Population pharmacokinetic of linezolid in inpatients
Thu Thuy Nguyen (1), Laurent Massias (2), Gilles Defrance (3), Nadège Bourgeois-Nicolaos (3,4), Xavier Duval (5), France Mentré (1), Antoine Andremont (6,7) and the Linezolid study group
(1) UMR738 INSERM – Université Paris Diderot, Paris, France; (2) Service de Pharmacie Clinique et des Biomatériaux, Hôpital Bichat, AP-HP, Paris, France; (3) EA4065 UFR des Sciences Pharmaceutiques et Biologiques – Université Paris Descartes, Paris, France; (4) Laboratoire de Bactériologie-Hygiène, Hôpital Béclère, AP-HP, Clamart, France; (5) CIC, Hôpital Bichat, AP-HP, Paris, France; (6) EA 3964 Univertsité Paris Diderot, Paris, France; (7) Laboratoire de Bactériologie, Hôpital Bichat, AP-HP, Paris, France
Objectives: Linezolid is the first antibiotic of a new class of antimicrobial agents, the oxazolidinones, to be approved for clinical use in United States in 2000 and in Europe in 2002. It is active against gram-positive bacteria. We performed a prospective trial to study the impact of linezolid on human commensal flora in inpatients. A pharmacokinetic (PK) substudy was performed. The objective of the present work is to characterize linezolid PK in inpatients using a population approach.
Methods: 28 inpatients treated by linezolid for the first time were enrolled in the trial. Linezolid was administrated orally (17 patients) or intravenously (8 patients) with an identical dose of 600 mg twice a day. Two patients were switched from intravenous (IV) to oral administration before day 7 (D7) and 1 patients after D7. At D7, blood samples were collected before dosing, 1.5, 4 and 8 hr after dosing. Linezolid concentrations were assayed by high performance liquid chromatographic method. The relay IV/oral before D7 was taken into account in the PK modelling. We described the population PK of linezolid by a model combining the two administration modes, using MLXTRAN in MONOLIX 3.1 [1]. We first performed an analysis without covariate. We fixed the absorption rate constant (ka) to 2.7 [2] and tested if the biodisponibility (F) is equal to 1 using likelihood ratio test. The SAEM algorithm [3] in MONOLIX was used to estimate population parameters. We then also performed an analysis with covariates (height, weight, age and sex) using forward selection.
Results: A one compartment model with first order linear elimination and with first order absorption for oral administration adequately described concentrations for all patients. F was not significantly different from 1 [4], and was consequently fixed to 1 in the chosen model. We found significant effects of weight (p=0.0013) and age (p=0.0026) on clearance (CL). When weight increased of 10kg from the mean weight, CL increased of 18.6%. When age increased of 10 years from the mean age, CL decreased of 11.1%. With inclusion of these covariate effects, the inter subject variability in CL decreased from 61.1% to 44.5%.
Conclusions: We described the population PK of linezolid by a model combining oral and IV administrations using MLXTRAN in MONOLIX 3.1. The 100% bioavailability of linezolid was confirmed in this study. We also pointed out the effect of inpatient weight and age on linezolid clearance.
References:
[1] http://www.monolix.org/.
[2] McGee, B., Dietze, R., Hadad, D.J., Molino, L. P., Maciel, E. L., Boom, W. H., Palaci, M., Johnson, J. L., Peloquin, C. A. (2009) Population pharmacokinetics of linezolid in adults with pulmonary tuberculosis, Antimicrobial Agents Chemotherapy, 53:3981-3984.
[3] Kuhn, E., Lavielle, M. (2005) Maximum likelihood estimation in nonlinear mixed effects model, Computational Statistics and Data Analysis, 49:1020-1038.
[4] Welshman, I.R., Sisson, T.A., Jungbluth, G.L., Stalker, D.J., Hopkins, N.K. (2001) Linezolid absolute bioavailability and the effect of food on oral bioavailability. Biopharmaceutics and Drug Disposition, 22:91-97.
