Tigecycline population pharmacokinetics in patients with severe sepsis or septic shock resulting from abdominal surgery
Agnieszka Borsuk (1), Paweł Wiczling (1), Elżbieta Rypulak (2), Beata Potręć (2), Paweł Piwowarczyk (2), Michał Borys (2), Justyna Sysiak (2), Dariusz Onichimowski (3), Mirosław Czuczwar (2)
(1) Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gdańsk, Poland, (2) Department of Anaesthesiology and Intensive Therapy, Medical University of Lublin, Poland, (3) Department of Anesthesiology and Intensive Care, Faculty of Medical Sciences, University of Warmia and Mazury, Poland
Objectives: Tigecycline is the first glycylcycline antimicrobial drug approved in Europe for the treatment of complicated skin and skin structure infections and complicated intra-abdominal infections at 100 mg initial dose followed by 50 mg every 12 h [1]. However, it has been reported that higher dose regimens of tigecycline may be more effective than recommended dosing [2]. In this study a higher dose of tigecycline was administered to adult patients with severe sepsis or septic shock resulting from abdominal surgery. The objectives of the study were to develop a tigecycline population pharmacokinetic model and assess the relationship between patient covariates and individual PK parameters.
Methods: The analyzed population included 37 patients aged 25-79 years old treated in Intensive Care Unit. Each patient received initial dose of 200 mg of tigecycline in a short 30 min infusion, followed by multiple doses of 100 mg in 30 min infusion every 12 h. The covariates recorded for each patient included time-independent covariates: age, weight, height, death, sex, the use of extracorporeal membrane oxygenation, the use of continuous renal replacement therapy and the time-dependent covariates: dialysis volume, ultrafiltration speed, extravascular lung water index, cardiac output, sequential organ failure assessment score and procalcitonin concentration. Population nonlinear mixed effects modeling was conducted using NONMEM software.
Results: Tygecycline pharmacokinetics was described by a two-compartment disposition model. The population model included inter-individual variability in CL, V1 and V terms and inter-occasion variability in individual CL and V2 parameter values. The typical values of elimination and inter-compartmental clearance were 22.1 L/h and 69.4 L/h; the typical values of volume of central and peripheral compartment were 162 L and 87.9 L. The inter-individual variability was intermediate for CL (17.3%) and V1 (19.2%) and higher for V2 (38.7%). The inter-occasion variability for CL and VT was 14.4% and 20.8%, respectively.
Conclusions: The population PK model was successfully developed to describe the time course of tigecycline concentrations in the analyzed population. None of the available covariates was found to explain part of the inter-individual or inter-occasion variability in the pharmacokinetic parameters. The model can be useful for further analysis of tigecycline exposure-response relationships.
References:
[1] Pfizer Limited (2006) Tygacil (tigecycline): EPAR - Product Information, Annex I - Summary of product characteristics. http://www.ema.europa.eu: EMEA/H/C/000644-IA/0100.
[2] Falagas, M. E., Vardakas, K. Z., Tsiveriotis, K. P., Triarides, N. A. & Tansarli, G. S. Effectiveness and safety of high-dose tigecycline-containing regimens for the treatment of severe bacterial infections. Int. J. Antimicrob. Agents 44, 1–7 (2014).
