Enrique BandÃn-Vilar (1,2,3), Laura GarcÃa-Quintanilla (1,2,3), Ana Castro-Balado (1,2,3), Irene Zarra-Ferro (1,2), Miguel Gonzalez-Barcia (1,2), Manuel Campos-Toimil (4); VÃctor Mangas-Sanjuan (5,6), Cristina Mondelo-Garcia (1,2), Anxo Fernández-Ferreiro (1,2)
(1) Pharmacy Department, University Clinical Hospital of Santiago de Compostela, Santiago de Compostela, Spain, (2) Clinical Pharmacology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain, (3) Department of Pharmacology, Pharmacy and Pharmaceutical Technology Department, Faculty of Pharmacy, University of Santiago de Compostela (USC), Santiago de Compostela, Spain, (4) Physiology and Pharmacology of Chronic Diseases (FIFAEC), Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Spain, (5) Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Valencia, Spain, (6) Interuniversity Research Institute for Molecular Recognition and Technological Development, Polytechnic University of Valencia - University of Valencia, Valencia, Spain.
Introduction: Linezolid is an oxazolidinone antibiotic used to treat serious infections caused by drug-resistant gram-positive bacteria. Different pharmacokinetic/pharmacodynamic (PK/PD) targets have been proposed: AUC0-24h/MIC = 80-120 and percentage of time above MIC (%T>MIC) greater than 85% [1]. As a linear relationship between Cmin and the area under the curve in 24 hours (AUC0-24h) has been described, a target therapeutic range of Cmin between 2-7 mg/L for steady-state linezolid has been proposed for treating gram-positive bacterial infections [2]. Nevertheless, large interindividual variability on linezolid exposure has been observed, especially in critically ill patients.
Objectives: The aims of this work were (i) to evaluate the correlation between Cmin and observed AUC in critically ill patients and (ii) to optimize the sampling strategy based on the AUC correlation for therapeutic drug monitoring
Methods: An intensive sampling scheme of 8 points (Ctrough, 0.5, 1, 2, 3, 6, 10, 12h) was performed in 9 critically ill patients who received at least four doses of linezolid (steady-state conditions). Non-compartmental analysis allowed to calculate the AUC using the library NonCompart in R Studio. The correlation between Cmin and AUC in critically ill patients was performed through a linear regression analysis.
Subsequently, a previously published population pharmacokinetic model performed in critically ill patients [3] was implemented in NONMEM to estimate individual PK parameters. Individual AUC values were estimated at two different conditions: (i) using one sample point (Cmin), or (ii) two sample points (Cmin, 0.5). The Bayesian prediction was conducted using MAXEVAL=0. Model-predicted AUC was compared with the observed AUC using a linear regression analysis. Clinical evaluation of the current dosing schedules was evaluated using the uncertainty on individual clearance estimates from NONMEM using one and two samples vs intensive sampling scheme.
Results: NCA average (range) values of Cmin and AUC0-24h were 2.3 (0.03-10.9) mg/L and 160.6 (34.96-530.62) mg·h/L using intensive sampling strategy. Only 3 out of 9 patients had Cmin concentration within the desired range (2-7 mg/L). Good correlation between Cmin and AUC0-24h was observed (R = 0.9855). The external evaluation of the two-compartment PK model was demonstrated since the range of CL, V1, Q, and V2 (6.3 L/h, 12.2 L, 71.7 L/h and 29 L/h) were similar as the population values. Individual creatinine clearance values (mean 86.3, range 35.5-210.1 ml/min) were incorporated into the population PK model. Model-predicted AUC using one and two sample point showed good correlation with the AUC (R = 0.9884 and R = 0.9938, respectively) vs AUC from NCA. The limited-sampling strategy under-estimates by 38% and 20% when one and two sample points were considered, respectively.
Conclusions: Therapeutic drug monitoring of linezolid using the Cmin as a surrogate marker of the AUC might lead to under and overestimation of linezolid exposure in critically ill patients as high interindividual variability was observed. Model-predicted AUC using a peak and trough sampling schema showed the best correlation with observed AUC and improved the prediction of individual AUC, which could be a useful tool to improve the probability of PK/PD target attainment in this group of patients.
References:
[1] Rayner CR, Forrest A, Meagher AK, Birmingham MC, Schentag JJ. Clinical pharmacodynamics of linezolid in seriously ill patients treated in a compassionate use programme. Clin Pharmacokinet. 2003;42(15):1411–23.
[2] Abdul-Aziz MH, Alffenaar J-WC, Bassetti M, Bracht H, Dimopoulos G, Marriott D, et al. Antimicrobial therapeutic drug monitoring in critically ill adult patients: a Position Paper. Intensive Care Med. 2020 Jun;46(6):1127–53.
[3] Soraluce A, Barrasa H, Asín-Prieto E, Sánchez-Izquierdo JÁ, Maynar J, Isla A, et al. Novel Population Pharmacokinetic Model for Linezolid in Critically Ill Patients and Evaluation of the Adequacy of the Current Dosing Recommendation. Pharmaceutics. 2020 Jan 9;12(1).
Reference: PAGE 30 (2022) Abstr 10235 [www.page-meeting.org/?abstract=10235]
Poster: Drug/Disease Modelling - Infection