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

Abstract

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 (␣ ‫؍‬ 0.05) and backward (␣ ‫؍‬ 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 (AUC 0-12 ) 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 AUC 0-12 in later exposure-response analyses of tigecycline safety and efficacy in patients with cSSSI or cIAI.

Evaluation of Tigecycline Penetration into Colon Wall Tissue and Epithelial Lining Fluid Using a Population Pharmacokinetic Model and Monte Carlo Simulation

“…Mean parameter values and standard deviations from the pharmacokinetic models are shown in Table 2. Serum clearance is modestly lower than that observed in previous analyses (15); this difference may reflect differences in demographics and/or disease state between studies. Clearly there was a high degree of interindividual variability in tissue pharmacokinetics, as evidenced by the high standard deviations.…”

Overexpression of the adeB Gene in Clinical Isolates of Tigecycline-Nonsusceptible Acinetobacter baumannii without Insertion Mutations in adeRS

“…The pharmacodynamic studies indicated that the validated TGC regimen could achieve a maximum steady-state serum drug concentration of 0.63 Ϯ 0.28 mg/liter (mean Ϯ standard deviation). Thus, the results do not support TGC use for bloodstream infections caused by organisms for which TGC MICs are Ͼ1 mg/liter (16,20,21). In Taiwan, the MIC 50 and MIC 90 of TGC for MRAB were reported to be 2 and 4 mg/ liter, respectively (10).…”

In Vitro Pharmacodynamics of Simulated Pulmonary Exposures of Tigecycline Alone and in Combination against Klebsiella pneumoniae Isolates Producing a KPC Carbapenemase

“…However, this experiment simulated a higher concentration of tigecycline than those used in our model, and that concentration was maintained over the entire course of the experiment. Clearly, this is not the concentration-time profile exhibited by tigecycline administered clinically at a dose of 50 mg every 12 h, even in the ELF (12,39,44). To achieve an fAUC exposure in ELF of 3.1 g-h/ml, our model simulated a steady-state tigecycline peak concentration of 0.57 g/ml, followed rapidly by an exponential decline in the concentration to approximately 0.21 g/ml, which was then maintained for the 12-h dosing interval (Fig.…”

“…A dosing strategy was developed using mean pharmacokinetic parameters from a previous population pharmacokinetic study of tigecycline to simulate steady-state tigecycline concentrations in epithelial lining fluid (ELF) after 50-mg doses every 12 h, as depicted in Fig. 1A (44). For these calculations, we assumed that the median area under the curve (AUC) for ELF over the dosing interval was 115% of that in serum, as observed in a population pharmacokinetic analysis of ELF data from healthy volunteers (39).…”