Tigecycline population pharmacokinetics in critically ill patients with decompensated cirrhosis and severe infections

Objectives Physiopathological changes in advanced cirrhosis could alter tigecycline pharmacokinetics (PK), thus affecting serum drug concentrations and compromising target attainment. We aimed to describe tigecycline PK in patients with decompensated cirrhosis and severe bacterial infections, identify the sources of PK variability and assess the performance of different dosing regimens to optimize the PK/pharmacodynamic (PD) target. Methods Serum concentrations and covariates were obtained from patients with severe infections under tigecycline treatment. A population PK analysis was performed using non-linear mixed-effects modelling and the final model was used to simulate tigecycline exposure to assess the PTA. Results Twenty critically ill patients were enrolled in the study. Data were best described by a two-compartment linear model. Mean +/- SD parameter estimates for clearance (CL), intercompartmental clearance (Q), central and peripheral volumes of distribution (V-1 and V-2) were 14.8 +/- 11 L/h, 38.4 +/- 24 L/h, 63.7 +/- 14 L and 233 +/- 30 L, respectively. MELD score significantly influenced tigecycline CL, and total serum proteins significantly affected V-1. Monte Carlo simulations showed that tigecycline elimination is hampered as MELD score values increase, consequently requiring lower drug doses. Patients with hypoproteinaemia would have lower peak tigecycline concentrations but similar steady-state concentrations compared with patients with normoproteinaemia. Conclusions Our study confirms that tigecycline dose adjustment is needed in severe hepatic dysfunction and suggests using the MELD score for dose optimization since it is identified as a covariate that significantly influences tigecycline CL. Dosing regimens are recommended to reach several PK/PD targets considering this clinical variable and any MIC within the susceptibility range.