Resource Center

Dec 16, 2005
  |  Poster

Population Pharmacokinetics of Tigecycline in Patients with Complicated Skin and Skin-Structure and Intra-Abdominal Infections

Abstract

Purpose: Tigecycline is a novel glycylcycline antibiotic with expanded broad-spectrum in vitro activity, including emerging multidrug-resistant pathogens. The goal of this analysis was to develop a PPK model for tigecycline in patients with complicated skin and skin-structure infections (cSSSI) or complicated intra-abdominal infections (cIAI) in Phase 2 studies and generate steady-state AUC0-12 values for use in exposure-response analyses of safety and efficacy.

Methods: A population PK model was developed using pooled data from two Phase 2 studies in patients with cSSSI or cIAI. Tigecycline was infused over 1 hr as either a 100-mg or 50-mg loading dose followed by either 50 or 25 mg every 12 hr for up to 14 days. Serial blood samples were collected to determine steady-state serum tigecycline concentrations using LC/MS/MS. Both 2- and 3-CMT models were evaluated using NONMEM®. Patient covariates were evaluated to explain interindividual variability in PK using stepwise forward selection (α = 0.05) and backward elimination (α = 0.001). The final model was used to generate individual tigecycline steady-state AUC0-12 values, which were assessed for bias (PE%) and precision (|PE|%) relative to noncompartmental estimates.

Results: A 2-CMT model with zero-order input and first-order elimination best described the steady-state tigecycline concentration-time data. Tigecycline clearance was increased with creatinine clearance, weight, and for male gender. Mean (SD) steady-state AUC0-12 values for the 25-mg and 50-mg dose groups were 1.34 (0.5) and 2.70 (0.8) mg⋅hr/L, respectively. Creatinine clearance had the largest apparent impact on the PK of tigecycline; AUC0-12 values were 31% to 48% higher across dose groups in patients with moderate or severe renal impairment relative to normal values. AUC0-12 was unbiased (median PE% ± 2%) and acceptably precise (median |PE|% < 10%).

Conclusions: A population PK model was developed to characterize steady-state tigecycline concentration-time data and to determine the impact of various patient covariates on the PK of tigecycline. Steady-state tigecycline exposures were obtained in the current Phase 2 patient population, and the model is available to estimate steady-state AUC0-12 in future Phase 3 trials.

Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Washington, DC, December 2005

By Scott A. Van Wart, Joel S. Owen, Alison K. Meagher, and Brenda B. Cirincione

Contact Us About This Poster