Joint use of population pharmacokinetics and machine learning for optimizing antiepileptic treatment in pediatric population.

Purpose: Unpredictable drug efficacy and safety of combined antiepileptic therapy is a major challenge during pharmacotherapy decisions in everyday clinical practice. The aim of this study was to describe the pharmacokinetics of valproic acid (VA), lamotrigine (LTG), and levetiracetam (LEV) in a pediatric population using nonlinear mixed-effect modeling, while machine learning (ML) algorithms were applied to identify any relationships among the plasma levels of the three medications and patients' characteristics, as well as to develop a predictive model for epileptic seizures. Methods: The study included 71 pediatric patients of both genders, aged 2-18 years, on combined antiepileptic therapy. Population pharmacokinetic (PopPK) models were developed separately for VA, LTG, and LEV. Based on the estimated pharmacokinetic parameters and the patients' characteristics, three ML approaches were applied (principal component analysis, factor analysis of mixed data, and random forest). PopPK models and ML models were developed, allowing for greater insight into the treatment of children on antiepileptic treatment. Results: Results from the PopPK model showed that the kinetics of LEV, LTG, and VA were best described by a one compartment model with first-order absorption and elimination kinetics. Reliance on random forest model is a compelling vision that shows high prediction ability for all cases. The main factor that can affect antiepileptic activity is antiepileptic drug levels, followed by body weight, while gender is irrelevant. According to our study, children's age is positively associated with LTG levels, negatively with LEV and without the influence of VA. Conclusion: The application of PopPK and ML models may be useful to improve epilepsy management in vulnerable pediatric population during the period of growth and development.

Pharmacokinetics and machine learning in epilepsy Abstract: Nowadays, combined antiepileptic therapy is the best option for a number of pediatric patients. Furthermore, there are no standard procedures in the therapy management of this complex treatment. Besides therapeutic monitoring, the population pharmacokinetic (PopPK) approach and machine learning (ML) are useful sources of information regarding the optimization of therapy. The aim of this study was to describe the pharmacokinetics of valproic acid (VA), lamotrigine (LTG), and levetiracetam (LEV) in a pediatric population using nonlinear mixed-effect modeling, while ML algorithms were applied to identify any relationships among the plasma levels of the three medications and patients' characteristics. The study included 71 pediatric patients of both genders, aged 2­18 years, on combined antiepileptic therapy. Population pharmacokinetic (PopPK) models were developed separately for VA, LTG, and LEV. Based on the estimated pharmacokinetic parameters and the patients' characteristics, three ML approaches were applied (principal component analysis, factor analysis of mixed data, and random forest). According to our study, children's age is positively associated with LTG levels, negatively with LEV and without influence from VA. However, the gender of patients has no influence on drug plasma concentration. Findings demonstrated that the application of PopPK and ML models may be useful to improve epilepsy management in vulnerable pediatric population during the period of growth and development.

Antibiotic utility and susceptibility changes of multidrug-resistant Escherichia coli and Klebsiella spp: 5-year experience in a tertiary healthcare centre.

OBJECTIVES: Multiple studies have identified cross-sectional relationships between antibiotic use and bacterial resistance. The aim of this study was to analyse the susceptibility of multidrug-resistant (MDR) and non-MDR (nMDR) isolates of Escherichia coli and Klebsiella spp to cephalosporins: ceftazidime (CTZ), ceftriaxone (CTX), cefepime (CEF) and fluoroquinolones: ciprofloxacin (CIP) and levofloxacin (LEV) in a tertiary healthcare centre from 2014 to 2018. In addition, we aimed to evaluate a correlation between the antibiotic utility and susceptibility of the selected enterobacteria. METHODS: Antibiotics consumption and antimicrobial resistance were monitored in a tertiary care university hospital from 2014 to 2018. Utilisation of antibiotics in the observed period was expressed as defined daily dose (DDD) per 100 bed/days (DBD). Bacterial susceptibility was reported as the percentage of susceptible results among all tested isolates from all patient samples. In further analysis, bacterial strains were considered as MDR or nMDR species. An MDR bacterial strain was defined as one with acquired non-susceptibility to at least one agent in three or more antimicrobial categories. RESULTS: Our results suggest that cephalosporins were the most used antibiotics, followed by fluoroquinolones, during the entire observed period 2014-2018. Our findings show that MDR isolates of E. coli had an increasing trend in susceptibility in relation to CTX (p=0.005), whereas a decreasing trend was observed for MDR isolates of E. coli susceptibility towards CIP and LEV (p<0.001). Klebsiella spp susceptibility for MDR isolates showed a decreasing trend in relation to CEF (p<0.001) and both fluoroquinolones (p<0.001). A significant negative association between CEF consumption and Klebsiella spp MDR isolates susceptibility was observed (p=0.045). CONCLUSION: Implementation of antimicrobial stewardship programmes with early detection and close monitoring of MDR bacterial strains of E. coli and Klebsiella spp may be a crucial step in reducing the menace of antimicrobial resistance, which is now a global problem.

Assessment of pharmacokinetic mycophenolic acid clearance models using Monte Carlo numerical analysis.

Previously, we performed population pharmacokinetic analysis and indicated age, mycophenolate mofetil (MMF)/mycophenolic acid (MPA) daily dose, and presence of nifedipine in patient therapy as significant predictors of MPA apparent clearance (CL/F) variability. This study aimed to determine the reliability of previously published population pharmacokinetic models derived from similar studies. Furthermore, this study investigated correspondence between chosen population models from the literature.By means of the Monte Carlo simulation method, pharmacokinetic models from different studies are simulated and analysed in the range of standard deviations of measured system parameters as well as the range of observed model parameters taken from the comparison studies.The 1000 numerical simulations were performed for every analysed model in order to calculate the most possible MPA CL/F values according to the expected values from the performed experiment. Fitting our results with other models showed how the presence of nifedipine makes difference in MPA CL/F values.By testing the data from selected studies into our model, a similar range of expected CL/F values was obtained, which may confirm the validity of our model. The results of our population pharmacokinetic study are partially applicable in models by other researchers.

Herbal self-medication use in patients with diabetes mellitus type 2.

BACKGROUND/AIM: A considerable number of patients suffering from diabetes mellitus (DM) turn to self-medication using medicinal plants, preparations, and medicine. The aim of this study was to investigate self-medication using medicinal plants and the potential influence of health care professionals' advice or media information regarding the use of herbal dietary supplements with hypoglycemic effect in a population of patients with type 2 DM. MATERIALS AND METHODS: This research, in the form of an analytic cross-sectional study, was conducted in 6 pharmacies in the territory of Nis, Serbia, during October 2013. The criterion set for the study was to include patients diagnosed with type 2 diabetes who used pharmacotherapy in addition to herbal supplements. RESULTS: Surveyed women showed a statistically significant difference in the frequency of using herbal supplements compared to men (P < 0.001). More frequent symptoms of hypoglycemia were reported in the group of diabetic respondents who used herbal dietary supplements (P < 0.05). The media was most responsible for influencing decisions about self-medication that included the use of herbal dietary supplements. CONCLUSION: The role of health professionals is indispensable and very important, especially when the media is a potential cause of seeking self-medication.

Correlation of inflammation parameters and biochemical markers of cholestasis with the intensity of lipid peroxidation in patients with choledocholithiasis.

BACKGROUND/AIM: During choledocholitiasis inflammatory oxidant stress involves the promotion of mitochondrial dysfunction through an intracellular oxidant stress in hepatocytes leading mainly to necrosis and less to apoptosis. The product of oxidative stress, malondialdehyde (MDA), is extremely cytotoxic and damages cell membranes and intracellular macromolecules. The toxicity of MDA is based on its ability to act as a mutagenic agent in a cell. Therefore, the aim of this prospective study was to establish correlation of the parameters of inflammation and biochemical markers of cholestasis with the intensity of oxidative stress in pathogenesis of liver function disorders. METHODS: Seventy adult subjects of either sex included in the study were devided into two groups: I--40 patients with obstructive icterus caused by choledocholithiasis, and II--30 healthy individuals. All the participants were subjected to a clinical, laboratory and ultrasonic check-up at the Internal Department of the Military Hospital in Nis. The parameters of oxidative stress: MDA, a measure of lipid peroxidation, and inflammation parameters: C-reactive protein (CRP), fibrinogen, albumins, number of leukocytes (Leu), granulocytes (Gr), lymphocytes (Ly) and monocytes (Mo) and biochemical markers of cholestasis: activity of gamma-glutamyltransferase (gamma-GT) and alkaline phosphatase (AP) enzymes, the level of total, direct and indirect bilirubin were determined by standard biochemical methods. RESULTS: Lower values of albumin (p < 0.001), and significantly higher values of fibrinogen (p < 0.05) and CRP (p < 0.001) were found in the blood of the patients with cholestasis due to choledocholithiasis in relation to the controls. Significantly higher values of Leu (p < 0.01) and Gr (p < 0.001) with decreasing number of Ly (p < 0.001) and Mo (p < 0.001) were found in blood of the patients with cholestasis due to choledocholithiasis in relation to the control. Similarly, higher values of gamma-GT, and AP (p < 0.001), as well as the level of total, direct and indirect bilirubin (p < 0.001) were found in blood of the patients with cholestasis due to choledocholithiasis in relation to the controls. The concentration of MDA (p < 0.001) was increased in the patients with choledocholithiasis in relation to the controls. There was a significant positive linear correlation of the number of leukocytes (r = 0.51, p < 0.05) and the concentration of total (r = 0.87, p < 0.01), direct (r = 0.85, p < 0.01) and indirect (r = 0.88, p < 0.01) bilirubin with the concentration of MDA in the group of patients with choledocholithiasis. CONCLUSION: Neutrophils and the levels of total, direct and indirect bilirubin have a significant positive linear correlation with the level of lipid peroxidation in patients with choledocholithiasis. Neutrophilia and hiperbilirubinemia observed in this way represent important parameters in estimating the level of liver tissue damage in choledocholithiasis.