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

Abstract

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 (V1 and V2) 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 V1. 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.

Population Pharmacokinetics of Tigecycline: A Systematic Review

“… 24 Besides, in Bastida’s study, the dosage of tigecycline administration was not provided. 25 The time of samples collection in patients in these eight studies varied widely, for example, in Broeker’s study, arterial blood samples were collected as follows: 0 (before the start of infusion), after the end of infusion (1, 1.25, 1.5, 1.75, 2, 4, 6, 8, and 12 h), while Zhou et al reported that the blood samples were obtained before the ninth dose of tigecycline and at 0, 3, and 8 h after the end of infusion. 18 , 23 To quantify tigecycline concentrations in these samples, the high-performance liquid chromatography and liquid chromatography method with tandem mass spectrometer detection systems were used in these studies.…”

“… A two-dimensional liquid chromatographic system, which contains two parts: the first separation system (LC1) and second separation system (LC2). 35 ng/mL Bastida et al 25 Prospective NR 30 min before drug administration (pre-dose), and 1, 2, 5 and 8–12 h after drug administration Liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) method 10 ng/mL Abbreviations : NR, not reported; LLQ, lower limit of quantifcation. …”

“… 20 , 22 Interestingly, Bastida et al recently reported that Model for End-stage Liver Disease (MELD) score and total serum proteins significantly influenced the clearance of tigecycline in critically ill patients with decompensated cirrhosis and severe infections. 25 In addition, other significant covariates on tigecycline clearance included BMI, body surface area, bilirubin, and aspartate aminotransferase.…”

All Roads Lead to Rome: Enhancing the Probability of Target Attainment with Different Pharmacokinetic/Pharmacodynamic Modelling Approaches

“…It was surprising that only a few PK/PD models were available for OMC. A glance at the other third-generation tetracyclines shows that, for tigecycline, for example, only a few PK/PD modelling studies have been published to date [ 96 , 97 , 98 ]. As adjusted doses of tigecycline have been suggested for patients with severe hepatic functions [ 98 ], the only factor found in PK models for OMC affecting PK was the timing of food consumption.…”

Population pharmacokinetics of tigecycline in critically ill patients

“…In critically ill patients, pathophysiological changes may affect drug PK, thus affecting the required dose ( Blot et al, 2014 ; Borsuk-De Moor et al, 2018 ; Broeker et al, 2018 ). PK changes in patients with severe illness include changes in the clearance (CL) rate caused by increased cardiac output or organ failure, and changes in distribution volume (Vd) caused by increased vascular permeability or changes in protein binding ( Bastida et al, 2022 ). The status of patients will change according to disease development.…”