POPULATION PHARMACOKINETICS OF 2-OXO-CLOPIDOGREL IN PATIENTS WITH ACUTE CORONARY SYNDROME

The aim of the study was to develop a population pharmacokinetic (PK) model for clearance of 2-oxo-clopidogrel in patients with acute coronary syndrome (ACS). Population pharmacokinetic analysis was performed by using 72 plasma concentrations from the same number of patients (mean age of 60.82±10.76 years; total body weight (TBW) of 73.63±9.67 kg) with ACS using non-linear mixed-effect modeling (NONMEM). Validation of the final PPK model was carried out through the bootstrap analysis with 200 runs and it was used to estimate the predictive performance of the pharmacokinetic model. The typical mean value for 2-oxo-clopidogrel clearance (CL), estimated by the base model (without covariates), in our population was 39.2 l h−1.The value of aspartate transaminase and co-medication with digoxin were determinants of a derived population model. The final regression model for the clearance of 2-oxo-clopidogrel was the following: CL (lh-1) = 1.7 + 1.31*AST + 115*DIGOXIN. The derived PK model describes the clearance of 2-oxo-clopidogrel in patients with ACS, showing that the value of aspartate transaminase and co-medication with digoxin are the most important covariate. This finding will provide the basis for future PK studies

Population pharmacokinetics of 25-hydroxyvitamin D in healthy young adults

Objectives: The aim of our study was to develop a population pharmacokinetic (PPK) model for 25-hydroxyvitamin D clearance in a healthy young adult population in Serbia. Methods: Study sample consisted of 70 healthy young students of the Faculty of Medical Science, University of Kragujevac, Serbia, with a mean age and body mass index of 22.39 +/- 1.82 years and 21.31 +/- 2.69 kgm(-2), respectively. Non-linear mixed-effect modeling (NONMEM) software was used for data analysis. A validation set of 16 participants was used to estimate the predictive performance of the pharmacokinetic model. Results: In the base model (without covariates), we had parameter estimates of 0.01 L/h for apparent clearance, 0.25 L for apparent volume of distribution, while value of minimum objective function (MOF) was 383.468. The full regression model was established by estimating the effects of 12 covariates. Mean intake of vitamin D from foods (DD) and value of phosphate in serum (PHO) were covariates included in the final model, while others were excluded in this process. The estimated value in the final MOF model was 274.555. The final regression model formula was: clearance (CL) (L/h) = 0.0711 + 0.738 x DD + 0.618 x PHO. Conclusions: The PPK model obtained determined clearance of 25-hydroxyvitamin D in a healthy young adult population in Serbia. Mean intake of vitamin D from foods and serum phosphate level are the most important covariates that influence value of 25-hydroxyvitamin D clearance in healthy young adults

Reslizumab versus placebo for poorly controlled, severe eosinophilic asthma: Meta-analysis

Background/Aim. Reslizumab is humanized monoclonal antibody produced by recombinant DNA technology which binds to circulating interleukin-5 (IL-5) and down-regulates the IL-5 signaling pathway. Reslizumab is indicated for the add-on maintenance treatment of patients 18 years and older with severe eosinophilic asthma phenotype whose symptoms were inadequately controlled with inhaled corticosteroids. The aim of this meta-analysis was to assess the efficacy and safety of reslizumab compared to placebo in patients suffering from inadequately controlled, moderateto- severe asthma with elevated blood eosinophil counts. Methods. Our meta-analysis was based on systematic search of literature and selection of high-quality evidence according to pre-set inclusion and exclusion criteria. The effects of reslizumab and placebo were summarized using Review Manager (RevMan) 5.3.5 and heterogeneity was assessed by the Cochrane Q test and I² values. Several types of bias were assessed and publication bias shown by Funnel plot and Egger’s regression. Results. The meta-analysis included 5 randomized, placebo-controlled clinical trials. Reslizumab 3.0 mg/kg produced substantial improvements in forced expiratory volume in 1. second (FEV 1) (mean difference 0.15 [0.10, 0.21]) and in forced vital capacity (FVC) (mean difference 0.21 [0.09, 0.32]) over the 15 or 16-week treatment period, substantial decrease versus placebo in Asthma Control Questionnaire (ACQ) score (mean difference -0.28 [-0.41, -0.16]), and substantial increase vs. placebo from baseline in Asthma Quality of Life Questionnaire (AQLQ) total score (mean difference 0.24 [0.06, 0.43]). Also, reslizumab 3.0 mg/kg caused less adverse events versus placebo (OR 0.67 [0.51, 0.88]), especially asthma worsening (OR 0.53 [0.36, 0.77]) or bronchitis (OR 0.42 [0.24, 0.74]). Conclusion. On the basis of published clinical trials reslizumab could be considered as an effective and safe therapeutic option for severe, poorly controlled eosinophilic asthma for the time being. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 175007

Translation to Serbian, cultural adaptation, reliability testing and validation of the questionnaire estimating the fear of injections

Background/Aim. The two-part questionnaire called Injection Phobia Scale (IPS)-Anxiety and IPS-Avoidance represents one of the most commonly used questionnaires for assessing the fear of injections. The aim of the present study was to translate and culturally adapt this questionnaire from English into Serbian as well as to assess reliability and validity of the translation. Methods. The translation and cultural adaptation of the IPS–Anxiety and IPS–Avoidance was performed in accordance with the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) guidelines. Reliability testing, factor analysis and validation of Serbian translation of IPS-Anxiety and IPS-Avoidance were carried out on a sample of 485 students of pharmacy, or medicine at the University of Kragujevac, Serbia. Results. Serbian translation of IPS-Anxiety and IPSAvoidance demonstrated high internal consistency with Cronbach’s alpha of 0.934 for IPS-Anxiety and 0.911 for IPS-Avoidance. Factor analysis of IPS-Anxiety showed that there are two domains, which we have called as Direct Experience (9 items) and Indirect Experience (9 items); factor analysis of IPS-Avoidance also pointed out on two domains referring to direct and indirect fear of injections. Female students scored higher on the scale showing more extensive injection phobia than male students. It is also interesting that students of pharmacy have higher level of injection phobia than students of medicine, and those students of the fifth year of study feel more fear of injections than students from the first four years. Conclusion. Serbian translation of IPS-Anxiety and IPS-Avoidance showed good psychometric properties on population consisted of students medicine and pharmacy. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 175007