Anne Ravix (1), Pascal André (2), Jan Novy (3), Chantal Csajka (1,4,5,*), Monia Guidi (1,2,*)
(1) Center for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland (2) Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland (3) Department of Clinical Neurosciences, Neurology Service, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. (4) Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, University of Lausanne, Geneva & Lausanne, Switzerland (5) School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland (*) Equal contribution
Objectives: Lacosamide is an antiepileptic drug prescribed intravenously or orally for the treatment of partial seizures with or without secondary generalization in patients older than 4 years as well as in status epilepticus. Lacosamide is excreted renally, 60% as metabolite and 40% unchanged. Therapeutic drug monitoring (TDM) may be performed for treatment management. The therapeutic target range remains debated. Three targets are commonly used in TDM: minimum concentrations (Cmin) between 3 and 10 mg/L (1, 2), average concentration (Cave) between 10 and 20 mg/L (3) and maximum concentrations (Cmax) between 10 and 20 mg/L (4, 5). The aim of this study was to investigate the most appropriate dosage regimen in the incisive treatment of status epilepticus and in the long-term treatment of epilepsy in order to achieve the targeted therapeutic range, using a population pharmacokinetic (popPK) approach.
Methods: This study retrospectively included patients older than 4 years with epilepsy followed by routine TDM at the Lausanne University Hospital. A popPK model was developed first on adult population by comparing different compartmental models and testing covariates considered biologically relevant (NONMEM). Allometric scaling of body weight on pharmacokinetic (PK) parameters allowed describing simultaneously the adult and pediatric populations. Creatinine clearance (CrCL) was estimated with Cockcroft-Gault formula for adults and modified Schwartz for children. Model based simulations including variability were performed on 1000 virtual patients to verify the adequacy of the recommended dosage regimens for the treatment of chronic epilepsy and status epilepticus, and to test alternative regimens. The adequacy of doses tested was quantified by calculating the percentage of patients below, within or above each therapeutic targets used in TDM.
Results: The population analysis was based on 130 lacosamide plasma concentrations from 63 adults and 24 from 10 children. Lacosamide was administered either by oral or intravenous routes, with a median maintenance dose of 200 mg (range: 25 mg, 400 mg) administered once to three times per day for adults and 100 mg (20 mg, 200 mg) twice daily for children. A one-compartment model, with first-order absorption and elimination, best described drug PK. As expected, oral lacosamide bioavailability was estimated at 100%. The base model popPK parameters estimates were a clearance (CL) of 1.5 L/h with an inter-individual variability (CV%) of 39%, a volume of distribution of 40.8 L and a first-order absorption of 2.1 h-1. Among the tested covariates, only CrCL was significantly associated with CL, with a 5.5% increase for a 10% increase in CrCL relative to the typical CrCL (i.e. 100 mL/min).
Simulations of the recommended dose of 400 mg/day divided into two doses for adults and children over 50 kg resulted in a trough concentration above the target range of 3-10 mg/L for more than 40% of patients with moderate renal impairment. The recommendation to decrease the dose by 25% for patients with severe renal impairment does not allow adequate Cmin target attainment in 56% of them. In contrast, for Cmax and Cave between 10 and 20 mg/L, the recommended doses seemed adequate. For these targets, only the dose recommended for patients with normal renal function could be increased to 600 mg/day. For children under 50 kg, the maximum recommended dose (i.e., 12 mg/kg/day for children under 20 kg, 10 mg/kg/day for 20-30 kg, and 8 mg/kg/day for 30-50 kg) was consistent with Cmax and Cave targets. However, if Cmin between 3 and 10 mg/L are targeted, lower doses are associate with a reduced risk of overdose. The results of the loading dose simulations support the use of a unique dose regardless of the patient’s renal function to achieve the desired concentration level. Similar doses were found for the Cmin and Cmax targets, with 450 mg for adults, 6 mg/kg for children over 20 kg and 7 mg/kg for children under 20 kg, while doses of 650 mg, 10 mg/kg and 11 mg/kg respectively seemed more appropriate for the Cave target.
Conclusions: This work allowed studying the adequacy of the recommended dosage regimens to achieve the desired therapeutic target in clinical settings and to propose more appropriate strategies. Further clinical studies are needed to verify the efficacy and toxicity of the identified regimens.
References:
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[2] Reimers A, Berg JA, Larsen Burns M, Brodtkorb E, Johannessen SI, Johannessen Landmark C. Reference ranges for antiepileptic drugs revisited: a practical approach to establish national guidelines. Drug Design, Development and Therapy. 2018;Volume 12:271-80.
[3] Patsalos PN, Spencer EP, Berry DJ. Therapeutic Drug Monitoring of Antiepileptic Drugs in Epilepsy: A 2018 Update. Therapeutic Drug Monitoring. 2018;40(5):526-48.
[4] Greenaway C, Ratnaraj N, Sander JW, Patsalos PN. A high-performance liquid chromatography assay to monitor the new antiepileptic drug lacosamide in patients with epilepsy. Ther Drug Monit. 2010;32(4):448-52.
[5] Greenaway C, Ratnaraj N, Sander JW, Patsalos PN. Saliva and serum lacosamide concentrations in patients with epilepsy. Epilepsia. 2010.
Reference: PAGE 30 (2022) Abstr 10027 [www.page-meeting.org/?abstract=10027]
Poster: Drug/Disease Modelling - CNS