Summary:
INTRODUCTION
Epilepsy requires long-term and often lifelong treatment. Consequently, long-term antiepileptic treatment could result in adverse effects, and several studies have already shown that anti-epileptic drugs affect cholesterol and lipoprotein levels in the blood. This has led to the need to add long-term anti-epileptics, low-fat diets and / or statin administration, if necessary, even if the precise blood cholesterol values are unknown before and during treatment. The improved clinical picture of epileptic patients with epilepsy during statin therapy, appear to confirm the findings of previous studies that statins, in the context of their pleiotropic effects exhibit anti-inflammatory, anticonvulsant, anti-stimulatory and neuroprotective effects. Taking this into account, the interaction between the anti-convulsant drug, levetiracetam, and the statin, atorvastatin, a combination not yet been studied at a clinical level, became the topic mof the present postgraduate dissertation.
PURPOSE OF THE STUDY
The purpose of this monocentric observational study was to investigate the effect of the statin,atorvastatin, on the clinical profile and anticonvulsant drug levels of patients undergoing treatment with levetiracetam, as well asto find an optimal pharmacokinetic model, to describe the concentration of levetiracetam in the plasma of stabilized epileptic patients, versus x using population pharmacokinetic analysis.
METHODOLOGY
For the purposes of the present, monocentric prospective observation study, medical and pharmaceutical data of epileptic patients were collected from the outpatient Neurosurgery Unit and the outpatient Hyperlipidemia Clinic of the Evangelismos Hospital in Athens.
The data collected from the study patients included demographic and clinical data, such as age, weight, height, type of epilepsy, number of epileptic seizures to date-, seizure frequency, duration of seizures, maximal period without seizures, when the epilepsy diagnosis was made, magnetic resonance imaging findings and the genetic predisposition for high cholesterol. Also, laboratory data relating to dyslipidemia i.e. cholesterol (CHOL), triglycerides (TRIGL), HDL and LDL levels, were obtained from blood samples collected from each study patient prior to the administration of antilipidemic treatment (N=6) and one month after stabilization of atorvastatin treatment (N=2), followed by statistical treatment for the purpose the extraction of statistically significant conclusions.
In addition, levetiracetam blood levels were measured atat time 0 h, +2h, +5h, prior to receiving atorvastatin and one month later. Levetiracetam plasma concentrations were determined, by high performance-HPLC liquid chromatographic analysis.
Finally, a population pharmacokinetic analysis of the data was performed using a non-linear mixed effects model.
RESULTS
After statistical analysis of the study results, using graphs and descriptive methods of statistical analysis performed with statistical software SPSS for Windows, the following results were obtained:
All participating patients with epilepsy who received antiepileptic drug therapy, that included levetiracetam, showed elevated levels of cholesterol (CHOL), triglycerides (TRIGL), HDL and LDL, before initiating treatment with atorvastatin.
After taking atorvastatin for one month, two patients showed an improved clinical profile of epilepsy, with respect to the number of seizures to date, seizure frequency, seizure duration, maximal period without seizures.
In addition, the highest levetiracetam plasma concentrations were noted 2 hours after receiving this drug either before or after taking atorvastatin. Focusing only on atorvastatin-treated patients, thelevetiracetam-plasma levels, showed no specific trend, as they were found to be higher in the one patient and lower in the other compared to corresponding concentrations prior to taking atorvastatin.
The population pharmacokinetic analysis of the stabilized epileptic patients taking levetiracetam, found that the best structural model for levetiracetam is mono-compartmental, while both clearance and absorption follow first-order kinetics and the model that best describes the remaining variability appears to be the analog model. Significant covariance appeared to be allometric to GFR / 100, and significant covariance was noted between the volume of distribution and clearance, ka = 0.616 h-1, Vd / F = 34.7 L, CL / F = 3.26 L / h
DISCUSSION-CONCLUSIONS
The results of the study showed that long-term anticonvulsant treatment affected the lipid profile of patients, by increasing total cholesterol (CHOL), triglyceride (TRIGL), HDL and LDL cholesterol blood levels.
The improved clinical profile of epilepsy noted in those patients on atorvastatin therapy, in terms of the number of epileptic seizures to date, the frequency of seizures, the duration of seizures and the maximum period without seizures, indicate that statins may have a positive effect on epilepsy. Apart from their antilipidemic action, statins also exhibit pleiotropic effects includinganti-inflammatory, anticonvulsant and / or anti-stimulatory and/or neuroprotective action.
With respect to levetiracetam plasma levels in the small sample of study patients, it appears that, like other antiepileptics, plasma levels either increase or decrease when co-administered with statins.
Using the plasma data from the small sample of stabilized epileptic patients taking levetiracetam, a simple pharmacokinetic model was found. The application of pharmacokinetic and pharmacodynamic models may significantly facilitate the individualization of pharmaceutical dosage regimens, especially in epileptic patients. Thus, further investigation is required in a larger sample of patients.
