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 (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 (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.

FIG. 1.

Measured and population mean predicted steady-state serum tigecycline concentration-time profiles obtained using the final phase 2 population PK model for patients given an initial bolus of 100 mg followed by 50 mg q12h.

FIG. 2.

Population mean clearance of tigecycline computed over the 5th to 95th percentiles of each covariate. WTKG, weight in kilograms.

FIG. 3.

Individual predicted versus observed steady-state tigecycline AUC_0-12 values for the phase 2 model development (top), phase 3 cSSSI (bottom left), and phase 3 cIAI (bottom right) patient data sets.