Idoia Bilbao (1,3), Helena Barrasa (2), María Ángeles Solinís (3), Ana Alarcia (3), Alicia Rodríguez (3), Goiatz Balziskueta (2), Javier Maynar (2), Arantxa Isla (3)
(1) Cruces University Hospital, Spain, (2) University Hospital Araba, Spain, (3) Faculty of Pharmacy, Lascary research Center, Spain
Introduction: Levetiracetam (LEV) is a broad spectrum antiepileptic drug with proven effective in treating multiple seizure types, status epilepticus and in seizure prophylaxis after a neurologic injury. The current reference range for LEV is 12-46 mg/L although there is no clear correlation between LEV serum concentration and efficacy or tolerability. The favourable pharmacokinetics profile together with the absence of major drug interactions and broad therapeutic window makes generally unnecessary to routinely therapeutic drug monitoring. However, therapeutic drug monitoring may be indicated in certain circumstances where LEV clearance has been shown to be altered such as critically ill patient with augmented renal clearance (ARC) [1,2,3]. The ARC, defined as a 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 LEV, resulting in subtherapeutic concentrations and poorer clinical outcomes [4].
Objectives:
- Develop a population model of LEV pharmacokinetics from data obtained from critically ill patients with normal or augmented renal clearance.
- Determine if the recommended dosage regimens provide concentrations in the therapeutic range (12-46 mg/L)[1].
Methods: A prospective observational study was developed with patients from the Intensive Care Unit (ICU) of a tertiary hospital. Clinical and demographic and laboratory data were collected. LEV (500, 1000 or 1500 mg) was administered prophylactically to prevent seizures as a short 30-minute intravenous infusion. Six blood samples were collected at steady state at different times after dose (predose, at the end of the infusion, 1-2h, 3-5 h, 6-8 h and 12h). One urine sample was also collected during the 0-12h period to calculate the renal clearance of the drug. LEV concentrations were quantified by high performance liquid chromatography. PK analysis was performed using Nonlinear mixed-effects modelling (NONMEM 7.4). LEV PK population parameters, were estimated using first-order conditional estimation method with interaction. The model selection was based on the decrease in objective function value (OFV), the relative standard errors (RSE) of the parameters, and the goodness-of-fit (GOF) plots. Residual error was shaped, and inter-individual variability (IIV) and possible covariance were also explored. Once the base model was selected, and in order to describe the IIV, the possible inclusion of covariates was studied. After selecting the final model, using the same dosing regimens administered to patients, 1,000 studies of 1,000 subjects with different weight (60, 75 and 100 kg) were simulated and the probability of being able to maintain trough concentrations above 12 mg/L and peak concentrations below 46 mg/L was calculated.
Results: A total of 23 critically ill patients (8 women) were included in the study and 132 plasma samples were analysed. Three of them received 1,500mg q12h, other 3 patients, 1,000mg q12 h and 17, 500 mg q12h. LEV plasma concentrations were best described by a two-compartment model. IIV was included for V1, V2 and CL. Variability was modelled using an exponential model for IIV and a proportional error model for the residual variability was found to be the most suitable. The inclusion of weight as covariate on V1 and V2 resulted in a significant reduction OFV and a decrease in IIV on V1 and V2. Mean V1, V2 and CL were 0,26L/kg, 0.45L/kg and 4,33L/h, respectively, and the mean renal clearance estimated from urinary data was 62%. The (IIV) for V1, and was estimated to be 46%, while for CL it was 35%. Almost all patients (21 out of 23) had trough concentrations below 12 mg/L. Montecarlo simulations confirmed that the probability to attain this target is near 10% with 500mg q12h in short perfusions. Higher doses and longer infusion times provided higher probabilities to attain LEV concentrations above 12 mg/L. However, with some dosing regimens the risk to obtain drug concentrations higher than 46 mg/L increased. The best results were obtained with the simulation of 1000mg q8h in 3h infusion.
Conclusions: The administration of LEV in 30-minute short infusions every 12h cannot reach trough drug concentrations above the Cmin value recommended by ILAE (12 mg/L) regardless the dose (500, 1000 or 1500 mg). The administration in prolonged infusions (3h) could be an adequate alternative.
References:
[1] 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.
[2] Sourbron J, Chan H, Wammes-van der Heijdenb EA, Klarenbeek P, Wijnen bfm, de Haan GJ, et al. Review on the relevance of therapeutic drug monitoring of levetiracetam. Seizure. 2018;62:131-135
[3] Jarvie D, Mahmoud SH. Therapeutic Drug Monitoring of Levetiracetam in Select Populations. J Pharm Pharm Sci. 2018;21(1s):149s-176s.
[4] 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.
Reference: PAGE () Abstr 9482 [www.page-meeting.org/?abstract=9482]
Poster: Clinical Applications