Population PK/PD modelling of meropenem in preterm newborns based on therapeutic drug monitoring data.

Background: Preterm neonates rarely participate in clinical trials, this leads to lack of adequate information on pharmacokinetics for most drugs in this population. Meropenem is used in neonates to treat severe infections, and absence of evidence-based rationale for optimal dosing could result in mismanagement. Aim: The objective of the study was to determine the population pharmacokinetic (PK) parameters of meropenem in preterm infants from therapeutic drug monitoring (TDM) data in real clinical settings and to evaluate pharmacodynamics (PD) indices as well as covariates affecting pharmacokinetics. Materials and methods: Demographic, clinical and TDM data of 66 preterm newborns were included in PK/PD analysis. The NPAG program from the Pmetrics was used for modelling based on peak-trough TDM strategy and one-compartment PK model. Totally, 132 samples were assayed by high-performance liquid chromatography. Meropenem empirical dosage regimens (40-120 mg/kg/day) were administered by 1-3-h IV infusion 2-3 times a day. Regression analysis was used to evaluate covariates (gestation age (GA), postnatal age (PNA), postconceptual age (PCA), body weight (BW), creatinine clearance, etc.) influenced on PK parameters. Results: The mean ± SD (median) values for constant rate of elimination (Kel) and volume of distribution (V) of meropenem were estimated as 0.31 ± 0.13 (0.3) 1/h and 1.2 ± 0.4 (1.2) L with interindividual variability (CV) of 42 and 33%, respectively. The median values for total clearance (CL) and elimination half-life (T1/2) were calculated as 0.22 L/h/kg and 2.33 h with CV = 38.0 and 30.9%. Results of the predictive performance demonstrated that the population model by itself gives poor prediction, while the individualized Bayesian posterior models give much improved quality of prediction. The univariate regression analysis revealed that creatinine clearance, BW and PCA influenced significantly T1/2, meropenem V was mostly correlated with BW and PCA. But not all observed PK variability can be explained by these regression models. Conclusion: A model-based approach in conjunction with TDM data could help to personalize meropenem dosage regimen. The estimated population PK model can be used as Bayesian prior information to estimate individual PK parameter values in the preterm newborns and to obtain predictions of desired PK/PD target once the patient's TDM concentration(s) becomes available.

Health-related quality of life in Russian adults with epilepsy: the effect of socio-demographic and clinical factors.

OBJECTIVE: The aim of this study was to evaluate socio-demographic and clinical factors influencing the health-related quality of life (HRQOL) of adult patients with epilepsy in a naturalistic treatment setting in Russia. METHODS: The QOLIE-31 questionnaire and the Beck Depression Inventory (BDI) were completed by 208 patients with a broad clinical spectrum of epilepsy (the mean age was 31.49±13.20 years and ranged from 18 to 74 years). RESULTS: In Russian adult patients with epilepsy, lower mean QOLIE-31 scores were obtained compared with previously published international data for overall HRQOL, emotional well-being, and cognitive functioning and social functioning subscales (p<0.001). Univariate analysis revealed that duration of epilepsy negatively correlated with all QOLIE-31 subscores (p<0.05), except for emotional well-being (p=0.1). In multivariate regression analysis, BDI depression score was the predictor of overall score and all QOLIE-31 domains, except for emotional well-being. Age could be considered as a predictor of cognitive and social functioning, medical effects, and the total QOLIE -31 score. Seizure frequency was a factor associated with all HRQOL domains, except for medication effects and emotional well-being, whereas gender, education, family status, seizure type, employment, lateralization of epileptic foci, number of antiepileptic drugs, and the reported adverse events did not significantly affect HRQOL. CONCLUSION: The present study has revealed that longer duration of epilepsy, older age, higher seizure frequency, and depression are the potential predictors of worse HRQOL in adult Russian patients with epilepsy.

Left ventricular myocardial remodeling in dogs with mitral valve endocardiosis.

BACKGROUND AND AIM: Left ventricular myocardial remodeling could play an important role in the progression of chronic heart failure (CHF) syndrome in dogs with mitral valve endocardiosis. The aim of this study was to evaluate the left ventricular myocardial remodeling in dogs with mitral valve endocardiosis and to study the dependence of the incidence of this pathological phenomenon on the functional class (FC) of progression of the CHF syndrome. MATERIALS AND METHODS: A total of 108 afflicted dogs and 36 clinically healthy dogs were examined using transthoracic echocardiography. The following structural and geometric parameters of the left ventricular remodeling were evaluated: Myocardial mass and its index, sphericity index at the end of systole and diastole, end-systolic and end-diastolic relative wall thickness, and integral remodeling index. RESULTS: In all clinically healthy dogs, a normal type of the left ventricular chamber geometry was revealed, whereas, in dogs with mitral valve endocardiosis, the normal geometry of the left ventricle occurred in 56.4%, eccentric hypertrophy in 24.1%, concentric remodeling in 10.2%, and concentric hypertrophy in 9.3% of the cases. In patients with endocardiosis, there was no dilatation type of cardiac remodeling observed. CONCLUSION: When compared to the clinically healthy animals, the dogs with mitral valve endocardiosis presented with indicators of structural and geometric remodeling, such as increased myocardial mass, myocardial mass index, and sphericity index at the end of systole and diastole, as well as relatively reduced integral systolic index of remodeling and systolic relative thickness of the walls of the heart. The parameters of the left ventricular myocardial remodeling correlated significantly with the FC of CHF syndrome.