Value of comparative studies of "real clinical practice" in modern cardiology. Position paper based on the expert council discussion dated 12/18/2020.

On December 18, 2020, an expert council was held with the participation of members of the Russian Society of Cardiology, the Eurasian Association of Ther-apists, the National Society for Atherothrombosis, the National Society for Evi-dence-Based Pharmacotherapy, and the Russian Heart Failure Society. The event was devoted to the discussion of the correct use of research data of "real clinical practice" in decision making.

[Age aspects of quality of life research in patients with epilepsy].

In spite of the fact that patients of advanced age are the fastest growing population of patients with epilepsy, there is no sufficient data on quality of life (QOL) questionnaires sensitivity in the elderly patients. The aim of this study was to evaluate correlations between QOLIE-31 and QOLIE-10 scores in the elderly and young patients with epilepsy before and after antiepileptic therapy optimization. Twenty-seven elderly (average age 65.36±3.88 years) and 30 young (average age 25.05±3.06 years) patients completed questionnaires QOLIE-31 and QOLIE-10 The analysis of QOL indicators was conducted at the following control points: 1) before the beginning or correction of antiepileptic therapy; 2) 6 months after the beginning of therapy or its optimization. In young patients after the beginning or optimization of therapy, the statistically significant negative correlation between the majority QOLIE-31 subscales and a total QOLIE-10 score, with the exception of the "Emotional well-being", was revealed. In the elderly patients, the positive correlations with the "Energy/fatigue" (r=0.46) and the "Medications effect" (r=0.20) subscales were noted. Considering the score estimation in QOLIE-31 and QOLIE-10 questionnaires, the revealed positive correlations could testify smaller sensitivity of questions in the brief version (QOLIE-10) in the elderly patients with epilepsy in comparison with young patients. According to the data received, the validity of QOLIE-10 appeared to be insufficient in the elderly patients, with the QOLIE-31 questionnaire being preferred. In young patients, the QOLIE-10 can be recommended as a screening QOL tool at the beginning of antiepileptic therapy, and later for estimation of AEDs efficiency.

Predictability of individualized dosage regimens of carbamazepine and valproate mono- and combination therapy.

WHAT IS KNOWN AND OBJECTIVE: Many investigators agree that appropriate rational utilization of therapeutic drug monitoring (TDM) with Bayesian feedback dosage adjustment facilitates epilepsy treatment with carbamazepine (CBZ) and/or valproate (VPA) by increasing the seizure control and safety, as well as by reducing treatment costs. In previous works we have developed and used in clinical practice population pharmacokinetic (PK) models of different dosage forms for VPA and post-induction CBZ behaviour, as well as for combined therapy with CBZ plus another 'old' antiepileptic drug (AED). An important step of external validation is to evaluate how well a procedure of Bayesian individualizing AED dosage regimens based on a proposed population PK model and sparse TDM data 'works', and how helpful it is in real practical clinical settings. The aim of this study was to evaluate the predictability of individualized dosage regimens for monotherapy with CBZ in the post-induction period or with VPA, as well as for CBZ and VPA given as combination therapy based on TDM data of epileptic patients and the earlier developed population models. METHODS: Four groups of TDM data were analysed using the USC*PACK software for PK/PD analysis: 556 predictions for adult epileptic patients on CBZ monotherapy, 662 predictions for VPA monotherapy, 402 predictions of CBZ serum levels and 430 predictions of VPA serum levels for adult epileptic patients on CBZ+VPA combination therapy. Statistical characteristics of the prediction errors (PE) and weighted PE were used to estimate bias and precision of predictions. Intraindividual and interoccasional variability of predictions were also estimated. RESULTS AND DISCUSSION: This study demonstrated that in most cases of CBZ and VPA monotherapy and combination therapy, predictions of future AED concentrations based on the earlier developed population PK models, TDM data and patient-specific maximum a posteriori probability Bayesian posterior parameter values provided clinically acceptable estimates. Statistical analysis of the residuals demonstrated that the distributions of residual and weighted residual were close to the normal distribution (Kolmogorov-Smirnov test, P > 0·05) and their mean values did not differ statistically significant from zero (no statistically significant bias, P > 0·05) for all groups of predictions. The observed decreased quality of predictions of VPA concentrations during VPA+CBZ combination therapy, especially when CBZ dosages were changed, might well be explained by their PK interactions. For all groups, in linear regression analysis, the observed trend of decreasing of the prediction quality over various future prediction time horizons was considered statistically significant (P < 0·05). Prediction of serum levels further in future was less precise than those closer to the present for a 1·5- to 3·5-year observation period. No bias in predictions was associated with the time horizons. WHAT IS NEW AND CONCLUSION: Our validation results suggest good predictive performance of the population models developed earlier, and quite acceptable predictions of future AED serum levels for individualized dosage regimens of CBZ and VPA therapy in real clinical settings.

Placebo responses in randomized trials of antiepileptic drugs.

This meta-analysis of published, randomized, controlled trials (RCTs) of antiepileptic drugs in adults with focal drug-resistant epilepsy was performed to estimate a mean placebo effect, to evaluate variability in placebo response rates, to investigate associations between placebo effect rates and study characteristics, and to determine whether there were changes in placebo response rates over recent years in RCTs (so-called "placebo drift"). One hundred ninety-eight potentially appropriate studies were identified after MEDLINE search and carefully reviewed. Twenty-seven RCTs (with 5662 randomized patients, including 1887 patients in placebo arms) were included in the meta-analysis. A random effects meta-analytic model estimated the pooled placebo response at 12.5% (95% CI: 10.03-14.94%). A statistically significant correlation between baseline median seizure frequency and placebo response rates was not observed. "Placebo drift" was not considered statistically significant.

Population pharmacokinetic modelling of carbamazepine in epileptic elderly patients: implications for dosage.

BACKGROUND: Proper use of antiepileptic drugs in the elderly involves knowledge of their pharmacokinetics to ensure a patient-specific balance between efficacy and toxicity. However, populations of epileptic patients on chronic carbamazepine (CBZ) therapy which have been studied have included data of relatively few elderly patients. AIMS: The aim of the present study was to evaluate the population pharmacokinetics of CBZ in elderly patients on chronic monotherapy. METHODS: We have used the non-parametric expectation maximization (NPEM) program in the USC*PACK collection of PC programs to estimate individual and population post-induction pharmacokinetics of CBZ in epileptic elderly patients who received chronic CBZ monotherapy. Age-related changes of CBZ population pharmacokinetics were evaluated from routine therapeutic drug monitoring (TDM) data of 37 elderly and 35 younger patients with epilepsy. As a 'historical control' we used previously published population modelling results from 99 young epileptic patients on chronic CBZ monotherapy. In that control group, TDM was performed in the same pharmacokinetic (PK) laboratory, using the same sampling strategy as in the present study, and the same PK population modelling software was used for data analysis. RESULTS AND CONCLUSIONS: A poor correlation was found between daily CBZ dose and serum concentrations in the elderly patients (r=0.2, P=0.25). Probably statistically significant difference in the median values of the CBZ metabolic rate constant (P<0.001) between elderly and relatively young epileptic patients was found. Our results showed that age-related influences in CBZ pharmacokinetics in elderly patients should be considered in the optimal planning of CBZ dosage regimens. Most elderly patients with epilepsy will usually need CBZ dosages lower than those based on the median population PK parameter values obtained from younger patients. The present population model is also uniquely well suited for the new 'multiple model' design of dosage regimens to hit target therapeutic goals with maximum precision.

Nonparametric population modeling of valproate pharmacokinetics in epileptic patients using routine serum monitoring data: implications for dosage.

Therapeutic drug monitoring (TDM) of valproate (VAL) is important in the optimization of its therapy. The aim of the present work was to evaluate the ability of TDM using model-based, goal-oriented Bayesian adaptive control for help in planning, monitoring, and adjusting individualized VAL dosing regimens. USC*PACK software and routine TDM data were used to estimate population and individual pharmacokinetics of two commercially available VAL formulations in epileptic adult and pediatric patients on chronic VAL monotherapy. The population parameter values found were in agreement with values reported earlier. A statistically significant (P < 0.001) difference in median values of the absorption rate constant was found between enteric-coated and sustained-release VAL formulations. In our patients (aged 0.25-53 years), VAL clearance declined with age until adult values were reached at about age 10. Because of the large interindividual variability in PK behavior, the median population parameter values gave poor predictions of the observed VAL serum concentrations. In contrast, the Bayesian individualized models gave good predictions for all subjects in all populations. The Bayesian posterior individualized PK models were based on the population models described here and where most patients had two (a peak and a trough) measured serum concentrations. Repeated consultations and adjusted dosage regimens with some patients allowed us to evaluate any possible influence of dose-dependent VAL clearance on the precision of total VAL concentration predictions based on TDM data and the proposed population models. These nonparametric expectation maximization (NPEM) population models thus provide a useful tool for planning an initial dosage regimen of VAL to achieve desired target peak and trough serum concentration goals, coupled with TDM soon thereafter, as a peak-trough pair of serum concentrations, and Bayesian fitting to individualize the PK model for each patient. The nonparametric PK parameter distributions in these NPEM population models also permit their use by the new method of 'multiple model' dosage design, which allows the target goals to be achieved specifically with maximum precision. Software for both types of Bayesian adaptive control is now available to employ these population models in clinical practice.

[Optimization of dosing of finlepsin and finlepsin-retard in patients with partial epilepsy on the basis of population modeling and drug monitoring]. / Optimizatsiia dozirovaniia preparatov finlepsin i finlepsin-retard u bol'nykh partsial'noi épilepsiei na osnove populiatsionnogo modelirovaniia i lekarstvennogo monitoringa.

Taking into account the drug monitoring data, twenty-six patients with partial epilepsy were treated with finlepsin (carbamazepin) and finlepsin-retard. According to the therapy, the patients were grouped as following: 11 patients were taking finlepsin, 10--finlepsin-retard and 5 were first treated with finlepsin and then, because of the lack of the effect, assigned to finlepsin-retard. The seizures severity was assessed using special seizures severity scale. Better clinical results (remission and reduction of seizures severity) were found in patients treated with finlepsin-retard as compared to those from other groups. Due to monitoring, a remission was reached using the lower finlepsin dosage. The authors confirm individuality of pharmacokinetic parameters, a need in precise individual treatment strategy and a necessity for controlling drug levels in plasma after replacing one form for another.

Population pharmacokinetic modelling of carbamazepine by using the iterative Bayesian (IT2B) and the nonparametric EM (NPEM) algorithms: implications for dosage.

OBJECTIVE: To estimate individual and population postinduction pharmacokinetics of carbamazepine (CBZ) in epileptic adult and paediatric patients who received chronic CBZ monotherapy. METHODS: We have used the USC*PACK collection of PC programs for the estimations. The preinduction CBZ metabolism was also estimated in 16 volunteers after a single dose of CBZ (200 mg). We used a linear one-compartmental model with oral absorption and found the pharmacokinetic parameter values of CBZ behaviour to be in good agreement with those reported earlier. RESULTS: Serum CBZ concentrations correlated poorly with daily doses in both the adult and child populations. Because of the diversity within the population, use of the mean population model without knowledge of an individual patient's pharmacokinetic characteristics gives poor prediction. In contrast, the individual Bayesian posterior models gave good prediction for all subjects in the population, due to the removal of the interindividual variability. CONCLUSION: This approach permits one to individualize drug therapy for patients even when only sparse therapeutic drug monitoring (TDM) data are available. Future individual CBZ serum level predictions were acceptable from a clinical point of view (mean absolute error = 13.2 +/- 9.7%). The optimal sampling strategy approach helped to design an optimal cost-effective TDM protocol for CBZ therapy management.

A non-linear mathematical model for the in vivo evaluation of the RES phagocytic function.

A new non-linear mathematical model was constructed in order to perform in vivo quantification of the RES phagocytic function. This method is based on the same technical facilities as used for the routine liver-spleen scintigraphy with radiocolloids [1, 2]. But kinetic modeling of dynamic Tc-99m-sulfur colloid data produced estimations of the functional RE-parameters: the clearance rate of the colloidal particles, the rate of phagocytosis, and the RES functional volume, which can not be obtained by classical approaches. This non-linear model was designed on the basis of the principal characteristics of particulate material interaction with macrophages (attachment, phagocytosis, digestion) [3, 4, 5]. The theoretically examined behavior of this in vivo mathematical model corresponds with the experimental behavior of the RES. The mathematical expression of the dynamics is the system of non-linear differential equations with constant coefficients that have no analytical solution. Fitting of the normalized heart blood time-activity curve was obtained to identify the unknown model parameters via non-linear regression. For this purpose general interactive PASCAL procedure IDPAR for a PDP-11/34 computer was used (an IBM PC version is also available). Two to three iterations were needed to estimate the set of unknown parameters for any patient study (1-1.5 min). A very good fitting was obtained between experimental and model curves in every case of different pathologies (error of the approximation is about 2-3%). Studies were performed using an in vivo bolus injection of 3.6 mg/80 kg commercially available colloid KOREN labeled with 3m-Ci 99m-Tc (analog of TCK-1). Our method was used to determine the RES functional parameters for patient groups with different levels of the RES dysfunction. Obtained results illustrate the possibilities of our technique to quantitatively estimate not only great pathology (portal cirrhosis), but also small changes of the RE-function (case of hyperlipidemia and ulcer gaster). In all patient groups marked changes of Tc-99m-sulfur colloid turnover were observed. In general, tracer clearance from the circulation was decreased, and the rate of phagocytosis and the RES volume were diminished compared with controls. The effect of a reduction of phagocytosis increases when the RES dysfunction becomes stronger. It can be shown that a non-parametric Wilcoxon-Mann-Whitney test gives a significant difference (P95%) for these patient groups. Further, we represent the possibility of using the model for monitoring changes of the RES-function parameters during and after therapy. The quantitative test of the RES function can significantly enhance the diagnosis and management of different diseases. Serial colloidal studies may document changes in the RES-function for the tumors, cirrhosis, hyperlipidemia, reticulosis, hepatitis, thrombosis, infection, AIDS, burn injury, shock and trauma patients. The technique may be useful for the different RES investigations with laboratory animals. Created computer software can be used as a tool for kinetic models, simulation, and unknown parameters identification.

[Identification of radiopharmaceutical transport models in functional radionuclide diagnosis]. / Identifikatsiia modelei transporta RFP v funktsional'noi radionuklidnoi diagnostike.

The paper is devoted to the problems of assessment of structural identification of parameters of compartmental models, employed for processing of the results of radionuclide investigations of function of various physiological systems. Methods for assessment of structural identifiability and a regularized algorithm for the identification of parameters of linear and nonlinear compartmental models of almost any structure were proposed. The algorithm possesses a high rate of convergence of the iteration searching process and a low sensitivity to errors of measurements. It was implemented as a software package in Pascal language and utilized on a RDR 11/34 computer for processing the results of radionuclide diagnosis (using 99mTc-COREN) of function of the reticuloendothelial system.

[Mathematical model of radioactive colloid transport in the evaluation of the functional state of the reticuloendothelial system]. / Issledovanie matematicheskoi modeli transporta radioaktivnogo kolloida dlia otsenki funktsional'nogo sostoianiia retikuloéndotelial'noi sistemy.

The authors assess the functional potentialities of a mathematical model of transport of labeled colloids in the body. Some additions to and modifications of the model were analyzed. They made it possible to get 4 diagnostically important indices: the rate of colloid excretion from the vascular bed, the rate phagocytosis, RES volume, and the rate of RP accumulation by the liver. Besides, the authors presented the results of a computerized experiment for the determination of maintenance characteristics of a program developed for computer. The iteration algorithm for parameter identification based on a method of linearization of minimized function, was used in the program. They also formulated recommendations for a choice of arbitrary components of a calculation procedure and the use of a method of barrier functions, developed as a result of prolonged maintenance of the program.

[The function of the reticuloendothelial system studied with the use of radioactive colloids]. / Izuchenie funktsii retikuloéndotelial'noi sistemy s pomoshch'iu radioaktivnykh kolloidov.

A new method for the interpretation of data obtained during radionuclide investigation of the reticuloendothelial system (RES) was proposed. It was based on a detailed description of the mechanism of reticuloendothelial extraction of a colloid injected intravenously. A model developed for this purpose included the main stages of radioactive colloid transport. The paper also represented a comparative analysis of the results of clinical examination of the controls and patients with liver cirrhosis. A 4-fold decrease of the blood flow in portal liver cirrhosis was noted as compared with normal mean indices in a 2-fold decrease in the specific blood supply of cells of the RES and in a 2-fold decrease in its volume. An increase in phagocytosis rate in patients with liver cirrhosis needs further verification.