A. Soraluce, H. Barrasa, E. Asín, E. Irazusta, A. Martín-López, S. Castaño Ávila, G. Balziskueta, F. Fonseca, J. Maynar, J.A. Sánchez-Izquierdo, F. Muñoyerro, A. Rodríguez-Oviedo, A. Rodríguez-Gascón, A. Isla
University of The Basque Country
Objectives: The main goal of this study was to build a population PK model for the antibiotic linezolid (LZD) in Intensive Care Unit (ICU) patients, treated or not with Continuous Renal Replacement Therapies (CRRT). Another aim was to apply PK/PD analysis with Monte Carlo simulation to predict safety and efficacy profiles.
Materials and methods: 45 adult ICU patients were included in the study, 26 of whom underwent CRRT. All patients received a 30 min infusion of linezolid (600 mg) every 12 hours. Blood and ultrafiltrate samples (when necessary) were collected during dosage interval (DI) and their LZD concentration was determined by a previously validated HPLC technique.
A population PK model was developed using NONMEM 7.2. Once base model was selected, covariates related to demographic and physiopathological aspects were considered in order to explain inter-individual variability (IIV). Stepwise covariate model building (SCM) was used. Parameter precision was evaluated by performing a 2000 dataset bootstrap.
In order to predict the probability of target attainment (PTA) for different DI (12 and 8 h), studies of 5000 subjects with several CLCR values were simulated using parameters obtained from the PK model. The target was attained when AUC24/MIC was greater than 100 [1]. Moreover, LZD´s security profile was evaluated, taking into consideration the percentage of simulated subjects that would reach toxic plasma concentrations (AUC24 >400 mg*h/L or Cmin >10 mg/L) [2]. Simulations were performed using mlxR package of R program.
Results: LZD plasma concentrations were best described by a 2 compartment model. IIV was included using an exponential model in CL (56.8%) and V1 (78.1%). CL was set as the sum of a non-renal (Θ =2.8 L/h) and a renal (Θ =3.68 L/h) component, which was influenced by CLCR. In those patients with CRRT, extracorporeal clearance was included in CL as a fixed value for each individual.
PK/PD analysis showed high PTA (> 90%) for MIC values equal or lower than 0.25 mg/L. When simulations were run for a dosage of 600 mg every 8 h, no improvement was achieved, while higher probabilities of drug overexposure were obtained [3].
Conclusions: The PK/PD analysis confirmed that LZD is not able to cover infections by pathogens for which the MIC values are higher than 0.25 mg/L, which is far away from the established clinical breakpoint (2 mg/L) [4], even when increasing the dosage to 600 mg every 8 h.
References:
[1] Pea F, Viale P, Cojutti P et al. Therapeutic drugmonitoring may improve safety outcomes of long-term treatment with linezolid in adult patients. J Antimicrob Chemother. 2012; 67:2034–42.
[2] Cattaneoa D, Orlandob G, Cozzia V, et al. Linezolid plasma concentrations and occurrence of drug-related haematological toxicity in patients with Gram-positive infections. Int J Antimicrob Agents. 2013; 41:586-589.
[3] Gerson SL, Kaplan SL, Bruss JB, et.al. Hematologic Effects of Linezolid: Summary of Clinical Experience. Antimicrob Agents Chemother. 2002 Aug; 46(8): 2723–2726. doi: 10.1128/AAC.46.8.2723-2726.2002.
[4] Asin E, Isla A, Canut A, Rodriguez-Gascón A et al. Comparison of antimicrobial pharmacokinetic/pharmacodynamic breakpoints with EUCAST and CLSI clinical breakpoints for Gram-positive bacteria. Int J Antimicrob Agents. 2012; 40:313-322.
Reference: PAGE 25 (2016) Abstr 5791 [www.page-meeting.org/?abstract=5791]
Poster: Drug/Disease modeling - Infection