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The study aimed to estimate and compare the prevalence and type of potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs) between the STOPP/START original (v1) and updated version (v2) among older patients in various settings, as well as associated factors. The study included 440 patients attending a community pharmacy, 200 outpatients and 140 nursing home users. An increase in the prevalence of STOPP v2 (57.9%) compared to v1 (56.2%) was not statistically significant in the total sample and within each setting (p>0.05). A decrease in the prevalence of START v1 (55.8%) to v2 (41.2%) was statistically significant (p

Background: Treatment of various types of cancer has been improved significantly with the discovery of biological drugs that act as immune checkpoint inhibitors (ICIs). Pembrolizumab is a humanized monoclonal anti- PD-1 antibody currently approved for the treatment of a wide range of tumors, with more indications still being investigated in ongoing clinical trials. Objective: The aim of this paper is to present all currently available data regarding pembrolizumab pharmacokinetic and pharmacodynamic characteristics. Also, the possibility of using predictive biomarkers to monitor patients during cancer treatment is discussed. Methods: Database research was carried out (PubMed, ScienceDirect). Information was gathered from original articles, the European Medicines Agency datasheets and results from clinical trials. Results: This review summarizes present-day knowledge about the pharmacokinetics, different modeling approaches and dosage regimens, efficacy and safety of pembrolizumab and therapeutic monitoring of disease progression. Conclusion: This review points out consistent pharmacokinetic characteristics of pembrolizumab in various cancer patients, the lack of pharmacokinetic-pharmacodynamic/outcome relationships, and the need for adequate biomarkers to predict treatment success. Hence, there is a clear necessity for more data and experience in order to optimize pembrolizumab treatment for each individual patient.

Introduction: The second most common form of cancer in the male population is prostate cancer. Therapeutic options include radical prostatectomy, different forms of radiotherapy, hormone treatment and chemotherapy. Radical prostatectomy and radiotherapy are the most frequently used strategies and enable a long survival for patients diagnosed on time. Because of the prostate anatomy, patients that are on radiotherapy experience a great range of side effects, and even after the therapy is finished, side effects such as urogenital and gastrointestinal toxicity can persist for years. Although survival is long regardless of the therapeutic option used, choosing the appropriate therapeutic options for the patients in terms of efficacy and safety is very important [1]. Objectives: We aimed in developing a model for repeated count data, i.e. fatigue, which is the most common adverse event that patients experience during radiotherapy. In addition, the objective of the study is to assess the effect of various covariates on the probability of the event happening using different modelling approaches [2]. Methods: Data collected from prostate cancer patients included: age, concentrations of glutamine and glutamate before radiotherapy and after 5, 15, 25 and 30 fractions of radiotherapy, as well as a month after the last fraction of radiotherapy (first follow – up visit), genetic testing results regarding variants in glutamine metabolic pathway, signs and symptoms of acute or chronic urogenital and gastrointestinal toxicity, fatigue, details of their treatment (e.g. radical prostatectomy, hormone therapy), their smoking and alcohol intake status, presence of hypertension or diabetes mellitus type II, and other laboratory findings of significance. Analysis was performed using nonlinear mixed effects modelling approach using NONMEM® software (version 7.4). We tested two approaches: modelling using the first-order estimation method and the Laplace method of estimation in order to create a Poisson model for count data. NONMEM outputs were handled in R software (graphical diagnostics). Model evaluation has been performed using numerical and visual approaches. Covariate model building was performed using a stepwise covariate procedure (SCM). Covariates that were tested are age, glutamine/glutamate concentrations (continuous, time-varying covariates). The influence of categorical covariates was also examined (smoking and alcohol intake, presence of aforementioned comorbidities). Results: In total, we analysed 143 data records from 28 male patients aged 53-82 years (mean±sd: 72.67±6.64), mainly older people (>65 years old) that were included in the analysis. The probability of fatigue occurrence was 78.3%, which was rather high but expected. The objective function value of the developed base model using the Laplace method of estimation was 546.346. The average number of fatigue events occurring in the period from the start of the radiotherapy until the first follow-up visit was estimated to be 2.48 with a 95% confidence interval of 1.655 - 3.305 and RSE of 17%. Interindividual variability in the number of fatigue events per patient was estimated at 48.3%, with a shrinkage of 11.1%. The inclusion of the covariates in the base model did not improve the model fit, so they were not kept in the model. Conclusion: Our results confirm that fatigue is one of the most common side effects of radiotherapy. Although our model did not show that examined covariates have an effect on the average number of fatigue events, further analysis will aim at testing different modelling approaches when it comes to modelling side effects of radiotherapy in order to minimize them in cancer patients. [1] Retrieved from https://www.nhs.uk/conditions/prostate-cancer/treatment/ . Last access: 19.3.2023. [2] Plan E.L. Modeling and simulation of count data. CPT Pharmacometrics Syst. Pharmacol. 2014: 3 (8): p. e129. PAGE 31 (2023) Poster: Drug/Disease Modelling - Oncology

Introduction: Infliximab (IFX), anti-tumour necrosis factor alpha antibody, is widely used in the treatment of inflammatory bowel diseases. Patients with Crohn’s disease may develop a more complicated form which involves fistulae formation, most commonly perianal. IFX has been effective in inducing fistula closure and maintaining disease remission [1]. In order to achieve fistulae healing adequate trough concentrations should be achieved [2]. Objectives: Obtaining PK parameters for patients with the fistulising disease form Comparing the results to the ones available in the literature for Crohn’s disease Methods: In a retrospective review of medical documentation (from 2013 to present), 42 patients (64% male, 18-65 years old) with fistulising Crohn’s disease were selected for analysis. IFX concentrations were measured just before dose administration (trough concentration) or earlier if the patient was experiencing severe disease symptoms. For the majority of patients concentration was measured at week 14, right before the first maintenance dose. Additional concentrations were obtained at scheduled check-ups or after patients experienced signs of relapse. After appropriate premedication, each patient received the calculated fixed dose based on their body weight (dose range was 200-800 mg) via two-hour infusion. The drug was administered according to the standard (week 0, 2 and 6) and accelerated induction (every two weeks) protocols, followed by maintenance therapy (every 4, 6 or 8 weeks). Population modelling approach was applied to characterize pharmacokinetic profile of IFX using NONMEM 7.3 software (ICON Development Solutions Inc., Dublin, Ireland) [3]. The obtained data were processed using Microsoft Excel and R software. Results: After exclusion of concentrations over the upper limit of quantification (12 μg/mL), a total of 161 concentrations were analysed. IFX concentrations below lower limit of quantification were accounted for using the M5 method [4]. Pharmacokinetics of IFX has, so far, been described by both one- and two-compartment models [5, 6], therefore both were assessed to determine which would best describe the data. Models were evaluated by comparing the objective function values (OFV) as well as goodness-of-fit diagnostic plots and visual predictive checks. A two-compartment model calling ADVAN3 TRANS3 subroutine with first order elimination was selected (OFV 600.03). The estimated values of parameters (with relative standard error) were as follows: Clearance = 0.38 L/day (12.4 %) Steady-state volume of distribution = 4.26 L (23.2 %) Intercompartmental clearance = 0.16 L/day (the value was fixed) Central volume of distribution= 1.05 L (the value was fixed) Inter-individual variability on clearance = 0.37 (28 %) Proportional error = 0.66 (8.6%) Additive error = 0.93 (37.8%) Compared to data available in the literature, the obtained value of IFX CL in our patient population was slightly higher, probably due to disease severity and inflammation status of patients. Therefore, further analysis of covariate effects and exposure-response relationship will be explored in further research. Conclusion: These preliminary results suggest that patients with fistulising form of Crohn’s disease may have higher IFX clearance and since higher trough concentrations are associated with fistulae healing, dose increase and/or dosing interval shortening could be beneficial to achieve disease remission. References: [1] Gecse K, Khanna R, Stoker J, Jenkins JT, Gabe S, Hahnloser D, D’Haens G. Fistulizing Crohn’s disease: Diagnosis and management. United European gastroenterology journal. 2013 Jun;1(3):206-13. [2] Gu B, Venkatesh K, Williams AJ, Ng W, Corte C, Gholamrezaei A, Ghaly S, Xuan W, Paramsothy S, Connor S. Higher infliximab and adalimumab trough levels are associated with fistula healing in patients with fistulising perianal Crohn’s disease. World journal of gastroenterology. 2022 Jun 6;28(23):2597. [3] Owen JS, Fiedler-Kelly J. Introduction to population pharmacokinetic/pharmacodynamic analysis with nonlinear mixed effects models. John Wiley & Sons; 2014 Jun 19. [4] Beal SL. Ways to fit a PK model with some data below the quantification limit. Journal of pharmacokinetics and pharmacodynamics. 2001 Oct 1;28(5):481. [5] Konecki C, Feliu C, Cazaubon Y, Giusti D, Tonye-Libyh M, Brixi H, Cadiot G, Biron A, Djerada Z. External evaluation of population pharmacokinetic models and Bayes-based dosing of infliximab. Pharmaceutics. 2021 Aug 3;13(8):1191. [6] Schräpel C, Kovar L, Selzer D, Hofmann U, Tran F, Reinisch W, Schwab M, Lehr T. External model performance evaluation of twelve infliximab population pharmacokinetic models in patients with inflammatory bowel disease. Pharmaceutics. 2021 Aug 31;13(9):1368. PAGE 31 (2023) Poster: Drug/Disease Modelling - Other Topics

Objective.Therapeutic monoclonal antibodies in oncology are slowly becoming the dominant treatment option for many different cancer types. The main route of administration, infusion, requires extensive product preparations, patient hospitalization and close monitoring. Patient comfort improvement, staff workload reduction and cost savings dictated the development of subcutaneous formulations. The aim of this review is to present pharmacokinetic characteristics of subcutaneous products, discuss the differences between intravenous and subcutaneous routes and to point out the advantages as well as challenges of administration route shift from the formulation development and pharmacometric angle.Data sources.Food and Drug administration's Purple book database and electronic medicines compendium were used to identify monoclonal antibodies in oncology approved as subcutaneous forms. Using keywordssubcutaneous, monoclonal antibodies, pharmacokinetics, model, as well as specific drugs previously identified, both PubMed and ScienceDirect databases were researched.. Data Summary.There are currently six approved subcutaneous onco-monoclonal antibodies on the market. For each of them, exposure to the drug was similar in relation to infusion, treatment effectiveness was the same, administration was well tolerated by the patients and costs of the medical service were reduced.Conclusion.Development of subcutaneous forms for existing and emerging new monoclonal antibodies for cancer treatment as well as shifting from administration via infusion should be encouraged due to patient preference, lower costs and overall lack of substantial differences in efficacy and safety between the two routes.

The atypical antipsychotic clozapine (CLZ) is primarily used for the treatment- resistant schizophrenia. Due to low therapeutic index and high pharmacokinetic variability, therapeutic drug monitoring (TDM) is highly recommended (1). The aim of this retrospective study was to analyze TDM data of CLZ and its active metabolite norclozapine (NCLZ) in adult patient with schizophrenia. The study included CLZ TDM data obtained from 69 patients (22- 67 years) treated at the Clinic for Psychiatry, Clinical Center of Serbia, while NCLZ data were available from 43 patients. Serum concentrations were determined at the Institute of Forensic Medicine, Belgrade, Serbia using liquid chromatography with tandem mass spectrometry (LC‐MS/MS). Statistical analysis was performed by SPSS software® (version 18). The daily doses of CLZ ranged between 37.5 and 600 mg. The mean value of CLZ and NCLZ levels were 0.285 ± 0.174 mg/L and 0.189 ± 0.132 mg/L, respectively. 73.06% and 26.83% of measured CLZ and NCLZ concentrations were outside reference range (mostly below), respectively. Significant positive correlation (p

Introduction: At the Faculty of Pharmacy University of Belgrade, the Objective Structured Clinical Examination (0SCE) was introduced to assess clinical competences and communication skills of pharmacy students following their 6-weeks practice in public pharmacies during the 10th semester. Methods: The OSCE consisted of one patient case that was presented to the student firstly in a short written form. The patient case had at least one drug-related problem that the student was expected to identify and solve. A teaching assistant played the role of the patient and a teacher assessed the communication skills and clinical competences during the student's interview with the „patient" using a structured form (checklist). The student had limited time (7 minutes) to identify and solve the drug-related problem(s) and to councel the patient. The use of a Drug register and Pharmacotherapy guide were allowed. Results: One hundred fifty students completed the OSCE so far. The students could achieve O-40 points during the exam, according to their performance. The maximal point score was achieved if the student obtained all relevant information from the patient”, identified and solved the drug-related problem(s) and offered appropriate information. The minimal point score (0) was assigned if the student made an error which could harm the patient. The median result of the OSCE was 28 points (interquatile range 10), while 7 students (4.7%) scored 0-9 points, 12 (8.0%) scored 10-19 points, 68 (45.3%) scored 20-29 points, 58 (38.79%) scored 30-39 points and 5 students (3.3%) scored 40 points. Conclusions: The introduction of the OSCE was successful and enabled the teaching staff to obtain a more accurate knowledge of the students’ clinical competences and communication skills as well as to identify gaps in the competences in skills which need to be improved. Poster Presentations

Primena benzodiazepina kod starijih pacijenata povezana je sa brojnim neželjenim ishodima, poput povećanog rizika od pada, fraktura, troškova u zdravstvenom sistemu, pa čak i smrtnih ishoda. Cilj rada bio je određivanje učestalosti primene benzodiazepina kod pacijenata starosti ≥65 godina, i procena povezanosti njihove primene sa karakteristikama pacijenata. Podaci su prikupljeni prospektivno u javnim apotekama primenom upitnika koji su obuhvatili demografske, kliničke i karakteristike terapije pacijenta. Obrada rezultata izvršena je primenom softvera SPSS (ver. 25). U istraživanju je učestvovalo 287 pacijenata, prosečne starosti 72,2±5,8 godina (ukupan opseg 65-91). Prosečan broj lekova po pacijentu iznosio je 7,6±2,2 (4-18), dok je prosečan broj indikacija iznosio 4,5±1,7 (1-11). Ukupna zastupljenost benzodiazepina iznosila je 28,9%, od čega su dugodelujući bili primenjivani kod 24.0%, a kratkodelujući kod 5,2% pacijenata. Najčešće primenjivan lek iz ove grupe bio je bromazepam (17,1%), potom diazepam (7.0%), lorazepam (3,8%) i alprazolam (1,4%). U grupi pacijenata starosti 65-69 godina prevalenca primene benzodiazepina iznosila je 29,3%, 70-74 godina 33,7%, 75-80 godina 23,3% i kod starijih od 80 godina 24.0%. Primena benzodiazepina bila je statistički značajno češća kod pacijenata sa dijagnozom anksioznosti, drugog mentalnog oboljenja, ali i primenom bisfosfonata, analgetika ili biljnog leka ekstrakta lista Ginko biloba (p

Kako glavobolje predstavljaju jedno od najčešćih onesposobljavajućih stanja u svetu, 1 a mogu se lečiti lekovima koji se izdaju bez recepta, uloga farmaceuta u zbrinjavanju ovih pacijenata prepoznata je kao veoma značajna. Cilj istraživanja bio je da se ispitaju percepcije farmaceuta u primarnoj zdravstvenoj zaštiti o pružanju usluge pacijentima, kao i o sprovedenoj edukaciji specijalizovanoj ka glavoboljama. Podaci su prikupljani putem ankete, prilagođene prema prethodnom radu2 i obrađeni u programima SPSS i Microsoft Excel. Popunjavanju ankete pristupilo je 43 farmaceuta iz primarne zdravstvene zaštite (90,7% žene, raspon godina 27-64). Provera pouzdanosti ankete potvrđena je upotrebom Cronbach- ovog testa (αB = 0,727; αC = 0,880). Najveći broj anketiranih farmaceuta smatra da pažljivo sluša pacijente sa glavoboljom (65% uvek, 27,9% često), interakcije uvek proverava čak 44,7%, dok o pravilnoj primeni leka njih 86,04% uvek posavetuje pacijenta. Međutim, 34,88% prijavljuje da nikada ne kontaktira lekare ukoliko je lek skup, ne refundira se ili izaziva neželjenu reakciju koja ograničava primenu, a 32,55% samo ponekad to učini. Većina farmaceuta smatra da je edukacija korisna za bolje razumevanje pacijenata i savetovanje o glavoboljama (97,67-100%), dok nešto manji procenat (93,02%) smatra da je edukacija korisna da lakše prepoznaju pacijenta sa migrenom i upute ga lekaru. Percepcija većine farmaceuta je da savetuje pacijente o terapiji glavobolje i bez prethodne edukacije, ali da bi uz edukaciju usluga koju pružaju bila kompletnija. Rezultati studije upućuju da buduće edukacije treba fokusirati na unapređenje komunikacije sa lekarima. Since headaches represent one of the most common disabling conditions in the world1 and can be treated with over-the-counter drugs, the role of pharmacists in caring for these patients has been recognized as very important. The research aim was to review primary health care pharmacists’ perception regarding patient service they provide and the conducted education devoted to headaches. Data were collected through a survey adapted from the published article 2 and analysed in SPSS and Microsoft Excel. The survey was completed by 43 primary health care pharmacists (90.7% women, age 27-64). The survey reliability was verified using the Cronbach’s test (αB = 0.727; αC = 0.880). Most of the surveyed pharmacists believe that they listen carefully to patients with headaches (65% always, 27.9% often), 44.7% always check interactions, while 86.04% always advise the patient on proper drug administration. However, 34.88% report that they never contact doctors if the drug is expensive, not reimbursable or causes an adverse reaction that limits its use, and 32.55% only sometimes do so. Most pharmacists believe education was useful to better understand patients and counsel them about headaches (97.67-100%), while a slightly smaller percentage (93.02%) thinks it helped them learn to identify a migraine patient and refer him to a doctor. The perception of most pharmacists is that they advise patients on headache treatment even without prior education, but after it, the service would be more complete. The study results indicate that future education should focus on improving communication with doctors. VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beograd

Monoclonal antibodies’ pharmacokinetics is, due to their specific properties, highly variable among different patients. Beside body weight and albumin levels, pembrolizumab pharmacokinetics may also be affected by patient's condition depicted as ECOG (Eastern Cooperative Oncology Group) performance status and tumor burden. The study aim was to compare pembrolizumab exposure in different patient subpopulations after administration of fixed (200 mg) and weight-based dosing regimen (2 mg/kg) every three weeks. Two virtual populations were generated in the R software: normal body weight patients with preserved renal function, normal albumin levels (3.4-5.8 g/dL) and good prognosis (ECOG 0, low burden); and underweight patients with decreased renal function, hypoalbuminemia (

Administration of high dose methotrexate (HDMTX) is common part of pediatric protocols for acute lymphoblastic leukemia (ALL) and non-Hodking lymphoma (NHL). Methotrexate is used in certain phase of therapy in doses 3 g/m 2 or 5 g/m 2 with the objective to achieve concentration that will ensure eradication of tumor cells with minimal toxic effect. The aim of this study is overview of drug concentration and assessment of therapy safety in relation to referent values. After obtaining Ethics committee approval at The Institute for mother and child Healthcare of Serbia “Dr Vukan Cupic” 50 pediatric patients with ALL or NHL were enrolled. Data on MTX usage was retrospectively collected from the patient history. Concentrations and normalized concentrations per applied dose were compared with nonparametric tests in SPSS (version 18). MTX concentration mean (± standard deviation) following administration of 3 g/m 2 respectively 5 g/m2 doses were 19.72±6.62 mg/L respectively 34.73±17.13 at 24 h, 0.20±0.36 mg/L respectively 0.24±0.58 mg/L at 48h and 0.14±0.44 mg/L respectively 0.12±0.89 mg/L at 72h after start of the infusion. Statistically significant difference (p

Generic medicines are bioequivalent (BE) and switchable with the reference medicine, however, between generics BE is not demonstrated. In practice, patients are often offered generic substitution, where information on BE between generics may be useful, especially when there is a doubt that substitution may potentially pose a risk to the patient. These information can be obtained by assessing BE between generics, applying the method of adjusted indirect comparison (AIC). This method is based on data from BE studies in which generics were compared with the same reference medicine. Thus, it is possible to identify generics for which efficacy and safety problems are not expected upon substitution (1,2). The AIC was used to compare four generic clopidogrel medicines. Publicly available data from original BE studies, in which each generic medicine was compared with the reference medicine Plavix film-coated tablets 75 mg, were analysed. Generics were considered BE if the 90% confidence interval (CI) for the ratio of their pharmacokinetic parameters maximum plasma concentration (Cmax) and area under the curve up to the last measurable concentration (PIK 0-t), was within the acceptance range 80.00-125.00%. In all the tested combinations, 90% CIs for PIK0-t were within the acceptance range, while for C max 90% CIs were within or very close to the limits, with the point estimate being within the range in all cases. The results obtained by the AIC indicated that the bioavailability of these four generic clopidogrel medicines is very similar, therefore they can be considered switchable with each other in clinical practice. Generički lekovi su biološki ekvivalentni (BE) i zamenjivi sa referentnim lekom, međutim, između samih generičkih lekova BE nije potvrđena. Pacijentima se u praksi često nudi odgovarajuća generička zamena, pri kojoj od koristi mogu biti informacije o BE između generika, naročito u slučaju kada postoji sumnja da zamena generika može potencijalno predstavljati rizik za pacijenta. Ove informacije mogu se dobiti procenom BE između generičkih lekova metodom prilagođenog indirektnog poređenja, na osnovu podataka iz već sprovedenih individualnih studija BE u kojima su generički lekovi poređeni sa istim referentnim lekom. Na taj način identifikuju se generički lekovi za koje se prilikom zamene u praksi ne očekuju problemi u pogledu efikasnosti i bezbednosti (1,2). Navedena metoda korišćena je za poređenje četiri generička leka koji sadrže klopidogrel. Analizirani su javno dostupni podaci iz studija BE u kojima je svaki generički lek poređen sa referentnim lekom Plavix film tablete 75 mg. Dva generička leka smatraju se BE ukoliko je 90% interval pouzdanosti (CI) za odnos njihovih farmakokinetičkih parametara maksimalna koncenracija u plazmi (C max) i površina ispod krive do poslednje merljive koncentracije (PIK 0-t ), unutar raspona 80,00-125,00%. U svim ispitanim kombinacijama 90% CI za PIK0-t bili su unutar dozvoljenog raspona, dok su 90% CI za Cmax bili unutar ili veoma blizu granica ovog raspona, pri čemu je point estimate u svim slučajevima bio unutar raspona. Rezultati dobijeni metodom prilagođenog indirektnog poređenja pokazali su da je biološka raspoloživost ova četiri generička leka koja sadrže klopidogrel veoma slična, te se oni mogu smatrati međusobno zamenjivim u kliničkoj praksi. VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beograd

Benigna hiperplazija prostate (BHP) predstavlja nekancerozno uvećanje prostate povezano sa simptomima donjeg urinarnog trakta i spada u najčešća oboljenja starijih muškaraca. Kako su u ovom dobu uobičajeni komorbiditeti, pre svega kardiovaskularna (KVS) oboljenja, može se očekivati veliki broj klinički značajnih interakcija lekova. Svrha ove studije bila je analiza učestalosti i vrste potencijalnih interakcija u terapiji starijih pacijenata sa BHP i KVS oboljenjem. Sprovedeno retrospektivno istraživanje uključilo je 93 muškaraca starijih od 65 godina, obolelih od BHP i hipertenzije ili nekog KVS oboljenja. Podaci o pacijentima su prikupljani iz medicinske dokumentacije. Potencijalne interakcije su identifikovane i procenjivane korišćenjem Lexicomp® elektronske baze podataka. Deskriptivna analiza je obavljena u programu Microsoft ® Office Excel 2010. Prosečna starost ispitanika iznosila je 75,3±6,05. Broj lekova u terapiji bio je u rasponu od 2 do 13. Pet ili više lekova primenjivalo je 72,04% pacijenata. Detektovano je ukupno 509 interakcija, od kojih čak 467 spada u klinički značajne (C, D, X). Najveći broj identifikovanih interakcija pripada klasi C (85,46%), dok je 4,91% iz klase D, a samo 1,38% iz klase X. U okviru klase X, koja ukazuje da treba izbegavati istovremenu primenu kombinacije lekova, najčešće se javljala interakcija između dva α-blokatora. Zabeleženo je 412 farmakodinamskih i 47 farmakokinetičkih interakcija. Dvojni mehanizam je detektovan kod 29 interakcija, a 21 se odvijao nepoznatim mehanizmom. Rezultati studije upućuju da uključivanje farmaceuta u praćenje pacijenata sa BHP može biti korisno, imajući u vidu značajan broj identifikovanih klinički značajnih interakcija. Benign prostatic hyperplasia (BPH) represents a non-cancerous prostate enlargement associated with lower urinary tract symptoms and is one of the most common diseases in older men. As comorbidities, primarily cardiovascular diseases (CVD) are common in this age group, a great number of clinically significant drug interactions can be expected. The aim of this research was to estimate the frequency and type of potential interactions in the treatment of elderly with BPH and CVD. A retrospective study included 93 men aged over 65 with BPH and hypertension or CVD. Patients’ data were collected from medical records. Potential interactions were identified and assessed using the Lexicomp ® database. Descriptive analysis was performed in Microsoft® Office Excel 2010. Patients’ average age was 75.3±6.05. The number of drugs in therapy ranged from 2 to 13. Five or more drugs were used by 72.04% of the patients. A total of 509 interactions were detected, of which 467 are clinically significant (C, D, X). Most interactions belonged to category C (85.46%), while 4.91% belonged to class D, and only 1.38% to class X. Within class X, which indicates that concomitant use of drugs should be avoided, the interaction between the two α-blockers was most frequent. 412 pharmacodynamic and 47 pharmacokinetic interactions were identified. The dual mechanism was detected in 29 interactions, while for 21 the mechanism was unknown. The obtained results suggest the involvement of pharmacists in the monitoring of patients with BPH may be useful, given the great proportion of identified clinically significant interactions. VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022, Beograd

Tacrolimus is an immunosuppressant used to prevent graft rejection after liver transplantation. The narrow therapeutic range and great variability in pharmacokinetics indicate the need for therapy individualization. The aim of the study was to develop and validate the base pharmacokinetic model of tacrolimus using data collected during therapeutic drug monitoring. The study included 29 liver transplant recipients followed up at Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia. Using the NONMEM® program, we analyzed tacrolimus concentrations (Ctrough) measured in whole blood (260). Pharmacokinetics have been described as one-compartment model with first- order absorption and elimination. Internal validation was performed using graphical assessment, bootstrap method and visual predictive check (VPC). Typical value of oral clearance (CL/F) was 30.4 L/h, while value of oral volume of distribution was 5770 L. The value of the absorption rate constant was fixed at 4.48 h-1 . Interindividual variability was best described by the exponential model, and residual by the additive model. Interindividual variability for CL/F was 38.2%. Individual predicted concentrations (IPRED) showed better agreement with the measured values than population predicted values (PRED). Conditional weighted residuals (CWRES vs PRED, CWRES vs TIME) were mostly between -2 and +2 standard deviations. The parameters obtained by bootstrap analysis do not deviate significantly from the model. Median, 5th and 95th percentiles in the VPC method mostly were within the simulated 95% confidence interval. The obtained population pharmacokinetic model, after additional optimization, can be used for individualization of the tacrolimus dosing regimen in the population of liver transplant recipients. Takrolimus je imunosupresiv koji se primenjuje za prevenciju odbacivanja grafta nakon transplantacije jetre. Uzak terapijski opseg i velika varijabilnost u farmakokinetici ukazuju na neophodnost individualizacije terapije. Cilj istraživanja bio je razvoj i validacija osnovnog farmakokinetičkog modela takrolimusa baziranog na podacima prikupljenim tokom terapijskog praćenja leka. Studija je uključila 29 pacijenata sa transplantiranom jetrom, praćenih na Klinici za gastroenterologiju i hepatologiju, Kliničkog centra Srbije. Primenom NONMEM® programa analizirane su koncentracije takrolimusa izmerene u punoj krvi (260), neposredno pre primene jutarnje doze (Ctrough). Farmakokinetika je opisana jednoprostornim modelom sa resorpcijom i eliminacijom prvog reda. Interna validacija je vršena primenom grafičke metode procene, metode umnožavanja podataka (bootstrap) i vizuelne prediktivne provere (VPC). Procenjena tipična vrednost oralnog klirensa (CL/F) iznosila je 30,4 L/h, dok je vrednost oralnog volumena distribucije bila 5770 L. Vrednost konstante brzine resorpcije je fiksirana na 4,48 h-1 . Interindividualna varijabilnost je najbolje opisana eksponencijalnim modelom, a rezidualna aditivnim modelom. Zabeležena je interindividualna varijabilnost za CL/F od 38,2%. Predviđene individualne koncentracije (IPRED) pokazuju bolje slaganje sa izmerenim vrednostima, nego populacione predviđene vrednosti (PRED). Uslovni težinski reziduali (CWRES vs PRED, CWRES vs TIME) su većinom raspoređeni između -2 i +2 standardne devijacije. Parametri dobijeni bootstrap analizom ne odstupaju značajno od modela, dok su vrednosti medijane, 5. i 95. percentila u VPC metodi uglavnom bile u okviru simuliranih 95% intervala pouzdanosti. Dobijeni populacioni farmakokinetički model, može se nakon dodatne optimizacije, primeniti u svrhu individualizacije režima doziranja takrolimusa u populaciji pacijenata sa transplantiranom jetrom. VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beograd

Cyclosporin A (CyA) is an immunosuppressant used as part of a post-transplant therapeutic protocol to prevent graft rejection. Due to the large pharmacokinetic variability that characterizes it, it is necessary to conduct therapeutic drug monitoring (TDM). The aim of the conducted research is to assess the exposure of CyA in the period of up to 3 months after transplantation (early post-transplantation period) with the identification of factors that influence the values of the pharmacokinetic parameters of CyA. From pediatric patients with kidney transplants, at the University Children ́s Hospital Tiršova, data about dosage regimens, cotherapy, and measured CyA concentrations (C0 - immediately before the next dose and C2 - 2 hours after the morning dose) were collected retrospectively. Data were analysed in NONMEM® (version 7.4). Twenty six patients (up to 12 years old) were included in the analysis. The pharmacokinetic model that best described the data is a one- compartment model with first-order absorption. Haematocrit, serum creatinine and body mass were identified as the main factors of variability. In further analysis, it is necessary to include data about genetic polymorphism, which is expected to have the greatest impact on drug exposure and change the power ratio of factors that influence CyA parameter values and concentrations.The obtained results are expected considering the characteristics of CyA. In addition to identification, quantification of the influence of the mentioned factors is crucial for establishing an optimal dosing regimen in the early post-transplantation period in children, when the risk of graft rejection is the highest. Ciklosporin A (CyA) je imunosupresiv koji se koristi kao deo posttransplantacionog terapijskog protokola u cilju prevencije odbacivanja grafta. Zbog velike farmakokinetičke varijabilnosti koja ga karakteriše, neophodno je sprovođenje terapijskog monitoringa (therapeutic drug monitoring, TDM). Cilj sprovedenog istraživanja je procena izloženosti CyA u periodu do 3 meseca nakon transplantacije (rani posttransplantacioni period) uz identifikaciju faktora koji utiču na vrednosti farmakokinetičkih parametara CyA. Od pedijatrijskih pacijenata sa transplantiranim bubregom, u Univerzitetskoj klinici Tiršova, retrospektivno su prikupljani podaci o primenjenoj dozi CyA, koterapiji, izmerenim koncentracijama CyA (C0 – neposredno pred davanje naredne doze i C2 – 2 sata nakon jutarnje doze) i vrednostima laboratorijskih parametara od značaja. Podaci su obrađivani upotrebom populacione farmakokinetičke analize u programu NONMEM® (verzija 7.4). U analizu je uključeno 26 pacijenata starosti do 12 godina. Farmakokinetički model koji najbolje opisuje dostupne podatke je jednoprostorni model sa apsorpcijom prvog reda. Kao glavni faktori varijabilnosti identifikovani su hematokrit, serumski kreatinin i telesna masa. U daljoj analizi, neophodno je uključiti podatke o genetskom polimorfizmu, za koje se očekuje da će imati najveći uticaj na izloženost leku i promeniti odnos snaga faktora koji utiču na vrednosti parametara CyA i koncentraciju. Dobijeni rezultati su očekivani imajući u vidu karakteristike CyA. Pored identifikacije, i kvantifikacija uticaja navedenih faktora je ključna za uspostavljanje optimalnog režima doziranja u ranom posttransplantacionom periodu kod dece, kada je rizik od odbacivanja grafta najveći. VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beograd