The significant role of dietary intake of vitamin D in non-menopausal women health.

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.

Population pharmacokinetic analysis of bisoprolol in type 2 diabetic patients with hypertension.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Contemporary surgical management of drug-resistant focal epilepsy.

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 by loss of consciousness, drug-resistant epilepsy could be treated by surgery.Areas covered: The aim of this article was to review current status of epilepsy surgery through description of the most important operative methods and narrative comparison of their benefits and harms. In total 1154 articles were retrieved from MEDLINE, SCOPUS, EBSCO, and SCINDEKS databases, and 78 included in the review. The review included systematic reviews, meta-analyses, clinical trials, observational studies on humans, case series, and case reports.Expert opinion: Sophisticated diagnostic methods nowadays offer much more precise localization of epileptogenic focus and detailed planning of a surgical procedure which will make minimal damage of neural pathways and structures essential for movements, speech, cognition, and emotions. Advent of perioperative care, and improved diagnostics and surgical techniques resulted with significant drop in rates of postoperative complications, long-term neurological deficit, and mortality in the last decade, while seizure freedom rate and quality of life increased.

Population Pharmacokinetic Analysis of Bisoprolol in Patients With Acute Coronary Syndrome.

To date, many questions about the extent and cause of pharmacokinetic (PK) variability of even the most widely studied and prescribed ß1-adrenergic receptor blockers, such as metoprolol and bisoprolol, remain unanswered. Given that there are still no published population pharmacokinetic (PopPK) analyses of bisoprolol in routinely treated patients with acute coronary syndrome (ACS), the aim of this study was to determine its PK variability in 71 Serbian patients with ACS. PopPK analysis was conducted using a nonlinear mixed-effects model (NONMEM), version 7.3.0 (Icon Development Solutions). In each patient, the same formulation of bisoprolol was administered once or twice daily at a total daily dose of 0.625-7.5 mg. We separately assessed the effects of 31 covariates on the PKs of bisoprolol, and our results indicated that only 2 covariates could have possible influence on the variability of the clearance of bisoprolol: the mean daily dose of the drug and smoking habits of patients. These findings suggest that possible autoinduction of drug metabolism by higher total daily doses and induction of cytochrome P450 isoform 3A4 (CYP3A4) by cigarette smoke in liver could be the potential causes of increased total clearance of bisoprolol in patients with ACS.

Population pharmacokinetics of 25-hydroxy vitamin D in children with asthma
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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.
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Population Pharmacokinetic Analysis of Bisoprolol in Patients with Stable Coronary Artery Disease.

BACKGROUND AND OBJECTIVES: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: These findings suggest that one of the causes of clearance of bisoprolol variability in patients with CAD is the difference in renal function.

Evaluation of brivaracetam: a new drug to treat epilepsy.

INTRODUCTION: High prevalence of therapy-resistant epilepsy demands development of anticonvulsants with new mechanisms of action. Brivaracetam is an analogue of levetiracetam which binds to the synaptic vesicle protein 2A (SV2A) and decreases release of excitatory neurotransmitters. Areas covered: Relevant published studies were searched for by predefined strategy in MEDLINE, EBSCO and SCINDEKS electronic databases. Brivaracetam is effective as adjunctive therapy for uncontrolled partial-onset seizures with or without secondary generalization in patients 16 years and older with epilepsy. It reduces baseline-adjusted focal seizure frequency per week from 7.3 to 12.8% over placebo. Adverse events rate in patients with brivaracetam is not higher than in patients with placebo. Expert opinion: Brivaracetam is an important step forward in the treatment of therapy-resistant partial-onset seizures with or without secondary generalization. Its development was systematic and targeted. Due to its efficacy and excellent safety profile, it is likely that brivaracetam will be often prescribed. In future, efficacy and safety of brivaracetam should be tested in monotherapy settings and also in the first-line therapy of partial-onset seizures.

Pharmacokinetics and Pharmacogenetics of Carbamazepine in Children.

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.

CYP1A2 genotype affects carbamazepine pharmacokinetics in children with epilepsy.

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Population Pharmacokinetics of Bisoprolol in Hemodialysis Patients with Hypertension.

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.

Variability of mycophenolic acid elimination in the renal transplant recipients ­ population pharmacokinetic approach.

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.

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.

Population pharmacokinetics of carvedilol in patients with congestive heart failure.

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: [Formula: see text] Our results suggest that the TBW, concomitant therapy with digoxin, and tobacco using are the main subjects of carvedilol PK variability.

Population pharmacokinetics of bisoprolol in patients with chronic heart failure.

PURPOSE: The aim of the study was to develop a population pharmacokinetic (PK) model for clearance of bisoprolol in patients with congestive heart failure (CHF). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

[Pharmacokinetic modelling of valproate in epileptic patients].

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.

Pharmacokinetic modeling of carbamazepine based on clinical data from Serbian epileptic patients.

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.