The influence of CYP2C8*3 on carbamazepine serum concentration in epileptic pediatric patients.

The aim of the present study was to investigate the distribution of CYP2C8 variants *3 and *5, as well as their effect on carbamazepine pharmacokinetic properties, in 40 epileptic pediatric patients on carbamazepine treatment. Genotyping was conducted using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and allele-specific (AS)-PCR methods, and steady-state carbamazepine plasma concentrations were determined by high performance liquid chromatography (HPLC). The CYP2C8 *3 and *5 polymorphisms were found at frequencies of 17.5 and 0.0%, respectively. After dose adjustment, there was a difference in daily dose in CYP2C8*3 carriers compared to non carriers [mean ± standard deviation (SD): 14.19 ± 5.39 vs. 15.46 ± 4.35 mg/kg; p = 0.5]. Dose-normalized serum concentration of carbamazepine was higher in CYP2C8*3 (mean ± SD: 0.54 ± 0.18 vs. 0.43 ± 0.11 mg/mL, p = 0.04), and the observed correlation between weight-adjusted carbamazepine dose and carbamazepine concentration after dose adjustment was significant only in CYP2C8*3 non carriers (r = 0.52, p = 0.002). However, the population pharmacokinetic analysis failed to demonstrate any significant effect of CYP2C8 *3 polymorphism on carbamazepine clearance [CL L/h = 0.215 + 0.0696*SEX+ 0.000183*DD]. The results indicated that the CYP2C8*3 polymorphism might not be of clinical importance for epilepsy treatment in pediatric populations.

Factors influencing carbamazepine pharmacokinetics in children and adults: population pharmacokinetic analysis.

OBJECTIVE: The aim of the present study was to build population pharmacokinetic models for the clearance of carbamazepine (CBZ) in two separate populations of Serbian patients with epilepsy, children and adults. METHODS: Analysis was performed using 114 and 53 steady-state concentrations of CBZ collected from 98 children and 53 adult epileptic patients, respectively. Mean values of total body weight and age were 31 ± 13 kg and 8 ± 3 years in the population of children, and 67 ± 13 kg and 32 ± 15 years in the population of adults. The one-compartment model with first order elimination and without absorption was used from the PREDPP (Prediction for Observation Population Pharmacokinetics) library of NONMEM software. RESULTS: The derived final models of CBZ clearance were similar in the target populations. The most important factors which affected typical mean value of CBZ clearance in both populations studied were age of the patients and total daily dose; the CBZ clearance linearly followed increase of these factors. However, the influence of the patients' age was almost 3.4 times higher in the pediatric population than that in adults while the influence of total daily dose of CBZ is similar. On the other hand, final model in the adult population revealed also influence of concomitant therapy with phenobarbital (PB). The magnitude of this effect was +1.61 l h-1. The pharmacokinetic models obtained were validated in groups of 18 children and 13 adults with epilepsy. CONCLUSIONS: The derived models describe well CBZ clearance in terms of Serbian pediatric and adult epileptic patient characteristics, offering a basis for rational individualization of CBZ dosage regimens.

Factors influencing valproate pharmacokinetics in children and adults.

OBJECTIVE: The aim of the present study was to build population pharmacokinetic models for the clearance of valproate (VPA) in 2 separate populations of Serbian patients with epilepsy, children and adults. METHODS: Analysis was performed using 65 and 63 steady-state concentrations of VPA collected from 58 children and 60 adult epileptic patients, respectively. Mean values for total body weight and age were 27.07 ± 13.08 kg and 7.21 ± 3.63 years in the pediatric population, and 69.67 ± 15.60 kg and 33.97 ± 16.41 years in the adult population. The one-compartment model with first order elimination and without absorption was used from the PREDPP (Prediction for Observation Population Pharmacokinetics) library of NONMEM software. RESULTS: The derived final models show that VPA clearance increased with total body weight of patients in both populations. However, the carbamazepine comedication was the main determinant of the final model in children whereas phenobarbitone comedication was the most important factor in the adult population. The magnitudes of these effects were +0.159 lh-1 and +0.539 lh-1 for carbamazepine and phenobarbitone, respectively. A significant decrease in interindividual and intraindividual variability was observed in the target populations. The pharmacokinetic models obtained were validated in groups of 15 epileptic patients, each showing good predictive performance of the model. CONCLUSIONS: The derived models describe well VPA clearance in terms of characteristics of Serbian pediatric and adult epileptic patients, offering a basis for rational individualization of VPA dosage regimens.

Population pharmacokinetics of tacrolimus in kidney transplant patients.

OBJECTIVE: The purpose of this study was to derive population pharmacokinetics (PPK) model of tacrolimus clearance, identify and describe factors that influence it in Serbian kidney transplant patients. METHODS: Population pharmacokinetics analysis was performed using nonlinear mixed-effects model (NONMEM) program from Serbian adult kidney transplant patients receiving triple immunosuppressive therapy, including oral tacrolimus. Details of drug dosage history, sampling time and tacrolimus concentration in 63 patients (44 males and 19 females), 27 - 57 years old (age mean 40.88 +/- 7.01 years) were collected retrospectively. Effects of several covariates on tacrolimus clearance were tested: total body weight, gender, age, posttransplantation days, hemoglobin count, CRP, alanine aminotransferase/aspartate aminotransferase, total daily dose of tacrolimus, co-medication with cotrimoxasole, omeprazole, mycophenolate mofetil and prednisone (> 25 mg). RESULTS: Typical mean value of tacrolimus clearance, estimated by the base model (without covariates), in our population was 1.03 l h-1. The final model showed that tacrolimus clearance increased with total daily dose and concomitant administration of high-dose prednisone (> 25 mg). The magnitude of prednisone effect was + 1.16 l h-1. Final model was validated in a group of 17 patients, showing good predictive performance. CONCLUSIONS: The derived model describes well tacrolimus clearance in terms of characteristics of Serbian kidney transplant patients, offering basis for rational individualization of tacrolimus dosing regimens.

Population pharmacokinetics of lamotrigine in patients with epilepsy.

OBJECTIVE: The purpose of this study was to derive a population pharmacokinetics (PPK) model of lamotrigine clearance as well as to identify and describe factors that influence it in Serbian patients with epilepsy. METHODS: A total of 40 steady-state serum concentrations from 38 adult and pediatric patients with epilepsy, collected during routine therapeutic drug monitoring, were used for the analysis. To determine the influence of different covariates on the estimate of lamotrigine clearance we built a non-linear mixed-effects one-compartment model with the first order elimination and without absorption. RESULTS: Typical mean value of lamotrigine clearance, estimated by the base model (without covariates), in our population was 1.15 l h-1. The final model showed that lamotrigine clearance increased with total body weight, daily dose and concomitant administration of carbamazepine, and decreased with concomitant administration of valproate. The magnitude of carbamazepine and valproate effect was +1.13 l h-1 and -1 l h-1, respectively. The final model was validated in a group of 15 epileptic patients, showing good predictive performance. CONCLUSIONS: The derived model describes well lamotrigine clearance in terms of characteristics of Serbian patients, offering basis for rational individualization of lamotrigine dosing regimens.

The Safety of Local Hormonal Treatment for Vulvovaginal Atrophy in Women With Estrogen Receptor-positive Breast Cancer Who Are on Adjuvant Aromatase Inhibitor Therapy: Meta-analysis.

Atrophic vaginitis is a relatively common adverse effect of aromatase inhibitors used as an adjunctive treatment for breast cancer. Vaginal estrogen therapy is a treatment option, but the safety of its use in estrogen receptor-positive breast cancer remains understudied. The aim of our study was to determine the safety of local hormonal treatment of vulvovaginal atrophy in women treated with aromatase inhibitors. Our meta-analysis was based on a systematic search of the literature and selection of high-quality evidence. The safety of local hormonal therapy of vaginal atrophy in women on aromatase inhibitors were summarized using calculators built by the authors; heterogeneity was assessed by the Cochrane Q test and I2 values. Several types of bias were assessed; publication bias was calculated by a funnel plot and the Egger regression. Eleven studies fulfilled the inclusion criteria for our study. After 8 weeks of local hormonal treatment, there was no change in the serum levels of luteinizing hormone and estradiol, whereas sex hormone binding globulins were low, and follicle stimulating hormone was almost doubled compared with the baseline. Adverse effect rates of vaginal discharge, facial hair growth, urinary tract or yeast infection, and vaginal or vulvar itching and/or irritation did not show significant changes in the sensitivity analysis, with exception of a single trial. Current evidence suggests that vaginal estrogen administration in postmenopausal women with a history of breast cancer is not associated with systemic absorption of sex hormones and may provide indirect evidence for the safety of their use.

Pharmacokinetic modeling of valproate from clinical data in Serbian epileptic patients.

The aim of this study was to define a population pharmacokinetic model that could estimate the clearance of valproate (VPA) in a Serbian epileptic population. For the analysis, 97 steady-state concentrations of VPA were used, collected from 93 patients with epilepsy during routine clinical care in our hospital. To build a final model, we selected the ADVAN1 program subroutine from the NONMEM library for estimating the drug clearance (CL) and determining the influence of different covariates. This is a one-compartment model with first-order elimination and without absorption. Estimation of the predictive performances of the final model was performed on a validation set consisting of 20 epileptic patients. Typical mean value of CL of VPA estimated by the base model in our population was 0.368 l h(-1). The results of the final model show that the CL of VPA increased linearly with total body weight (TBW) and patients' age, while carbamazepine (CBZ) comedication did not affect it significantly. Interindividual variability (coefficient of variation) for CL was 27.2%. Residual error, including intraindividual variability, was 29.68%. The results of the validation process and the analysis of prediction errors suggest a good predictive performance of the final population model. The defined model describes CL of VPA in terms of specific Serbian patient characteristics, using serum concentration data obtained from routine therapeutic drug monitoring.

Translation of the Medical Fear Survey to Serbian: psychometric properties.

BACKGROUND: Medical Fear Survey (MFS) is an instrument designed for measuring fear of medical and related treatments. OBJECTIVE: Aim of the present study was MFS translation into Serbian, measurement of its psychometric properties and MFS validation using other Blood-injury-injections and related stimuli instruments that have been translated from English into Serbian. METHOD: After obtaining permission from the author of the original MFS, double forward translation from English to Serbian and backward translation to English were conducted in ten steps, according to International Society for Pharmacoeconomics and Outcomes Research (ISPOR) guidelines. Reliability, factorial analysis and concurrent validation of Serbian version of MFS were conducted on a sample of 485 medical or pharmacy students at University of Kragujevac, Serbia. RESULTS: Serbian version of MFS showed high internal consistency with a Cronbach's alpha 0.968 and good temporal stability after testing-and-retesting (Spearman's correlation coefficient 0.838, and intraclass correlation coefficient 0.877). Factorial analysis confirmed the same five factors demonstrated in the original English version: fear of mutilated bodies (10 items), fear of blood (11 items), fear of injections and blood draws (9 items), fear of sharp objects (10 items), and fear of medical examinations and physical symptoms (10 items). The total score of MFS correlated significantly with the total scores of Injection Phobia Scale-Anxiety (Spearman's correlation coefficient 0.391, p <0.001), Blood/Injection Fear Scale (Spearman's correlation coefficient 0.502, p <0.001) and Medical Avoidance Survey (Spearman's correlation coefficient 0.396, p <0.001). CONCLUSIONS: Serbian version of the 50-item MFS showed similar psychometric properties as the original English version of this scale, with the same factorial structure. It could be used for measurement of fear of medical and related treatments in Serbian socio-cultural milieu, preferably self-administered. Hippokratia 2016, 20(1): 44-49.