A Microdialysate-based Integrated Model with Nonlinear Elimination for Determining Plasma and Tissue Pharmacokinetics of Linezolid in Four Distinct Populations
I.K. Minichmayr (1,2), A. Schaeftlein (1,2), M. Zeitlinger (3), C. Kloft (1)
(1) Dept. of Clinical Pharmacy and Biochemistry, Freie Universitaet Berlin, Germany, (2) and Graduate Research Training program PharMetrX, Germany, (3) Dept. of Clinical Pharmacology, Medical University Vienna, Austria
Objectives: Linezolid (LZD) provides a valuable treatment option in a wide range of infections across variant patient groups. Sufficient drug concentrations at the target site of infection form a key prerequisite for treatment success and can be assessed e.g. by means of microdialysis. The objective of the present study was to build a population pharmacokinetic (PK) model accommodating both an integrated model for microdialysis data [1] and a concentration- and time-dependent nonlinear elimination model [2] for the simultaneous description of LZD concentrations in plasma and peripheral tissues of four heterogeneous populations.
Methods: In total, 52 individuals (healthy volunteers (n=10, [2]) and patients with sepsis (n=24, [2]), diabetes-related soft-tissue infections (n=10, [3]) or cystic fibrosis (n=8, [4])) from three different studies were pooled for analysis. Modelling of plasma (n=1635), ultrafiltrate (n=1182) and microdialysis (s.c.: n=1468, i.m.: n=1127) concentrations obtained after single and multiple dosing of 600 mg LZD was conducted in NONMEM 7.2.
Results: Both total LZD concentrations and unbound concentrations in plasma, interstitial s.c. and i.m. tissue fluid were adequately described by a two-compartment (CMT) model. Due to rapid tissue penetration of LZD the measurements of all matrices were assigned to the central CMT. In order to distinguish between the matrices, scaling factors (SF) related to plasma were introduced, suggesting highest concentrations in plasma followed by ultrafiltrate (SF 0.88), i.m. (SF 0.86) and s.c. interstitial concentrations (SF 0.81). Interindividual variability was included for ten model parameters and tendentially high (%CV 3.8-90). Overall, the model yielded plausible estimates (V=44.7 L, initial CL 8.17 L/h, maximal decrease to 5.23 L/h) with overall good precision (0.9-33% RSE).
Conclusions: A complex PK model incorporating both a microdialysate-based integrated model and a nonlinear concentration- and time-dependent elimination model was successfully developed and able to simultaneously describe plasma, ultrafiltrate, interstitial s.c. and i.m. concentrations after both single and multiple applications of LZD. In order to account for differences between healthy volunteers and the distinct patient groups and thereby decrease the remarkable unexplained variability in the estimated model parameters, a covariate model needs to be established.
References:
[1] Tunblad et al. Pharm Res 21:1698 (2004).
[2] Plock et al. Drug Metab Dispos 35:1816 (2007).
[3] Badr Eslam et al. Abstract presented at the 23rd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), Berlin (2013).
[4] Keel et al. Antimicrob Agents Chemother 55:3393 (2011).