Resource Center

Nov 6, 2005
  |  Poster

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

Abstract

Purpose: Tigecycline is a novel glycylcycline antibiotic demonstrating broad-spectrum in vitro activity. A previously developed population pharmacokinetic (PK) model was utilized to generate individual predicted AUC0-12 estimates in patients with complicated skin and skin-structure infections (cSSSI) or complicated intra-abdominal infections (cIAI) in Phase 3 studies for use in future exposure-response analyses of safety and efficacy.

Methods: In 4 Phase 3 studies, tigecycline was infused over 0.5 hour (cIAI patients, n=155) or 1 hour (cSSSI patients, n=24) as a 100-mg loading dose followed by 50 mg every 12 hours for up to 14 days. A population PK model (2-compartment, zero-order input and first-order elimination; clearance as a function of creatinine clearance, weight, and sex) was previously developed using steady-state data from Phase 2 studies of patients with cSSSI and cIAI. The final Phase 2 parameter estimates were used as population priors. The model was applied separately to the Phase 3 cSSSI and cIAI data in NONMEM® to estimate empirical Bayesian PK parameters. Model performance was evaluated for both datasets by assessing goodness-of-fit, bias (PE%), and precision (⎪PE⎪%) for individual predicted tigecycline concentrations and steady-state AUC0-12 values.

Results: The patient populations in Phase 2 and 3 cSSSI and cIAI studies had similar demographic characteristics and steady-state tigecycline concentrations. Goodness-of-fit plots revealed that the Phase 2 model provided a relatively unbiased fit to both Phase 3 datasets: the median PE% was ± 3% and 4%, while ⎪PE⎪% was within 10% and 4% for the individual predicted tigecycline concentrations and AUC0-12 values, respectively.

Conclusions: The feasibility of using a previously developed population PK model to predict individual AUC0-12 in a new population with similar demographic and pharmacokinetic characteristics was explored. The Phase 2 population PK model for tigecycline provided an acceptably precise and relatively unbiased fit to the Phase 3 data, and resulted in unbiased estimates of AUC0-12, without the need for further model refinement.

American Association of Pharmaceutical Scientists (AAPS), Nashville, Tennessee, November 2005

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

Contact Us About This Poster