Tigecycline Population Pharmacokinetics in Patients with Community- or Hospital-Acquired Pneumonia

Abstract

Tigecycline is a new-generation of tetracycline (glycylcyclines) and is active in vitro against bacteria that possess any of the classical genes that confer tetracycline resistance through ribosomal protection or efflux pumps. Herein, tigecycline disposition in patients with community-or hospital-acquired pneumonia was described using a population pharmacokinetic model. Additionally, the influence of covariates, such as body surface area, severity of illness, and clinical laboratory measures, on tigecycline disposition was evaluated. An intravenous loading dose of 100 mg was followed by 50 mg of tigecycline every 12 h. The final population pharmacokinetic model was a two-compartment model with linear elimination and with a relationship between tigecycline clearance and body surface area and creatinine clearance. The model was parameterized using total clearance (CL), the volume of the central compartment, distributional clearance from the central to the peripheral compartment, and volumes of distribution at steady state. Relationships between body surface area and creatinine clearance were identified as significant predictors of interindividual variability on CL. This model will serve as the basis for estimating tigecycline exposure for pharmacokinetic-pharmacodynamic analyses for efficacy and safety among patients with community-or hospital-acquired pneumonia.

Tigecycline Is Highly Efficacious against Mycobacterium abscessus Pulmonary Disease

“…The peripheral compartments of 8 HFSs were each inoculated with 20 ml of 6 log 10 CFU/ml M. abscessus. Treatment was administered daily for 21 days at doses that mimicked the non-proteinbound or free AUC 0 -24 , peak concentrations, and times to maximum concentration achieved in the lungs of humans treated with tigecycline doses of 0, 12.5, 25, 50, 100, 200, 400, and 800 mg, assuming linear increases in AUC 0 -24 with dose since clearance is constant over a range of doses (14)(15)(16). The doses were administered to the central compartment of each HFS once daily via computerized syringe pumps.…”

Pharmacokinetics-Pharmacodynamics of Tigecycline in Patients with Community-Acquired Pneumonia

“…where dose is equal to the total daily dose of tigecycline (100 mg) and CL T is the Bayesian post hoc clearance value generated from a previously conducted population PK analysis (6). In brief, the final population PK model was a two-compartment model with linear elimination.…”

“…Patient-specific PK parameter estimates were available from a population PK analysis of these data and were used to provide the most accurate estimates of exposure possible (6). These exposure estimates were indexed to the MIC of the infecting pathogen(s) and used to explore exposureresponse relationships for efficacy.…”

In Vitro Pharmacodynamics of Polymyxin B and Tigecycline Alone and in Combination against Carbapenem-Resistant Acinetobacter baumannii

“…Tigecycline was simulated with higher doses of 100 mg every 12 h and 200 mg every 12 h based on data from a murine pneumonia infection model, in which it was observed that the fAUC/MIC ratio was the pharmacodynamic parameter of importance predicting tigecycline efficacy against A. baumannii, and dosing regimens of Ն200 mg daily were required to achieve a 1-to 2-log reduction in organism density (25). Tigecycline pharmacokinetics were extrapolated from a study of patients infected with community-or hospital-acquired pneumonia (26) and used to simulate steady-state fAUC 0-12 exposures of 2.3 and 4.6 g · h/ml, as previously described (27). The targeted fC peak values were 0.6 g/ml and 1.2 g/ml for the 100-mg and 200-mg dosages, respectively, and protein binding was assumed to be 70%.…”