Idoia Bilbao-Meseguer 1,2, Ana Alarcia 2, Helena Barrasa 3, Eduardo Asín 4,5, Alicia Rodríguez-Gascón 2, Javier Maynar 3, José Ángel Sánchez-Izquierdo 6, Goiatz Balziskueta 3, Maria Sánchez-Bayton Griffith 6, Nerea Quilez Trasobares 6, María Ángeles Solinís 2*, Arantxa Isla 2*.
1 Department of Pharmacy, Cruces University Hospital. Barakaldo, Spain. 2 Pharmacokinetic, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, Centro de investigación Lascaray ikergunea, University of the Basque Country UPV/EHU. Vitoria-Gasteiz, Spain; Bioaraba, Vitoria-Gasteiz, Spain. 3 Bioaraba, Intensive Care Unit, Vitoria-Gasteiz, Spain; Osakidetza Basque Health Service, Araba University Hospital, Intensive Care Unit. Vitoria-Gasteiz, Spain. 4 Inserm U1070: Pharmacologie des anti-infectieux, Pôle Biologie Santé, Université de Poitiers, Poitiers, France. 5Present address: Pharma Mar S.A. Colmenar Viejo, Spain. 6 Intensive Care Unit, Doce de Octubre Hospital. Madrid, Spain.
Objectives: Levetiracetam is a broad-spectrum antiepileptic drug commonly used in seizure treatment and prophylaxis in the intensive care units (ICUs). Augmented renal clearance (ARC), defined as a creatinine clearance (CrCl) >130 mL/min/1.73 m2, is present in 20–65% of critically ill patients. It could lead to faster elimination of renally excreted drugs, such as levetiracetam, potentially resulting in subtherapeutic concentrations and poorer clinical outcomes [1-3]. The objective of this study is to evaluate the adequacy of levetiracetam dosing in patients with normal or ARC admitted to the ICU by population modelling and simulation.
Methods: A multicentre prospective study including critically ill patients with urinary CrCl > 50 mL/min and treated with levetiracetam was developed. Each patient received 500, 1,000 or 1,500 mg of levetiracetam every 12 h by 30 minute intravenous infusion. Six blood samples per patient were drawn at previously defined times and drug concentration was quantified using a validated HPLC-UV technique. Nonlinear mixed-effects modelling was implemented by NONMEM 7.4, using first-order conditional estimation method with interaction (FOCE+I). The model selection was based on biological plausibility, the decrease in objective function value (OFV), the relative standard errors (RSE) of the parameters, and the goodness-of-fit plots. Demographic and clinical variables were studied as potential covariates. The parameter precision was evaluated by running a 2,000 sample bootstrap (PsN v.4.8) and model performance was assessed with a prediction-corrected visual predictive check (pcVPC). Finally, simulations were performed to predict levetiracetam plasma minimum concentrations (Cmin) under various dosing regimens and to estimate the probability of target attainment (Cmin between 12 and 46 mg/L) [4].
Results: Twenty-seven critically ill patients were included. Levetiracetam plasma concentrations were best described by a two-compartment model. The mean parameter estimates and RSE (%) were: clearance (CL) 3.5 L/h (9%), central volume of distribution (V1) 20.7 L (18%), intercompartmental clearance 31.9 L/h (22%), peripheral volume of distribution 33.5 L (13%), interindividual variability estimates were, for the CL, 32.7% (21%) and, for V1, 56.1% (29%). The CrCl showed significant influence over CL. The bootstrap demonstrated good precision in the parameter estimates and pcVPC evidenced that the model correctly characterizes the temporal evolution of the plasma concentrations of levetiracetam. Simulations showed that the administration of at least 500 mg every 8 h or 1,000 mg every 12 h are needed in patients with normal renal function. Higher doses and shorter dosing interval are needed in patients with ARC.
Conclusions: Critically ill patients with normal or ARC treated with levetiracetam are at high risk of being underdosed. Even the maximum dose approved in the summary of product characteristics (1,500 mg every 12 h) seems insufficient in the presence of ARC. Further studies are necessary to determine effective and safe dose regimens in ARC patients.
References:
[1] Bilbao-Meseguer I, Rodríguez-Gascón A, Barrasa H, Isla A, Solinis MA. Augmented Renal Clearance in Critically Ill Patients: A Systematic Review. Clin Pharmacokinet. 2018;57(9):1107-1121.
[2] Cook AM, Hatton-Kolpek J. Augmented Renal Clearance. Pharmacotherapy. 2019; 39(3): 346-354.
[3] Mahmoud SH, Shen C. Augmented Renal Clearance in Critical Illness: An Important Consideration in Drug Dosing. Pharmaceutics. 2017 Sep 16;9(3):36.
[4] Patsalos PN, Berry DJ, Bourgeois BFD, Cloyd JC, Glauser TA, Johannessen SI, et al. Antiepileptic drug-best practice guidelines for therapeutic drug monitoring, ILAE commission on therapeutic strategies. Epilepsia. 2008; 49:1239-76.
Reference: PAGE 29 (2021) Abstr 9750 [www.page-meeting.org/?abstract=9750]
Poster: Clinical Applications