Ella Widigson (1, 2), David Busse (1, 2), Davide Bindellini (1, 2), David Petroff (3), Christoph Dorn (4), Alix Démaris (1, 2), Linda Aulin (1), Robin Michelet (1), Markus Zeitlinger (5), Wilhelm Huisinga (6), Hermann Wrigge (7, 8), Philipp Simon (8, 9), Charlotte Kloft (1)
(1) Dept. of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany, (2) and Graduate Research Training program PharMetrX, Germany, (3) Clinical Trial Centre Leipzig, University of Leipzig, Germany, (4) Institute of Pharmacy, University of Regensburg, Germany, (5) Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria, (6) Institute of Mathematics, University of Potsdam, Germany, (7) Bergmannstrost Hospital Halle, Department of Anaesthesiology, Intensive Care and Emergency Medicine, Pain Therapy, Halle, Germany, (8) Medical Centre and Integrated Research and Treatment Center (IFB), Adiposity Diseases, University of Leipzig, Germany, (9) Department of Anesthesiology and Intensive Care, Faculty of Medicine, University of Augsburg, Germany
Objectives: Tigecycline is a broad-spectrum antibiotic [1] used to treat complicated intraabdominal infections (cIAI), community acquired pneumonia (CAP) and complicated skin- and skin structure infections (cSSI) [2]. Its antimicrobial efficacy correlates with the area under the unbound concentration-time curve in relation to minimum inhibitory concentration (fAUC/MIC) [3]. Since tigecycline demonstrates atypical plasma protein binding (PPB) behaviour, in which the unbound fraction decreases for increasing total plasma concentrations within clinically relevant concentrations [4], pharmacokinetic and pharmacodynamic (PK/PD) targets based on unbound concentrations are challenging to apply in probability of PK/PD target attainment (PTA) analysis. Previously, the importance of accounting for the atypical PPB of tigecycline in the identification of these targets, as well as for performing PTA analysis, has been demonstrated [5] in non-obese patients. Yet, a comparison of tigecycline pharmacokinetics between obese and nonobese patients, including its atypical PPB, is still lacking. As obesity, defined as individual body mass index (BMI) above 30 kg/m2 [6], has been linked to decreased PTA for several antibiotics [7], assessing the adequacy of tigecycline standard dosing regimen in obese patients is crucial.
The objectives of this analysis were to (i) characterise the atypical PPB of tigecycline, and (ii) to evaluate the adequacy of the tigecycline standard dosing regimen in obese and nonobese patients.
Methods: A population pharmacokinetic model characterising tigecycline plasma concentration-time data in 15 obese (BMI=35.0 – 62.0 kg/m2) and 15 nonobese patients (BMI=21.0 – 28.0 kg/m2), receiving 100 or 50 mg tigecycline (30-min intravenous infusion) before abdominal surgery [8], was developed using NONMEM 7.4.3, PsN 4.2.0 and Pirana 2.9.6. Based on this model, plasma exposure after a loading dose (100 mg) followed by maintenance doses (50 mg) every 12 h was simulated using Monte‑Carlo simulations (n=1000). PTA at steady state was investigated for cIAI (fAUC/MIC=2.05) [5] and CAP (fAUC/MIC=0.9) [9], using the non-species related resistance breakpoint (MIC=0.500 mg/L) [10], in R 4.1.1 and RStudio 1.4.17. PTA≥90% was considered adequate.
Results: A two-compartment model with first order elimination adequately described the tigecycline plasma concentration-time data. The atypical PPB was adequately accounted for with a linear relationship between tigecycline plasma concentration and fraction unbound, with an estimated slope of -0.323 L/mg (95% confidence interval, (CI): -0.440 – -0.206) and intercept of 69.0% (95% CI: 64.5 – 73.5). Interindividual variability was implemented as exponential functions on all estimated model parameters and a proportional error model adequately described the residual unexplained variability. Body weight (BW) was found to increase the degree of PPB (p<0.001) by increasing the intercept of the PPB regression model according to a power model, in which the factor of change for an individual was calculated as the quotient of the individual’s BW and the study population’s median BW, to the power of 0.270 (95% CI: 0.0753 – 0.465). Increased calculated creatinine clearance (CLCR) (p=0.0213) and plasma leukocyte concentration (LEU) (p=0.0198) were found to increase clearance, also according to power models with the exponents 0.406 (95% CI: 0.260 – 0.552) and 0.433 (95% CI: 0.108 – 0.974), respectively. The tigecycline standard dosing regimen was adequate (PTA>90%) at steady state (day 2 of treatment) for the evaluated ranges of BW (54.0 – 145 kg), CLCR (50.0 – 185 mL/min) and LEU (3.50 – 12.5 particles∙109/L), for both the indications cIAI and CAP. No PK/PD target referring to unbound concentrations was found in literature for cSSI and thus no PTA was performed for this indication.
Conclusions: The standard tigecycline dosing regimen appeared adequate for indications cIAI and CAP in obese and nonobese patients, as no clinically relevant difference in PTA was observed based on plasma exposure. The atypical PPB was characterised using linear regression, which could be refined in the future by further unbound concentration determinations beyond the currently observed interval. The developed model should be used to re-evaluate existing PK/PD targets related to total plasma concentrations to improve PK/PD evaluations of tigecycline treatment.
References:
[1] G.A. Pankey. Tigecycline. J Antimicrob Chemother 56: 470–480 (2005).
[2] Tygacil (tigecycline) [package insert]. Philadelphia, PA: Pfizer Inc; 2021.
[3] B. Leng, G. Yan, C. Wang et al. Dose optimisation based on pharmacokinetic/pharmacodynamic target of tigecycline. J Glob Antimicrob Resist 25: 315–322 (2021).
[4] C. Dorn, A. Kratzer, U. Liebchen et al. Impact of Experimental Variables on the Protein Binding of Tigecycline in Human Plasma as Determined by Ultrafiltration. J Pharm Sci 107: 739–744 (2018).
[5] R.S.P. Singh, J.K. Mukker, S.K. Drescher et al. A need to revisit clinical breakpoints of tigecycline: effect of atypical non-linear plasma protein binding. International Journal of Antimicrobial Agents 49: 449–455 (2017).
[6] WHO. Obesity. https://www.who.int/health-topics/obesity#tab=tab_1. Published 2022. Accessed 03 Jan 2022.
[7] A.S. Alobaid, M. Hites, J. Lipman et al. Effect of obesity on the pharmacokinetics of antimicrobials in critically ill patients: A structured review. Int J Antimicrob Agents 47: 259–268 (2016).
[8] P. Simon, D. Petroff, C. Dorn et al. Measurement of soft tissue drug concentrations in morbidly obese and non-obese patients – A prospective, parallel group, open-labeled, controlled, phase IV, single center clinical trial. Contemp Clin Trials Commun 15: 100375 (2019).
[9] S.M. Bhavnani, C.M. Rubino, J.P. Hammel et al. Pharmacological and patient-specific response determinants in patients with hospital-acquired pneumonia treated with tigecycline. Antimicrob Agents Chemother 56: 1065–1072 (2012).
[10] The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 12.0, 2022. https://www.eucast.org/clinical_breakpoints/. Accessed 02 Feb 2022.
Reference: PAGE 30 (2022) Abstr 10196 [www.page-meeting.org/?abstract=10196]
Poster: Drug/Disease Modelling - Infection