Browsing by Author "Vučićević, Katarina (6505905498)"

Purpose: The goal of the study was to examine clozapine (CLZ) and norclozapine (NCLZ) therapeutic drug monitoring (TDM) data and associated sources of pharmacokinetic variability, particularly the impact of valproic acid (VPA) use. Methods: This study included 126 patients with psychiatric disorders on mono- or co-therapy with CLZ. Patients’ data during routine TDM were collected retrospectively from clinical records. The descriptive and statistical analysis was computed using IBM SPSS Statistics software (version 22, NY, USA). Multiple linear regression, based on the last observations, was used to assess correlation between demographic characteristics, life habits and co-therapy with dose-corrected serum levels (C/D) of CLZ and NCLZ, as well as CLZ/NCLZ. Results: A total of 295 CLZ concentrations were measured in 126 patients, with a mean of 275.5 ± 174.4 µg/L, while 124 NCLZ concentrations were determined in 74 patients, with a mean of 194.6 ± 149.8 µg/L. A statistically significant effect on ln-transformed CLZ C/D was confirmed for sex and smoking, whereas sex, smoking and VPA therapy were associated with ln-transformed NCLZ C/D. According to the final models, lower values of NCLZ C/D for about 45.9% can be expected in patients receiving VPA. Concomitant use of VPA was the only factor detected to contribute in CLZ/NCLZ variability. Conclusion: The results of this study may help clinicians interpret TDM data and optimize CLZ dosing regimens, especially in patients concomitantly treated with VPA. Our results show that VPA primarily decreases NCLZ levels, while alteration of the parent drug is not statistically significant. © 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Purpose: The goal of the study was to examine clozapine (CLZ) and norclozapine (NCLZ) therapeutic drug monitoring (TDM) data and associated sources of pharmacokinetic variability, particularly the impact of valproic acid (VPA) use. Methods: This study included 126 patients with psychiatric disorders on mono- or co-therapy with CLZ. Patients’ data during routine TDM were collected retrospectively from clinical records. The descriptive and statistical analysis was computed using IBM SPSS Statistics software (version 22, NY, USA). Multiple linear regression, based on the last observations, was used to assess correlation between demographic characteristics, life habits and co-therapy with dose-corrected serum levels (C/D) of CLZ and NCLZ, as well as CLZ/NCLZ. Results: A total of 295 CLZ concentrations were measured in 126 patients, with a mean of 275.5 ± 174.4 µg/L, while 124 NCLZ concentrations were determined in 74 patients, with a mean of 194.6 ± 149.8 µg/L. A statistically significant effect on ln-transformed CLZ C/D was confirmed for sex and smoking, whereas sex, smoking and VPA therapy were associated with ln-transformed NCLZ C/D. According to the final models, lower values of NCLZ C/D for about 45.9% can be expected in patients receiving VPA. Concomitant use of VPA was the only factor detected to contribute in CLZ/NCLZ variability. Conclusion: The results of this study may help clinicians interpret TDM data and optimize CLZ dosing regimens, especially in patients concomitantly treated with VPA. Our results show that VPA primarily decreases NCLZ levels, while alteration of the parent drug is not statistically significant. © 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

The choice of an antiepileptic drug (AED) is usually based upon the epileptic seizure type. However, pharmacokinetic (PK) characteristics of AEDs may be valuable support in choosing the optimal therapeutic option for the individual patient. The novel (second and third generation) AEDs include: eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide. Although, these drugs belong to the same group, their individual PK characteristics differ. Gabapentin, unlike other new AEDs, is characterised by dose-dependent absorption, which is presumably caused by saturable L-amino acid transport system, and therefore its bioavailability ranges from 35-60%. Furthermore, gabapentin, pregabalin and vigabatrin are eliminated completely, while levetiracetam and topiramate are eliminated predominantly through the renal system. Therefore, PK variability of these individual drugs is less pronounced and more predictable in comparison to older AEDs. Their potential for drug interactions is minor, and consequently they have major clinical importance for patients with impaired hepatic function. On the other hand, felbamate, lamotrigine, oxcarbazepine, tiagabine and zonisamide are eliminated via metabolic pathways, either cytochrome P (CYP) 450, or conjugation dependent transformation. Oxcarbazepine is a prodrug, and its active metabolite is licarbazepine. These drugs interact with other drugs, and disease conditions, which alter the activity of metabolic enzymes; thus these changes in PK commonly have clinical implications. Gabapentin, levetiracetam and tiagabine do not induce or inhibit hepatic metabolism enzymes. Felbamate demonstrated an inducing effect on CYP 3A4 isoenzyme, and inhibition effect on CYP 2C19 and on β-oxidation of valproic acid. Lamotrigine induces its own metabolism, and some reports imply a decrease of valproic acid levels during concomitant treatment with lamotrigine. Oxcarbazepine induces CYP 3A4, 3A5, and uridine diphosphate glucuronyl transfereases (UGT), and inhibits the metabolism of phenytoin via CYP 2C19 isoenzyme. Similar induction and inhibition characteristics are attributed to topiramate, while some studies indicate that zonisamide may have inhibition potential on phenytoin metabolism. In general, novel AEDs have linear PK, low plasma protein binding, and renal elimination, so their PK is more favorable in comparison with carbamazepine, phenobarbitone and valproic acid. This chapter gives a review of PK parameters of novel AEDs and its' variability based on age, comorbidities, concomitant therapy, and highlights the need of therapeutic drug monitoring. © 2012 Nova Science Publishers, Inc. All rights reserved.

The choice of an antiepileptic drug (AED) is usually based upon the epileptic seizure type. However, pharmacokinetic (PK) characteristics of AEDs may be valuable support in choosing the optimal therapeutic option for the individual patient. The novel (second and third generation) AEDs include: eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide. Although, these drugs belong to the same group, their individual PK characteristics differ. Gabapentin, unlike other new AEDs, is characterised by dose-dependent absorption, which is presumably caused by saturable L-amino acid transport system, and therefore its bioavailability ranges from 35-60%. Furthermore, gabapentin, pregabalin and vigabatrin are eliminated completely, while levetiracetam and topiramate are eliminated predominantly through the renal system. Therefore, PK variability of these individual drugs is less pronounced and more predictable in comparison to older AEDs. Their potential for drug interactions is minor, and consequently they have major clinical importance for patients with impaired hepatic function. On the other hand, felbamate, lamotrigine, oxcarbazepine, tiagabine and zonisamide are eliminated via metabolic pathways, either cytochrome P (CYP) 450, or conjugation dependent transformation. Oxcarbazepine is a prodrug, and its active metabolite is licarbazepine. These drugs interact with other drugs, and disease conditions, which alter the activity of metabolic enzymes; thus these changes in PK commonly have clinical implications. Gabapentin, levetiracetam and tiagabine do not induce or inhibit hepatic metabolism enzymes. Felbamate demonstrated an inducing effect on CYP 3A4 isoenzyme, and inhibition effect on CYP 2C19 and on β-oxidation of valproic acid. Lamotrigine induces its own metabolism, and some reports imply a decrease of valproic acid levels during concomitant treatment with lamotrigine. Oxcarbazepine induces CYP 3A4, 3A5, and uridine diphosphate glucuronyl transfereases (UGT), and inhibits the metabolism of phenytoin via CYP 2C19 isoenzyme. Similar induction and inhibition characteristics are attributed to topiramate, while some studies indicate that zonisamide may have inhibition potential on phenytoin metabolism. In general, novel AEDs have linear PK, low plasma protein binding, and renal elimination, so their PK is more favorable in comparison with carbamazepine, phenobarbitone and valproic acid. This chapter gives a review of PK parameters of novel AEDs and its' variability based on age, comorbidities, concomitant therapy, and highlights the need of therapeutic drug monitoring. © 2012 Nova Science Publishers, Inc. All rights reserved.

Due to wide intra-and inter-individual pharmacokinetic variability and narrow therapeutic index of sirolimus, the therapeutic drug monitoring (TDM) of sirolimus with detailed biochemical and clinical monitoring is necessary for dose individualization in kidney transplant patients. The purpose of the study was to explore and identify factors that contribute to pharmacokinetic variability by developing and validating a population model using routine TDM data and routinely monitored biochemical and clinical parameters. The data obtained by routine monitoring of 38 patients over a period of one year from the sirolimus treatment initiation, were collected from patients' records. Population analysis was performed using the software NONMEM®. The validity of the model was tested by the internal and external validation techniques. The pharmacokinetic variability was partially explained with patient's age and liver function. CL/F was found to decrease with age. According to the developed model, sirolimus CL/F decreases by, in average, 37% in patients with aspartate aminotransferase (AST) greater than 37 IU/L. The internal and external validation confirmed the satisfactory prediction of the developed model. The population modeling of routinely monitored data allowed quantification of the age and liver function influence on sirolimus CL/F. According to the final model, patients with compromised liver function expressed via AST values require careful monitoring and dosing adjustments. Proven good predictive performance makes this model a useful tool in everyday clinical practice. © 2019 Bojana Golubović, Katarina Vučićević, Dragana Radivojević, Sandra Vezmar Kovačević, Milica Prostran, Branislava Miljković.

Due to wide intra-and inter-individual pharmacokinetic variability and narrow therapeutic index of sirolimus, the therapeutic drug monitoring (TDM) of sirolimus with detailed biochemical and clinical monitoring is necessary for dose individualization in kidney transplant patients. The purpose of the study was to explore and identify factors that contribute to pharmacokinetic variability by developing and validating a population model using routine TDM data and routinely monitored biochemical and clinical parameters. The data obtained by routine monitoring of 38 patients over a period of one year from the sirolimus treatment initiation, were collected from patients' records. Population analysis was performed using the software NONMEM®. The validity of the model was tested by the internal and external validation techniques. The pharmacokinetic variability was partially explained with patient's age and liver function. CL/F was found to decrease with age. According to the developed model, sirolimus CL/F decreases by, in average, 37% in patients with aspartate aminotransferase (AST) greater than 37 IU/L. The internal and external validation confirmed the satisfactory prediction of the developed model. The population modeling of routinely monitored data allowed quantification of the age and liver function influence on sirolimus CL/F. According to the final model, patients with compromised liver function expressed via AST values require careful monitoring and dosing adjustments. Proven good predictive performance makes this model a useful tool in everyday clinical practice. © 2019 Bojana Golubović, Katarina Vučićević, Dragana Radivojević, Sandra Vezmar Kovačević, Milica Prostran, Branislava Miljković.

Monitoring and optimization procedures improved high dose methotrexate (HDMTX) treatment outcomes. However, there are still some concerns regarding unexplained concentration variability. The objective of this study was to evaluate drug concentrations and associated variability factors in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) on HDMTX. Fifty patients (aged 1–18 years), receiving in total 184 HDMTX cycles of 3 or 5 g/m2/24 h infusion, were included in the study. Comparisons of MTX concentrations and concentrations to dose ratio between two dosing groups were conducted by Mann-Whitney U test. Regression analysis was performed with transformed data to assess relationship between MTX concentration to dose ratio and patient characteristics, biochemical analysis and therapy data. Statistically significant difference in concentrations between 3 and 5 g/m2 dosing groups was detected only at 24 h after the start of infusion (p < 0.001), but not at 48 and 72 h (p > 0.05). There was no difference between dose-normalized concentrations. Regression analysis showed that 73.9% of variability in dependent variable can be explained by included variables: time since dose, creatinine clearance (CrCl), hemoglobin and certain concomitant therapy. Our results highlight the importance of not only renal function and concomitant therapy, but also hemoglobin in reducing the variation in MTX concentrations. Therefore, monitoring of aforementioned biochemical parameters during HDMTX is important not only to assess toxicity, but also in predicting their impact on drug level. © 2023 Taylor & Francis Group, LLC.

Purpose: The purpose of the study was to examine and describe adjunctive lamotrigine (LTG) pharmacokinetics in paediatric and young adult patients using a nonlinear mixed effects modelling (NONMEM) approach. Methods: The study included 53 patients (age range 3-35 years) who were concomitantly treated with carbamazepine (CBZ) and/or valproic acid (VPA). A total of 70 blood samples corresponding to trough levels were available for analysis. Data were modelled, and the final model was evaluated using NONMEM and auxiliary software tools. Results: The final LTG population model included the effects of concomitant drugs and patient's weight (WT) which stratified the population into three groups: ≤25 kg, >25 to <60 kg and ≥60 kg. Based on the final model, the estimated LTG oral clearance (CL/F) for a typical patient weighing ≤25 kg, >25 to <60 kg or ≥60 kg who was concomitantly treated with CBZ was estimated to be 3.28, 4.23, or 7.15 l/h, respectively. If a patient was concomitantly treated with CBZ + VPA, the CL/F decreased on average by 69.5 % relative to LTG + CBZ co-therapy. VPA was found to decrease the LTG CL/F by 87.6 % compared to co-therapy with only CBZ. Conclusion: The LTG population pharmacokinetic model developed in this study may be a reliable method for individualising the LTG dosing regimen in paediatric and young adult patients on combination therapy during therapeutic drug monitoring. © 2013 Springer-Verlag Berlin Heidelberg.

Purpose: The purpose of the study was to examine and describe adjunctive lamotrigine (LTG) pharmacokinetics in paediatric and young adult patients using a nonlinear mixed effects modelling (NONMEM) approach. Methods: The study included 53 patients (age range 3-35 years) who were concomitantly treated with carbamazepine (CBZ) and/or valproic acid (VPA). A total of 70 blood samples corresponding to trough levels were available for analysis. Data were modelled, and the final model was evaluated using NONMEM and auxiliary software tools. Results: The final LTG population model included the effects of concomitant drugs and patient's weight (WT) which stratified the population into three groups: ≤25 kg, >25 to <60 kg and ≥60 kg. Based on the final model, the estimated LTG oral clearance (CL/F) for a typical patient weighing ≤25 kg, >25 to <60 kg or ≥60 kg who was concomitantly treated with CBZ was estimated to be 3.28, 4.23, or 7.15 l/h, respectively. If a patient was concomitantly treated with CBZ + VPA, the CL/F decreased on average by 69.5 % relative to LTG + CBZ co-therapy. VPA was found to decrease the LTG CL/F by 87.6 % compared to co-therapy with only CBZ. Conclusion: The LTG population pharmacokinetic model developed in this study may be a reliable method for individualising the LTG dosing regimen in paediatric and young adult patients on combination therapy during therapeutic drug monitoring. © 2013 Springer-Verlag Berlin Heidelberg.

Background/Objectives: Several population pharmacokinetic models of vedolizumab (VDZ) are available for inflammatory bowel disease (IBD) patients. However, their predictive performance in real-world clinical settings remains unknown. This study aims to externally evaluate the published VDZ pharmacokinetic models, focusing on their predictive performance and simulation-based clinical applicability. Methods: A literature search was conducted through PubMed to identify VDZ population pharmacokinetic models. A total of 114 VDZ concentrations from 106 IBD patients treated at the University Medical Center “Zvezdara”, Republic of Serbia, served as the external evaluation cohort. The predictive performance of the models was assessed using prediction- and simulation-based diagnostics. Furthermore, the models were utilized for Monte Carlo simulations to generate concentration–time profiles based on 24 covariate combinations specified within the models. Results: Four published pharmacokinetic models of VDZ were included in the evaluation. Using the external dataset, the median prediction error (MDPE) ranged from 13.82% to 25.57%, while the median absolute prediction error (MAPE) varied between 41.64% and 47.56%. None of the models fully met the combined criteria in the prediction-based diagnostics. However, in simulation-based diagnostics, pvcVPC showed satisfactory results, despite wide prediction intervals. Analysis of NPDE revealed that only the models by Rosario et al. and Okamoto et al. fulfilled the evaluation criteria. Simulation analysis further demonstrated that the median VDZ concentration remains above 12 μg/mL at week 22 during maintenance treatment for approximately 45–60% of patients with the best-case covariate combinations and an 8-week dosing frequency. Conclusions: None of the published models satisfied the combined criteria (MDPE, MAPE, percentages of prediction error within ±20% and ±30%), rendering them unsuitable for a priori predictions. However, two models demonstrated better suitability for simulation-based applications. © 2024 by the authors.

Background/Objectives: Several population pharmacokinetic models of vedolizumab (VDZ) are available for inflammatory bowel disease (IBD) patients. However, their predictive performance in real-world clinical settings remains unknown. This study aims to externally evaluate the published VDZ pharmacokinetic models, focusing on their predictive performance and simulation-based clinical applicability. Methods: A literature search was conducted through PubMed to identify VDZ population pharmacokinetic models. A total of 114 VDZ concentrations from 106 IBD patients treated at the University Medical Center “Zvezdara”, Republic of Serbia, served as the external evaluation cohort. The predictive performance of the models was assessed using prediction- and simulation-based diagnostics. Furthermore, the models were utilized for Monte Carlo simulations to generate concentration–time profiles based on 24 covariate combinations specified within the models. Results: Four published pharmacokinetic models of VDZ were included in the evaluation. Using the external dataset, the median prediction error (MDPE) ranged from 13.82% to 25.57%, while the median absolute prediction error (MAPE) varied between 41.64% and 47.56%. None of the models fully met the combined criteria in the prediction-based diagnostics. However, in simulation-based diagnostics, pvcVPC showed satisfactory results, despite wide prediction intervals. Analysis of NPDE revealed that only the models by Rosario et al. and Okamoto et al. fulfilled the evaluation criteria. Simulation analysis further demonstrated that the median VDZ concentration remains above 12 μg/mL at week 22 during maintenance treatment for approximately 45–60% of patients with the best-case covariate combinations and an 8-week dosing frequency. Conclusions: None of the published models satisfied the combined criteria (MDPE, MAPE, percentages of prediction error within ±20% and ±30%), rendering them unsuitable for a priori predictions. However, two models demonstrated better suitability for simulation-based applications. © 2024 by the authors.

Background: Balkan endemic nephropathy (BEN) hemodialysis patients require a higher dose of recombinant human erythropoietin for maintaining target hemoglobin level than patients with other kidney diseases. Objectives: Comparison of the pharmacokinetics of betaerythropoietin given subcutaneously to hemodialysis patients with BEN or other kidney diseases (non-BEN). Methods: Recombinant human erythropoietin (75U/kg) was administered subcutaneously to 10 BEN and 14 non-BEN hemodialysis patients. The predose plasma level of erythropoietin (Epo) was subtracted from all postdose levels. The relevant pharmacokinetic parameters were calculated after noncompartmental pharmacokinetic analysis using Kinetica software (Thermo Scientific, ver.5.0). Results: Although basal plasma Epo concentration was similar in BEN (20.1±10.3U/L) and non-BEN (15.1±8.1U/L; p=.1964) patients, there were significant differences between the groups for elimination rate constant (0.016±0.006 vs 0.026±0.011 hr-1; p=.020) and elimination half-life (50.24±19.12 vs 33.79±18.91 hr, p=.048). These differences remained significant after adjustment for patient characteristics (age, sex, hemodialysis duration, ferritin, PTH and ACEI use). No significant differences between groups were found in maximal Epo concentration, time to maximum Epo concentration, area under the curve from time of dosing extrapolated to infinity, clearance, mean residence time of Epo between groups both before and after adjustment. Conclusion: Pharmacokinetic analysis of betaerythropoietin detected a significantly longer elimination half-life in BEN than in non BEN patients. This finding needs to be confirmed in a well-controlled study with a larger sample size © 2013 Revista Nefrología. Official Publication of the Spanish Nephrology Society.