Is a pooled population pharmacokinetic model predictive of plasma and microdialysate pharmacokinetics of linezolid in obese and non-obese patients?
Ehmann L. (1,2), Simon P. (3), Petroff D. (4), Minichmayr I.K. (1,2), Burau D. (1), Zeitlinger M. (5), Dorn C. (6), Huisinga W. (7), Wrigge H. (3), Kloft C. (1)
(1) Dept. of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany, (2) and Graduate Research Training program PharMetrX, Germany, (3) Dept. of Anaesthesiology and Intensive Care Medicine and Integrated Research and Treatment Center (IFB), Adiposity Diseases, University of Leipzig, Germany, (4) Clinical Trial Centre Leipzig, University of Leipzig, Germany, (5) Dept. of Clinical Pharmacology, Medical University of Vienna, Austria, (6) Dept. of Clinical Pharmacy, University of Regensburg, Germany, (7) Institute of Mathematics, Universitaet Potsdam, Germany
Objectives: Linezolid (LZD) is an oxazolidinone antibiotic exhibiting wide activity against gram-positive pathogens. Antibiotic concentrations at the site of infection are crucial for treatment success and can be obtained by the microdialysis technique. This work aims at investigating the applicability of a pooled population pharmacokinetic (PK) model [1] to predict LZD plasma and microdialysis data of a new population of obese and non-obese patients.
Methods: The evaluation dataset originated from 15 obese (BMImedian=45 kg/m2) and 15 non-obese patients (BMImedian=24 kg/m2, ~2/3 cancer patients) treated with 600 mg LZD (30-min i.v.) for infection prophylaxis before abdominal surgery. Rich sampling was performed for 8 h in plasma (n=269) and via microdialysis in the interstitial space fluid of s.c. adipose tissue (n=322). Unbound plasma concentrations were determined by ultrafiltration (n=90). For external model evaluation, concentration-time profiles of obese and non-obese patients were predicted using PK parameters estimated based on an overweight diabetic (BMImedian=31 kg/m2) and a healthy population (BMImedian=23 kg/m2), respectively. The MAXEVAL=0 functionality in NONMEM® 7.3 was used for Bayesian estimation of individual PK parameters. Model adequacy was assessed by goodness-of-fit plots, visual predictive checks and calculation of prediction errors (PE).
Results: The external model evaluation showed that maximum LZD concentrations were less well captured than those measured in the elimination phase: Whereas total and unbound plasma concentrations were underpredicted (PEmedian of Ctotal_max obese/non-obese: ‑5.6%/-6.9%), an overprediction was observed for initial microdialysate concentrations especially in the obese population (PEmedian of C0‑90min obese/non-obese: 40%/28%), indicating slower tissue distribution in the patients of the evaluation dataset.
Conclusions: Although the overall model structure (2-CMT with nonlinear elimination) seemed adequate, the distribution processes did not seem satisfactorily captured. This might be caused by patient- and disease-specific differences in the populations underlying the original model building and model evaluation (e.g. regarding BMI, diabetes vs. non-diabetes, healthy volunteers vs. cancer patients). Next, the model will be further refined to adequately describe the PK of LZD in plasma and microdialysate and to ultimately assess the need of dose adjustments in the special population of obese patients.
References:
[1] Minichmayr IK, Schaeftlein A, Kuti JL, Zeitlinger M, Kloft C. Clinical Determinants of Target Non-Attainment of Linezolid in Plasma and Interstitial Space Fluid: A Pooled Population Pharmacokinetic Analysis with Focus on Critically Ill Patients. Clin. Pharmacokinet. (2016)
