Khalid Iqbal (1), Beatrix Wulkersdorfer (2), Markus Zeitlinger (2), Sebastian G. Wicha (1)
(1) Department of Clinical Pharmacy, Institute of Pharmacy, Bundestraße 45, University of Hamburg, Germany (2) Medical University of Vienna, Vienna General Hospital (AKH), Department of Clinical Pharmacology, Währinger Gürtel 18-20, 1090 Vienna, Austria
Objectives: Tedizolid is a new oxazolidinone antibiotic with antimicrobial activity against multidrug-resistant Gram-positive bacteria. Recent preclinical studies have shown immune modulatory effects of tedizolid via alteration of proinflammatory cytokine production [1] which potentially can affect coagulation and subsequent tedizolid protein binding. A pharmacokinetic study of tedizolid was performed in a lipopolysaccharide (LPS) induced inflammatory human model to provide insight into the tedizolid induced immune modulation, potential alteration in protein binding and associated changes in plasma and tissue pharmacokinetics (PK). The aim of the current study was to describe the plasma pharmacokinetics of tedizolid in healthy individuals, and explore the impact of LPS induced inflammation on tedizolid pharmacokinetics using a pharmacometric approach.
Methods: A total of fourteen healthy male volunteers received once daily oral dosing of 200 mg tedizolid for three days followed by intravenous once daily dosing of 200 mg tedizolid at days 4, 5 and 6. For the LPS challenge, a bolus dose of 2 ng/kg LPS was administered over a period of 1-2 min on day 6 before the tedizolid dose. Plasma (total and unbound) samples were collected on day 5 and 6 at prespecified time points while a trough plasma (total) sample was taken on day 4. The impact of LPS as a potential covariate on pharmacokinetic and/or variability parameter was explored. Numerical and graphical model diagnostic criteria (goodness of fit plots and visual predictive checks (VPC’s)) were used to guide model building. The parameter uncertainty was determined using the LLP-SIR method [2] to guide parameter uncertainty in small-n studies. NONMEM® 7.4 was used for all estimation and simulation tasks.
Results: A two compartment model best described the plasma PK of tedizolid. The estimated clearance (CL) was 9.53 L/h (interindividual variability, IIV: 17.8 %CV), central volume of distribution (V1) was 42.2 L (IIV: 30.6 %CV), intercompartmental clearance (Q) was 71.2 L/h and peripheral volume of distribution (V2) was 74.4 L (IIV: 18.5 %CV). An inter-occasion variability on V1 (31.3 %CV) significantly improved the model fit (∆OFV of -63.34). The LPS dose was neither a covariate for population parameters (applied as a covariate, ∆OFV of -1.32) nor superior to explain variability (applied as one occasion (day 6), ∆OFV of -38.56) as compared to inter-occasion variability (∆OFV of -63.34). The fraction unbound was estimated to 20.8% (IIV: 6.6 %CV).
Conclusions: A two-compartment model successfully described the plasma pharmacokinetics of tedizolid. The LPS administration did not significantly alter the PK of tedizolid. The CL and tedizolid fraction unbound values were in the range of already published values of 9.5 L/h and 10-30%, respectively [3, 4]. In the next step, the developed model will be linked to tedizolid tissue concentration data sampled through microdialysis to develop an integrated approach for exploring the LPS effect on tedizolid tissue pharmacokinetics.
References:
[1] Kaku N, Morinaga Y, Takeda K, Kosai K, Uno N, Hasegawa H, Miyazaki T, Izumikawa K, Mukae H, Yanagihara K. Antimicrobial and immunomodulatory effects of tedizolid against methicillin-resistant Staphylococcus aureus in a murine model of hematogenous pulmonary infection. Int J Med Microbiol. (2016); 306(6):421-8
[2] Broeker A, Wicha S.G. Parameter uncertainty in small datasets – evaluation approaches at their limit. PAGE 28 (2019) Abstr 8981 [www.page-meeting.org/?abstract=8981]
[3] Prokocimer P, Bien P, Surber J, Mehra P, DeAnda C, Bulitta J. B, Corey G. R. Phase 2, randomized, double-blind, dose-ranging study evaluating the safety, tolerability, population pharmacokinetics, and efficacy of oral torezolid phosphate in patients with complicated skin and skin structure infections. Antimicrob Agents Chemother. (2011); 55(2):583–592
[4] https://www.ema.europa.eu/en/documents/product-information/sivextro-epar-product-information_en.pdf
Reference: PAGE () Abstr 9326 [www.page-meeting.org/?abstract=9326]
Poster: Drug/Disease Modelling - Infection