Population pharmacokinetics of high-dose tigecycline in patients with sepsis or septic shock [PublishAheadOfPrint]

Background and objective: Tigecycline is a glycylcycline often used in critically ill patients as antibiotic of last resort. The pharmacokinetics (PK) of tigecycline in Intensive Care Unit (ICU) patients can be affected by severe pathophysiological changes so that standard dosing might not be adequate. The aim of this study was to describe population PK of high dose tigecycline in patients with sepsis or septic shock and evaluate relationship between individual PK parameters and patient's covariates.

Materials and Methods: The study population consisted of 37 adult ICU patients receiving 200 mg loading dose of tigecycline followed by multiple doses of 100 mg every 12 h. Blood samples were collected at 0.5, 2, 4, 8 and 12 h after dose administration. Two-compartment model with inter-individual (IIV) and inter-occasion (IOV) variability in PK parameters was used to describe the concentration-time course of tigecycline.

Results: The estimated values of mean population PK parameters were 22.1 L/h and 69.4 L/h for elimination and inter-compartmental clearance, 162 L and 87.9 L for volume of central and peripheral compartment. The IIV and IOV in clearance was lower than 20%. The estimated values of distribution volumes were different than previously published values, which might be due to pathophysiological changes in ICU patients. No systematic relationship between individual PK parameters and patient's covariates was found.

Conclusions: The developed model does not show evidence that individual tigecycline dosing adjustment based on patient's covariates is necessary to obtain the same target concentration in patients with sepsis or septic shock. Dosing adjustments should be based on the pathogens, their susceptibility and PK targets.

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