ИСТИНА

Antiepileptic therapy is associated with a number of objective difficulties. Anticonvulsants has some peculiar traits, for example, low therapeutic index, chronic reception, variability of pharmacokinetics parameters, drug-drug interactions in polytherapy, pronounced side effects etc. One of the most pressing problems of the epileptology is the widespread phenomenon of the patient's resistance to anticonvulsants therapy. The main way to overcome the above problems seems to be widespread adoption of therapeutic drug monitoring approaches (TDM). Thus, since 2010th we established TDM service in The Research Center of Neurology RAMS on the basis of the laboratory of clinical pharmacokinetics. Laboratory to date equipped with the most modern analytical devises. For the quantitative determination of drugs in body fluids of patients we employ liquid chromatograph with UV-Vis detector Beckman Coulter System Gold, gas chromatography-mass spectrometer Agilent 5975/6850, HPLC-mass-spectrometer LCQ Fleet. In laboratory we perform TDM of a wide range of anticonvulsants. We investigate the pharmacokinetics of the drugs such as levetiracetam, topiramate, carbamazepine, lamotrigine, valproic acid, and also studied the blood levels of carbamazepine’s metabolite - carbamazepine -10,11- epoxide. By 2014, the total number of patients receiving antiepileptic therapy accompanied TDM in The Research Center of Neurology exceeded the number of 300 people. The concentrations data are stored in the TDM database and processed using pharmacokinetic program MM-USCPACK that was gently donated by professor Jelliffe. This program allow us to determine individual pharmacokinetic characteristics of patients and identify individual metabolic characteristics to differentiate fast and slow metabolizers for the making targeted correction of pharmacotherapy. The personal data about metabolic peculiarities of the particular patient in respect of certain drugs makes possible to take an informed decision to change the medication in case of loss of remission. In our laboratory, we conduct the investigation to develop non-invasive TDM methods based on drug content estimation in the patients saliva for the purpose of anticonvulsants pharmacokinetic study. There is a strong opinion that the TDM is purely utilitarian and routine procedure. However, it is not so, because right now, we are witnessing the transformation of TDM to independent discipline of clinical pharmacology. As is known, the information on the pharmacokinetics obtained during registration trials are not exhaustive. For example, studies of drug-drug interactions are carried out only in the small number of drugs. Therefore, we conducted a post hoc investigation of the influence of different types co-medication on lamotrigine concentration in plasma and saliva of patients with epilepsy. It has been found that the pharmacological effects caused polytherapy make unidirectional changes in lamotrigine concentrations as in plasma and saliva occurs. It has been found that the combination with valproate (VPA) enhances the stationary concentration of lamotrigine, and the combined use of lamotrigine with inducers of microsomal liver enzymes significantly reduces the concentration of lamotrigine as in plasma and saliva. In the blood plasma concentration of lamotrigine VPA increases by 35 %, in contrast inductors reduces the concentration of lamotrigine, 46%. At the same time, increases of the of saliva lamotrigine concentrations by VPA was approximately 25%, inducers reduce the concentration of salivary lamotrigine by more than 70 %. Interpretation of the detected differences in the intensity of polytherapy effects in saliva and plasma may require additional studies to evaluate the parameters of lamotrigine binding to albumine.