Population pharmacokinetics of tigecycline in critically ill patients

Abstract

Objective: In critically ill patients, the change of pathophysiological status may affect the pharmacokinetic (PK) process of drugs. The purpose of this study was to develop a PK model for tigecycline in critically ill patients, identify the factors influencing the PK and optimiz dosing regimens.Method: The concentration of tigecycline was measured LC-MS/MS. We established population PK model with the non-linear mixed effect model and optimized the dosing regimens by Monte Carlo simulation.Result: A total of 143 blood samples from 54 patients were adequately described by a one-compartment linear model with first-order elimination. In the covariate screening analysis, the APACHEII score and age as significant covariates. The population-typical values of CL and Vd in the final model were 11.30 ± 3.54 L/h and 105.00 ± 4.47 L, respectively. The PTA value of the standard dose regimen (100 mg loading dose followed by a 50 mg maintenance dose at q12 h) was 40.96% with an MIC of 2 mg/L in patients with HAP, the ideal effect can be achieved by increasing the dosage. No dose adjustment was needed for Klebsiella pneumoniae for AUC0–24/MIC targets of 4.5 and 6.96, and the three dose regimens almost all reached 90%. A target AUC0–24/MIC of ≥17.9 reached 100% in patients with cSSSI in the three tigecycline dose regimens, considering MIC ≤ 0.25 mg/L.Conclusion: The final model indicated that APACHEII score and age could affect the Cl and Vd of tigecycline, respectively. The standard dose regimen of tigecycline was often not able to obtain satisfactory therapeutic effects for critically ill patients. For patients with HAP and cIAI caused by one of three pathogens, the efficacy rate can be improved by increasing the dose, but for cSSSI infections caused by Acinetobacter baumannii and K. pneumoniae, it is recommended to change the drug or use a combination of drugs.

Population pharmacokinetics and individualized dosing of tigecycline for critically ill patients: a prospective study with intensive sampling

“…Most of the published population pharmacokinetic (PPK) studies on tigecycline were conducted in special subpopulations (e.g., patients with intra-abdominal infections, hospital-acquired pneumonia, sepsis or septic shock, as well as patients with decompensated cirrhosis and severe infections, etc. ), while only two studies with limited sampling were carried out on critically ill patients ( Wart et al, 2006 ; Rubino et al, 2010 ; Xie et al, 2017 ; Broeker et al, 2018 ; Moor et al, 2018 ; Yang et al, 2021 ; Zhou et al, 2021 ; Amann et al, 2022 ; Bastida et al, 2022 ; Luo et al, 2023 ). On the other hand, although the recommended dose of tigecycline in drug labels appears to be straightforward (an initial dose of 100 mg followed by 50 mg every 12 h for 5–14 days), increasing evidence shows that the common dose may result in higher all-cause mortality, whereas a high-dose tigecycline therapy strategy (an initial dose of 200 mg followed by 100 mg every 12 h) may have higher clinical cure rate ( McGovern et al, 2013 ; Xie et al, 2014 ; Zha et al, 2020 ).…”