Tigecycline Dosing Strategies in Critically Ill Liver-Impaired Patients

Abstract

This study investigated tigecycline exposure in critically ill patients from a population pharmacokinetic perspective to support rational dosing in intensive care unit (ICU) patients with acute and chronic liver impairment. A clinical dataset of 39 patients served as the basis for the development of a population pharmacokinetic model. The typical tigecycline clearance was strongly reduced (8.6 L/h) as compared to other populations. Different models were developed based on liver and kidney function-related covariates. Monte Carlo simulations were used to guide dose adjustments with the most predictive covariates: Child-Pugh score, total bilirubin, and MELD score. The best performing covariate, guiding a dose reduction to 25 mg q12h, was Child-Pugh score C, whereas patients with Child-Pugh score A/B received the standard dose of 50 mg q12h. Of note, the obtained 24 h steady-state area under the concentration vs. time curve (AUC_ss) range using this dosing strategy was predicted to be equivalent to high-dose tigecycline exposure (100 mg q12h) in non-ICU patients. In addition, 26/39 study participants died, and therapy failure was most correlated with chronic liver disease and renal failure, but no correlation between drug exposure and survival was observed. However, tigecycline in special patient populations needs further investigations to enhance clinical outcome.

Keywords: Child–Pugh score; dose adjustment; population pharmacokinetics.

Figure 1

Simulated AUC_ss in patients with Child–Pugh A/B and C and standard-dose tigecycline (50 mg q12h MD) compared to the simulated AUC_ss-vW ‘reference’ of high-dose tigecycline (100 mg q12h MD) in non-critically ill patients.

Figure 2

AUC_ss from dose-adjusted low-dose tigecycline (25 mg q12h MD) groups vs. non-adjusted groups receiving standard-dose tigecycline (50 mg q12h MD) in our cohort, compared to the 95% interval of 100 mg q12h MD tigecycline from van Wart et al. in non-ICU patients without hepatic impairment (AUC_ss-vW, vertical lines). Optimal cutoffs for dose adjustment investigation were CPS_C, total bilirubin ≥ 10 mg/dL, MELD score ≥ 30, and eGFR ≤ 30 mL/min. The quantity [%] of simulated individuals within the 95% interval of AUC_ss-vW is displayed.

Figure 3

Probability of target attainment (PTA) analysis of AUC_ss/MIC ratio ≥ 17.9 and ≥ 6.96 over minimal inhibitory concentration (MIC). Dose adjustment (25 mg q12h MD) was applied for individuals with bilirubin ≥ 10 mg/dL, MELD score ≥ 30, and eGFR ≤ 30 mL/min and compared to non-adjusted (50 mg q12h MD) groups, as well as Child–Pugh score-based dose adjustment. Horizontal dotted line denotes 90% PTA_90%.