs Road, Buffalo, NY 14221. Phone: (716) 633-3463, ext. 241. Fax: (716) 633-7404. E-mail: scott.vanwart{at}cognigencorp.com.

{triangledown} Published ahead of print on 28 August 2006.

Antimicrobial Agents and Chemotherapy, November 2006, p. 3701-3707, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.01636-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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