Search

Valproate represents one of the most commonly used anticonvulsants worldwide, whose narrow therapeutic range and high potential for drug-drug interactions leads to pronounced intra- and inter-individual variability in plasma concentration and response. The aim of our study was to apply population pharmacokinetics analysis to comprehensively investigate and detect the most important factors affecting pharmacokinetics of valproate in Serbian children with epilepsy. This retrospective observational study was based on demographic and medical data retrieved from the medical records on epileptic patients treated with valproate at the pediatric department of the Clinical Centre, Kragujevac, Serbia. Valproate serum concentrations were obtained as a part of routine medical practice. Population pharmacokinetics analysis was performed by MonolixSuite 2019R1 (Lixoft, Antony, France) software, using one-compartment model with first order absorption and linear elimination. The study included 1642 valproate concentrations obtained from 232 patients, of which 201 (1420 concentrations) were included in the index set used for the modelling, while the other 31 (222 concentrations) were the validation set used for external validation of the final model. Covariate testing based on the whole index set revealed that only total daily valproate dose significanly affected the clearance of valproate: Cl (l/h)= 0.135×1.002DD. When only compliant patients were included, co-treatment with carbamazepine was shown to be of significance as well: Cl(l/h)=0.121×1.002DD×1.2CBZ. Our study demonstrated that valproate clearance correlates with total valproate daily dose. The influence of co-treatment with carbamazepine on valproate pharmacokinetics can be observed and used for clearance estimation only in compliant patients.

Vancomycin is a tricyclic glycopeptide antibiotic, mostly used in the treatment of severe staphylococcal and enterococcal infections, especially in orthopedic surgery. The purpose of this analysis was to develop a population pharmacokinetic (PPK) model of vancomycine in hospitalized patients with bone fractures and identify important factors which influence its clearance (CL). A total of ninety-nine measurements of vancomycin serum concentrations were used in our population modeling. A two-compartment model was applied to describe the pharmacokinetics of vancomycin using subroutines ADVAN3 and TRANS4. The study population included patients of both sexes, with the mean age of 62.12±14.69 years and body weight of 80.32±12.44kg. Vancomycin was administered as intravenous infusion with average daily dose of 1772.73±521.34mg. Out of twenty different factors evaluated in the study (including demographic, clinical and laboratory data), only daily dose of vancomycin (DD) and co-medication with piperacillin/tazobactam (PT) showed significant effect on clearance of vancomycin. The final model was described by the following equation: CL (l/h) = 0.03 + 0.000468 x DD + 0.675 x PT. Bootstrapping was used for validation of the final model. In conclusion, the main causes of variability in the clearance of vancomycin among adult patients with bone fractures are daily dose of vancomycin and co-medication with piperacillin/tazobactam.

Optimal vitamin D status is very important for reflecting not only bone but overall woman's health. The aim of the study was to determine pharmacokinetic variability of 25-hydroxy vitamin D, to reveal and quantify the most significant factors that affect its variability in the population of healthy non-menopausal women using the population pharmacokinetic (PopPK) approach. The study population consisted of 74 healthy reproductive women aged from 35 to 50 years, without the use of any supplement. A population pharmacokinetics analysis was conducted using a nonlinear mixed-effects model software. A total of 35 factors were assessed: demographic, clinical, biochemical data and lifestyle factors. The average age and bodyweight of our participants were 40.11 ± 4.35 years 65.30 ± 6.80 kg, respectively. The observed mean serum concentration of 25-hydroxy vitamin D was 26.51 ± 13.49 ng/mL with a wide range of 6.97 to 59.89 ng/mL. Development final PopPK model of the clearance of 25-hydroxy vitamin D showed that only the average daily dose of vitamin D intake from food had a significant influence, with a magnitude of its effects of 0.00401. These results could help when individualizing vitamin D intake in the form of supplements, especially during the wintertime, in healthy reproductive women.

Background and Objectives: Although vitamin D insufficiency or deficiency is prevalent in children with allergic diseases, recommendations for supplementation dosing regimens are imprecise and variable in the literature, because clinical trials aiming to determine optimal doses were scarce in the past. This study aimed to investigate supplementation of vitamin D3 that may achieve therapeutically effective but not toxic serum levels in a subpopulation of children with allergic diseases and concomitant hypovitaminosis D. Materials and Methods: The retrospective, observational study with a cross-sectional design included 94 children suffering from allergic diseases and having vitamin D deficiency/insufficiency who were prescribed high-dose vitamin D3 supplementation by a pediatrician for at least 6 weeks and not more than 9 weeks. Serum levels of the major metabolite of vitamin D (25-(OH)D) were determined in all children twice: before and two weeks after the end of vitamin D3 supplementation. Results: An increase in serum level of the 25-(OH)D after supplementation was significant. However, if the subjects had higher serum levels of the 25-(OH)D before the supplementation, and if the supplementation lasted 8 instead of 6 weeks, the absolute increase in serum level of the 25-(OH)D was lower. Patients taking corticosteroids as inhalation or intranasally had a more intense effect of vitamin D3 supplementation, i.e., the absolute increase in levels of 25-(OH)D was higher than in patients not using such medication. Conclusions: Vitamin D deficiency and insufficiency in children with allergic diseases can be treated with maximal recommended doses of vitamin D3 for a short period of time, especially if they were prescribed with inhalation or intranasal corticosteroids.

Introduction: Seizures, which could not be controlled by drug therapy, have profound negative influence on the quality of life of the affected person. If with clear locus of origin and accompanied ...

The aim of this systematic review was to determine the causal role of Erysipelatoclostridium ramosum in specific invasive infections in humans, and to assess the clinical outcome of antibiotic therapy used to treat them. Several electronic databases were systematically searched for clinical trials, observational studies or individual cases on patients of any age and gender with a systemic inflammatory response syndrome (SIRS) due to E. ramosum isolated from body fluids or tissues in which it is not normally present. Only reports identifying E. ramosum as the only microorganism isolated from a patient with SIRS were included. This systematic review included 15 studies reporting 19 individual cases in which E. ramosum caused invasive infections in various tissues, mainly in immunocompromised patients. E. ramosum was most often isolated by blood cultures and identified by specific biochemical tests. Severe infections caused by E. ramosum were in most cases effectively treated with antibiotics, except in two patients, one of whom died. More than one isolate of E. ramosum exhibited 100% susceptibility to metronidazole, amoxicillin/clavulanate and piperacillin/tazobactam. On the other hand, individual resistance of this bacterium to penicillin, ciprofloxacin, clindamycin, imipenem and ertapenem was reported. This systematic review confirmed the clinical relevance of E. ramosum as a cause of a number of severe infections mainly in immunocompromised inpatients. Metronidazole and meropenem appear to be the antibiotics of choice that should be used in combination or as monotherapy to treat E. ramosum infections, depending on the type and severity of the infection.

There are many determinants of vancomycin clearance, but these have not been analyzed separately in populations with different levels of renal function, which could be why some important factors have been missed. The aim of our study was to compare the pharmacokinetic parameters and factors that may affect vancomycin pharmacokinetics in groups of patients with normal renal function and in those with chronic kidney failure. The study used a population pharmacokinetic modeling approach, based on plasma vancomycin concentrations and other data from 78 patients with chronic kidney failure and 32 patients with normal renal function. The model was developed using NONMEM software and validated by bootstrapping. The final model for patients with impaired kidney function was described by the following equation: CL (L/h) = 0.284 + 0.000596 x DD + 0.00194 x AST, and that for the patients with normal kidney function by: CL (L/h) = 0.0727 + 0.205 x FIB. If our results are confirmed by new studies on two similar populations, these factors could be considered when dosing vancomycin in patients with chronically damaged kidneys, as well as in patients with normal kidneys who frequently require high doses of vancomycin.

The aim of this study was to perform screening for anxiety disorders among children with asthma and to reveal factors associated with general anxiety disorder and its specific forms. This was a cross-sectional study conducted among out-patients with asthma during routine visits to pediatricians. They were screened for anxiety disorders using SCARED self-reported questionnaire. Additional data were collected using specially designed questionnaire as well as the patient files. Statistical analysis was performed by the SPPS software using descriptive statistics and logistic regression. Study population consisted mostly of schoolchildren (n=58), 8-12 years old, and adolescents (13-17 years) (n=13). Approximately 33.8% respondents were positive for general anxiety disorder. The most common were separation anxiety and social anxiety, recorded among 49.3% and 32.4% of patients, respectively. Generalized anxiety and panic/somatic disorder were recorded in the same percentage of patients (21.3%), while avoiding school was the least frequent (14.08%). Influence of numerous factors was tested, but only the following showed significant effects: peak expiratory flow test was associated with general anxiety disorder, patient’s age and gender with PD, and living place, asthma control according to GINA and age on GAD. Parent’s smoking was associated with SAD, age and patient’s weight status with SPH, and GINA asthma control with SA. These findings suggest that anxiety disorders are common among children and adolescents with asthma. Various factors can be associated with general anxiety disorder and its specific forms, but some of them being preventable as avoiding smoking in the family.

Given that it has been reported that type 2 diabetes mellitus may affect the pharmacokinetics of a large number of drugs and that there are still no published population pharmacokinetic (PopPK) analyses in routinely treated patients with hypertension and type 2 diabetes mellitus as comorbid condition, the aim of this study was to determine PK variability of bisoprolol in 70 Serbian patients using the PopPK approach. PopPK analysis was conducted using a nonlinear mixed effects model (NONMEM), version 7.3.0 (Icon Development Solutions). In our patients, a total daily dose of bisoprolol ranged from 1.25 to 10 mg. The drug was administrated orally as a single daily dose or in two divided doses per day. A wide range of the drug concentrations were noted (1–103 ng/mL) in the population consisted of the adult patients with type 2 diabetes mellitus. From a total of 21 separately assessed covariates, our results indicated that only creatinine clearance could have a potential impact on the variability of the clearance of bisoprolol. Routine assessment of renal function should be carried out before the initiation of treatment with bisoprolol in order to individualize the dose and to prevent possible accumulation and adverse drug reactions.

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.

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.

Second-generation triazoles were developed in response to the quest for more efficacious and safer therapeutic options for the treatment of severe systemic aspergillosis and candidiasis. These agents include voriconazole, posaconazole, isavuconazole, and ravuconazole. The aim of this review was to present and compare the pharmacokinetic characteristics of second-generation triazoles for the treatment of invasive aspergillosis and candidiasis, emphasizing their clinical implications. The MEDLINE, Scopus, EBSCO, Google Scholar, and SCIndeks databases were searched using advanced search options, including the names of second-generation triazoles and pharmacokinetic terms as keywords. The intravenous administration of voriconazole, posaconazole, and isavuconazole results in stable pharmacokinetics of these drugs, with mostly predictable variations influenced by common and usually known factors in routine clinical settings. The high oral bioavailability of isavuconazole and, to some extent, voriconazole makes them suitable for intravenous-to-oral switch strategies. Except for intravenous voriconazole (due to the accumulation of the toxic vehicle hydroxypropyl betadex), dose reduction of second-generation triazoles is not needed in patients with renal failure; patients with hepatic insufficiency require dose reduction only in advanced disease stages. The introduction of therapeutic drug monitoring could aid attempts to optimize the blood concentrations of triazoles and other drugs that are known to or that possibly interact, thus increasing treatment efficacy and safety. There is a need for new studies that are designed to provide useful data on second-generation triazole pharmacokinetics, particularly in special circumstances such as central nervous system and ocular infections, infections in newborns and infants, and in subjects with genetic polymorphisms of metabolizing enzymes.

Carbamazepine exhibits significant inter-individual variability in its efficacy and safety, which leads to unpredictable therapy outcomes for the majority of patients. Although its complex biotransformation depends on CYP3A5 activity, evidence of association between carbamazepine treatment outcomes and CYP3A5 functional variations remains inconclusive. The aim of the present study was to investigate the distribution of two of the functionally important CYP3A5 variants *2 and *3 as well as their effects on carbamazepine dose requirements, plasma concentrations and clearance in a Serbian population. The study involved 40 paediatric epileptic patients on steady-state carbamazepine treatment. Genotyping was conducted using the PCR-RFLP method, and carbamazepine plasma concentrations were determined using the HPLC method. CYP3A5*2 and *3 polymorphisms were found at frequencies of 0.0% and 97.5%, respectively, which corresponds well to previously published data for Caucasians. No differences in CYP3A5*3 allele frequencies were detected among epileptic patients in comparison to healthy volunteers within similar ethnic populations (p>0.08), indicating that CYP3A5 polymorphism does not represent a risk factor for epilepsy development. There was an observed tendency towards lower dosage requirements (mean±SD: 15.06±4.45 mg/kg vs. 18.74±5.55 mg/kg; p=0.26), higher plasma concentrations (mean±SD: 0.45±0.13 mg/kg vs. 0.38±0.03 mg/kg; p=0.47) and lower clearance (mean±SD: 0.14±0.05 mg/kg vs. 0.15±0.01 mg/kg; p=0.79) of carbamazepine in homozygous carriers of CYP3A5*3/*3 compared to heterozygous CYP3A5*1A/*3 Serbians. Because these genotype groups did not differ significantly in terms of their carbamazepine pharmacokinetics parameters, the proposed effects of CYP3A5*3 on carbamazepine metabolism could not be confirmed.

Objectives Asthma and vitamin D deficiency are widespread in the pediatric and adolescent population. The aim of this study was to develop a population pharmacokinetic (PPK) model and to evaluate the most important factors that can significantly affect clearance of 25-hydroxy vitamin D in asthmatic children using PPK analysis. Materials and methods The study population included school children and adolescents from 7 to 18 years of age of both sexes. PPK analysis was performed by non-linear mixed-effects modeling (NONMEM), and 19 covariates were assessed. Goodness-of-fit plots, validation set and bootstrap analysis were conducted to confirm predictive performance of the final model. Results A total of 60 patients were included in the basic NONMEM data set for PPK modeling with a mean age of 10.2 years and body weight of 41.3 kg. The final pharmacokinetic model for the clearance of 25-hydroxy vitamin D included as covariates intake of vitamin D from foods (DD), hereditary predisposition to asthma (HPA) and the ratio of forced expiratory volume in first second and forced vital capacity (FEV1/FVC ratio). A validation set consisted of 14 separate patients with similar characteristics to the basic data set. The final model was confirmed by internal and external validation and also through goodness-of-fit plots. Conclusion These results could be of help for individualization of vitamin D supplementation doses in this vulnerable population. .

The aim of this study was to develop a population pharmacokinetic (PK) model for clearance of mycophenolic acid (MPA) in adult renal transplant recipients, to quantify the PK parameters and the influence of covariates on the MPA pharmacokinetic parameters. Parameters associated with plasma concentrations of MPA at steady-state were analyzed in 70 renal transplant recipients (mean age 42.97 years; mean total body weight 75.33 kg) using nonlinear mixed-effect modeling (NONMEM). Characteristics of patients screened for influence on the pharmacokinetic parameters were gender, age, body weight, time after transplantation, whether the patient was diagnosed as having diabetes mellitus, organ source (living or deceased donor), biochemical parameters and co-therapy (tacrolimus, cyclosporine, prednisolone, omeprazole, bisoprolol, carvedilol, nifedipine). A validation set of 25 renal transplant recipients was used to estimate the predictive performance of population pharmacokinetic model. Typical mean value of MPA oral clearance, estimated by base model (without covariates) was 0.741 L h(-1). During population modeling, the full model showed that clearance of the MPA was significantly influenced by age, total daily dose of MPA, creatinine clearance, albumin level, status and gender of a donor, and the nifedipine and tacrolimus co-therapy. In the final model, clearance of MPA was reported to be significantly influenced by age, total daily dose of MPA and thenifedipine co-therapy. The derived model describes adequately MPA clearance in terms of characteristics of our patients, offering basis for individual pharmacotherapy approach.

Bisoprolol is a selective beta adrenergic antagonist commonly used in treatment of coronary artery disease (CAD). The aim of our analysis was to estimate and identify different factors that could affect bisoprolol clearance (CL) and develop a population pharmacokinetic model in patients with stable coronary artery disease (CAD). Population pharmacokinetic analysis was performed by using sixty-six plasma concentrations from the same number of patients (mean age 60.26 ± 9.68 years; mean total body weight 80.37 ± 12.93 kg) with CAD. We examined the effects of various clinical and demographic parameters using nonlinear mixed-effect modeling (NONMEM) with ADVAN1 with TRANS2 subroutine. The pharmacokinetics of bisoprolol in patients with CAD were suitably defined by an oral one-compartment model. The typical mean value for bisoprolol CL, estimated by the base model, in the target population was 6.76 l/h. The only demographic covariate which affected bisoprolol pharmacokinetic variability was creatinine clearance (CLcr). The final model of bisoprolol clearance was described by following equation: CL (l/h) = 2.83 + 0.0385 × CLcr (ml/min). Validation of the final model was performed in a group of 17 patients using the validation set and bootstrapping analysis. These findings suggest that one of the causes of clearance of bisoprolol variability in patients with CAD is the difference in renal function.

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.

The aim of this study was to derive population pharmacokinetic (PK) model for clearance (CL) of carvedilol in adult patients with chronic heart failure (CHF). Medication and demographic data were obtained from 52 Caucasian patients with CHF taking carvedilol. Population PK analysis was performed by nonlinear mixed-effects modeling (NONMEM) to estimate and identify different factors that could affect carvedilol CL. A total of 55 plasma concentrations were collected from 52 patients with mean age of 63.02 ± 11.95 years and total body weight (TBW) of 77.96 ± 13.46 kg. Total daily doses of carvedilol in the target population had wide range of variability (6.25–50 mg), followed by high variability of drug plasma concentrations (1–59.07 ng/mL). The typical mean value for carvedilol CL, estimated by the base model, in the target population was 43.8 L/h. The TBW, concomitant therapy with digoxin, and tobacco using were determinants of a derived population model. The final regression model for the CL of carvedilol is: CL(L/h) = 10 + 0.434 * TBW + 22.5 * Digoxin + 29.9 * Tobacco Our results suggest that the TBW, concomitant therapy with digoxin, and tobacco using are the main subjects of carvedilol PK variability. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2851–2858, 2013

This article reviews a population pharmacokinetics studies conducted during the past few years in Serbia. Studies have included three the most frequently used antiepileptic drugs (valproate, carbamazepine and lamotrigine) and different populations of epileptic patients: children, adults and heterogeneous population composed of both children and adults. The review compares obtained values of population pharmacokinetic models of clearance of these drugs, and factors that are significantly determined, making brief comments on the results of other authors on the same topic. Individualization of drug dosage is the basis of rational therapy, and factors of variability will always be subject of scientific research.

Although carbamazepine is one of the oldest anticonvulsant drugs, it is still heavily utilized for treatment of epilepsy in children. The aim of this article was to review the current knowledge about pharmacokinetics and pharmacogenetics of carbamazepine in children. The literature for this review was systematically searched for in the MEDLINE and SCINDEKS databases. Oral bioavailability of carbamazepine in children is about 75–85%, and it is approximately 75–85% bound to plasma proteins. Apparent volume of distribution is 1.2–1.9 l/kg and total clearance between 0.05 and 0.1 l/h/kg. Pharmacokinetics of carbamazepine in children is age and body weight dependent and highly variable due to influence of dosing regimen and co-medication. The current evidence on the importance of pharmacogenetics for carbamazepine efficacy and safety in children supports the association of PXR*1B, HNF4a rs2071197, CYP1A2*1F, ABCC2 1249G>A, and PRRT2 c.649dupC with either pharmacokinetics or pharmacodynamics of carbamazepine. The importance of human leukocyte antigen (HLA) typing for prediction of adverse drug reactions to carbamazepine in children is also confirmed. Both genetic and environmental factors are responsible for shaping pharmacokinetics and pharmacodynamics of carbamazepine in children. To ensure safe and effective use of carbamazepine in this population, physicians should adjust dosing regimen according to existing pattern of genetic and environmental influences.

There are contradictory opinions if late-onset systemic lupus erythematosus (SLE) is associated with a different, more benign disease course and better prognosis than early-onset SLE. The objective of this study was to evaluate the clinical manifestations, course, treatment, and prognosis of late-onset SLE. Patients who developed SLE after/or at the age of 50 years were considered late-onset SLE and compared to a group of randomly selected patients aged younger than 50 years at the diagnosis, matched for disease duration. Lower frequency of cutaneous manifestations (p = 0.01) and higher frequency of cytopenias (p = 0.02) were registrated at the SLE onset in the late-onset group. Atypical clinical presentation of SLE contributed to a longer delay of diagnosis in late-onset SLE patients (p = 0.005), who fullfiled less American College of Rheumatology criteria at the diagnosis (p = 0.022). Cumulative incidence of clinical manifestations showed lower frequency of cutaneous (p = 0.017), neuropsychiatric manifestations (p = 0.021), lupus nephritis (p = 0.006), and higher frequency of Sjogren's syndrome (p = 0.025) in the late-onset group. Late-onset SLE patients received lower doses of corticosteroid (p = 0.006) and cyclophosphamide (p = 0.001) and had more cyclophosphamide-induced complications (p = 0.005). Higher prevalence of comorbid conditions in the late-onset group (p = 0.025), and higher Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index was noticed (p = 0.018). Despite the less major organ involvement and more benign course of disease, late-onset SLE has poorer prognosis, because of the higher frequency of comorbid conditions and higher organ damage, due to the aging and longer exposition to a classical vascular risk factors.

The aim of the study was to develop a population pharmacokinetic (PK) model for clearance of bisoprolol in patients with congestive heart failure (CHF).Parameters associated with the plasma concentrations of bisoprolol at steady-state were analyzed in 61 patients (mean age 66.21 ± 9.49 years; mean total body weight 8.90 ± 12.26 kg) with CHF using non-linear mixed-effect modeling (NONMEM). A validation set of 17 patients with heart failure was used to estimate the predictive performance of the pharmacokinetic model.The typical mean value for bisoprolol clearance (CL), estimated by the base model (without covariates), in our population was 11.4 l h(-1). In the full model, covariates such as bisoprolol total daily dose (DD) and creatinine clearance were included. The final regression model for the clearance of bisoprolol was the following: CL (l h(-1)) = 4.68 + 0.859 * DD.The derived PK model describes the clearance of bisoprolol in patients with CHF, showing that the total daily dose of bisoprolol is the most important covariate. This finding will provide the basis for future PK studies on beta blockers in this specific patient population and lead to better overall management of heart failure.

The aim of our study was to estimate clearance of bisoprolol and reveal the factors that could influence its pharmacokinetic (PK) variability in hypertensive patients on hemodialysis, using the population PK analysis. Parameters associated with plasma concentration of bisoprolol at steady state were analyzed in 63 patients (mean age 62.12 years, mean total weight 69.63 kg) who were hypertensive and on hemodialysis due to severe renal failure using non-linear mixed-effect modeling with ADVAN1 subroutine. The final regression model for the clearance of the drug included only creatinine clearance (CLcr) out of 12 tested covariates. The equation that describes CL of bisoprolol is the following: CL (l/h) = 0.12 + 6.33 * CLcr. These findings suggest that the routine measuring of serum creatinine level may be used to facilitate administration of bisoprolol in patients on hemodialysis.

The purpose of this study is to investigate the effect of two of the most important functional CYP1A2 variations −3860G > A and −163C > A on carbamazepine pharmacokinetics in Serbian pediatric epileptic patients. The study involved 40 Serbian pediatric epileptic patients on steady-state carbamazepine treatment. Genotyping for −3860G > A and −163C > A was carried out using PCR-RFLP method, and carbamazepine plasma concentrations were determined by high pressure liquid chromatography (HPLC) method. For pharmacokinetic analysis, NONMEM software with implementation of ADVAN 1 subroutine was used. CYP1A2 polymorphism −163C > A was found at the frequency of 65.0 %, while −3860G > A was not detected. The correlation between weight-adjusted carbamazepine dose and carbamazepine concentration after dose adjustment was significant only in carriers of −163C/C and C/A genotypes (r = 0.68, p = 0.0004). The equation that described population clearance (CL) was CL (l/h) = 0.176 + 0.0484 * SEX + 0.019 * CYP1A2 + 0.000156 * DD, where SEX has a value of 1 if male and 0 if female, CYP1A2 has a value of 1 if −163A/A and 0 if −163C/C or C/A, and DD is the total carbamazepine daily dose (mg/day). CYP1A2 −163A/A genotype influence carbamazepine pharmacokinetics. In addition to sex and total carbamazepine daily dose, −163C > A CYP1A2 polymorphism should be considered as a predictor of carbamazepine clearance.

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.

1 , Jasmina Milovanovic 2 , Snežana V Jankovic 2 , Natalija Todorovic 3 , Nemanja Rancic 4 , Nikola Jestrovic 5 , 6 , Slobodan Jankovic 2 , Mihajlo Jakovljevic 2 1 Centar za radiolosku dijagnostiku , Klinicki centar Kragujevac, Srbija 2 Odsek za farmakologiju I toksikologiju, Fakultet medicinskih nauka, Kragujevac, Srbija 3 Klinika za neurologiju, Klinicki centar Kragujevac, Srbija 4 Fakultet medicinskih nauka, Univerzitet u Kreagujevcu, Srbija 5 Merck Sharp & Dohme Idea Inc., AG Beograd, Srbija 6 Farmaceutski fakultet, Univerzitet u Ljubljani, Slovenija Epilepsy, one of the most common neurological dis- eases, demands persistent and long-term therapy. In spite of the available therapeutic interventions for seizure dis- orders, the incidence of epilepsy and mortality associated with "status epilepticus" remain significant (1). The goal of seizure management is satisfying seizure control with minimal side effects (2). Quality of life (QoL) studies have suggested that patients who suffer even a single seizure per year exhibit significantly reduced QoL (3). Among the wide range of medications offered in the market, valproic acid is still considered by many to be "a gold standard" to treat many convulsive disorders, including absence , gen- eralised tonic-clonic seizures, myoclonic juvenile seizures, and photosensitive seizures . It also exhibits an acceptable toxicity profile compared with other anticonvulsants (4). The Serbian health care system is still not capable of sys- temic therapeutic drug monitoring in clinical practice. The underlying reasons are typical for an upper-middle income transitional market and are attributed to both financial con- straints and the lack of skilled, highly educated human re- source availability in the field. These reasons influenced the authors to report pilot trial results to provide a small move forward on the issue among local clinicians (5). The core aim of the trial presented was an exploration of the dose-response relationship in a small group of twelve adults suffering from epilepsy. The authors studied fre- quencies of drug adverse effects associated with long-term monotherapy and evaluated the appropriateness and clini- cal value of regular therapeutic drug monitoring (TDM) of valproic acid. The presence of a correlation between drug plasma concentration as an independent variable and fre- quency of seizures, frequency of adverse events and over- all life quality as dependent variables was also tested. The reported results are an unpublished fragment originating from a large-scale collaborative project on pharmacoki- netic modelling in juvenile epilepsy treatment (3-6).

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.

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.

The purpose of this study was to perform population pharmacokinetic (PPK) analysis on carbamazepine and to determine the population model of clearance of this drug in terms of individual patient characteristics. A total of 107 steady-state serum concentrations from 97 adult and pediatric epileptic patients, collected during routine clinical care, were used for the analysis. To determine the influence of different covariates on the estimate of carbamazepine clearance we used the non-linear mixed effects modeling (NONMEM) software package with ADVAN1 subroutine. This is a one-compartment model with first-order elimination and without absorption. The typical mean value for carbamazepine clearance, estimated by the base model (without covariates), in our population was 3.43 l/h. The final results of our analysis show that carbamazepine clearance increased nonlinearly with total body weight and age, and linearly with concomitant administration of valproate. The magnitude of the effect of valproate was +0.874 l/h. The interindividual variability (coefficient of variation) for clearance and the residual variability (including intraindividual variability), described by an exponential error model, were 16.76% and 31.14%, respectively. The results of this PPK analysis were validated in a group of 16 epileptic patients and suggested good predictive performance of the final model. The derived model describes carbamazepine clearance in terms of characteristics of Serbian patients, using minimal data obtained from routine clinical care of epileptic patients. This is the basis for future pharmacokinetic studies on a specific epileptic population, which will lead to better overall management of epilepsy in Serbia.

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.

INTRODUCTION: The aim of our study was to develop and use a population pharmacokinetic model for assessment of individual valproate clearance in children and young adults suffering from epilepsy.MATERIAL AND METHODS: The analysis was performed using 52 steady-state concentrations of valproate collected from 26 epileptic patients during the routine clinical practice in our hospital. The mean values of age and total body weight were 19.92 years and 57.12 kg, respectively. NONMEM software with ADVAN 1 subroutine was used for model building and assessing the influence of different covariates. A validation set of 20 epileptic patients (one blood sample per a patient) was used to estimate predicted performances of the pharmacokinetic model.RESULTS: The typical mean value of the clearance of valproate estimated by the base model in our population was 0.3 77 I/h. Out of five considered covariates (total body weight, age, total daily dose, gender and polytherapy) only the age of the patients was a significant determinant of the clearance of valproate. The final regression model for the clearance of valproate was as following: CL (l/h) = 0.223 + 0.00819 * AGE CONCLUSION: The derived pharmacokinetical model describes the clearance of valproate in relation to patient's age in the observed population. it will help to improve the seizure control in young patients with epilepsy in Serbian population. (Less)