Katarina Vučićević

Potentially Inappropriate Prescribing in Older Primary Care Patients

Objectives The aim of the study was to determine the rate of Potentially Inappropriate Medicines (PIM) and Potential Prescription Omissions (PPO) according to Screening Tool of Older Persons potentially inappropriate Prescriptions/Screening Tool to Alert doctors to the Right Treatment (STOPP/START) criteria. Study Design A cross-sectional survey in community pharmacy. Method A prospective cross-sectional study was performed, during March-May 2012, in five community pharmacies. Patients aged ≥65 years, who collected one or more prescribed medications, were asked to participate in the study, and an interview was scheduled. Patients were asked to provide their complete medical and biochemical record from their general practitioner. Results 509 patients, mean age 74.8±6.5 years, 57.4% female, participated in the study. 164 PIM were identified in 139 patients (27.3%). The most common were: long-term use of long-acting benzodiazepines (20.7%), use of non-steroidal antiinflammatory drugs (NSAID) in patients with moderate-severe hypertension (20.1%), use of theophylline as monotherapy for chronic obstructive pulmonary disease (COPD, 15.9%) and use of aspirin without appropriate indication (15.2%). Patients with more than four prescpritions had a higher risk for PIM (OR 2.85, 95% CI 1.97–4.14, p<0.001). There were 439 PPO, identified in 257, (50.5%) patients. Predictors for PPO were older age, presence of diabetes, myocardial infarction, osteoporosis, stroke, COPD and/or angina pectoris. Conclusion STOPP/START criteria may be useful in identifying inappropriate prescribing and improving the current prescribing practices. Pharmacists should focus more on patients with more than four medications and/or patients with gout or pain accompanied with arterial hypertension because those patient may be at higher risk of PIM. Additionlly, patients older than 74 years with diabetes, osteoporosis, myocardial infarction, stroke, angina pectoris and/or COPD may have an increased risk of PPO.

Impact of age, weight and concomitant treatment on lamotrigine pharmacokinetics

What is known and Objective:  Lamotrigine metabolism may be substantially altered with concomitant administration of valproic acid and/or carbamazepine. Such alterations may require the adjustment of lamotrigine dose to ensure optimal treatment efficacy and safety.

Population pharmacokinetics of topiramate in adult patients with epilepsy using nonlinear mixed effects modelling

The objective of the study was to develop population pharmacokinetic model of topiramate (TPM) using nonlinear mixed effects modelling approach. Data were collected from 78 adult epileptic patients on mono- or co-therapy of TPM and other antiepileptic drugs, such as carbamazepine (CBZ), valproic acid, lamotrigine, levetiracetam, phenobarbital and pregabalin. Steady-state TPM concentrations were determined in blood samples by high performance liquid chromatography with fluorescence detection. A one-compartment model with first order absorption and elimination was used to fit the concentration-time TPM data. Volume of distribution of TPM was estimated at 0.575 l/kg. The influence of demographic, biochemical parameters and therapy characteristics of the patients on oral clearance (CL/F) was evaluated. Daily carbamazepine dose (DCBZ) and renal function estimated by Modification of diet in renal disease (MDRD) formula significantly (p<0.001) influenced CL/F and were included in the final model: CL/F · (l/h)=1.53(l/h) · [1+0.476 · DCBZ(mg/day)/1000(mg/day)] · EXP[0.00476 · [MDRD(ml/ min)-95.72(ml/min)]]. Increase of CL/F with DCBZ and MDRD was best described by linear and exponential models. Mean TPM CL/F during CBZ co-therapy was 2.46 l/h, which is higher for 60.8% than in patients not co-treated with CBZ. Evaluation by bootstrapping showed that the final model was stable. The predictive performance was evaluated by adequate plots and indicated satisfactory precision. This model allows individualisation of TPM dosing in routine patient care, especially useful for patients on different CBZ dosing regimen.

Comparison of HPTLC and HPLC for determination of econazole nitrate in topical dosage forms

HPTLC and HPLC methods have been established for separation and quantitative determination of econazole nitrate. HPTLC was performed on silica gel plates with n-butyl acetate–carbon tetrachloride–methanol–diethylamine, 3 + 6 + 2.5 + 0.5 (v/v), as mobile phase. Chromatographic zones, or spots, of econazole base and nitrate were used to quantify econazole nitrate. HPLC was performed on amino and C8 columns with acetonitrile–water, 30 + 70 (v/v), pH 2.5 (adjusted with phosphoric acid), as a mobile phase. The chromatograms were characterized by single peaks of econazole (amino column) or nitrate (C8 column). The methods were successfully used for determination of econazole nitrate in spray solution and vaginal pessaries.

Effect of Long-term Topiramate Therapy on Serum Bicarbonate and Potassium Levels in Adult Epileptic Patients

Background: Topiramate (TPM) is a sulfamate-substituted monosaccharide that is structurally different from other antiepileptic drugs. TPM inhibits carbonic anhydrase activity, which is associated with loss of bicarbonate from the kidney and consequently metabolic acidosis or electrolyte imbalance. Objective: The objectives of the study were to investigate the influence of TPM therapy on bicarbonate and potassium levels in adult epileptic patients. Methods: Data were collected from 59 adult patients on monotherapy or co-therapy of TPM and other antiepileptic drugs. Serum bicarbonate and potassium levels were available from all patients. Steady-state TPM trough concentrations were determined in blood samples by high-performance liquid chromatography. Data analysis was performed by SPSS software (version 17, Chicago, IL). Results: Patients were divided into group A (duration of therapy shorter than or equal to 5 years) and group B (duration of therapy longer than 5 years). Significant difference (P < 0.05) in serum bicarbonate levels was observed between these 2 groups. Bicarbonate levels were linearly related to the TPM therapy duration. No correlation was found between the TPM dose or patient age and bicarbonate or potassium levels, as well as between therapy duration and potassium level. Linear regression analysis showed no significant association among 54 available TPM trough concentrations and bicarbonate or potassium levels. Conclusions: Results highlight the frequent occurrence of lower bicarbonate level associated with prolonged TPM therapy. Monitoring bicarbonate levels in patients on long-term TPM therapy might be useful.

A case study on the in silico absorption simulations of levothyroxine sodium immediate-release tablets.

The aim of this case study was to develop a drug‐specific absorption model for levothyroxine (LT4) using mechanistic gastrointestinal simulation technology (GIST) implemented in the GastroPlus™ software package. The required input parameters were determined experimentally, in silico predicted and/or taken from the literature. The simulated plasma profile was similar and in a good agreement with the data observed in the in vivo bioequivalence study, indicating that the GIST model gave an accurate prediction of LT4 oral absorption. Additionally, plasma concentration–time profiles were simulated based on a set of experimental and virtual in vitro dissolution data in order to estimate the influence of different in vitro drug dissolution kinetics on the simulated plasma profiles and to identify biorelevant dissolution specification for LT4 immediate‐release (IR) tablets. A set of experimental and virtual in vitro data was also used for correlation purposes. In vitro–in vivo correlation model based on the convolution approach was applied in order to assess the relationship between the in vitro and in vivo data. The obtained results suggest that dissolution specification of more than 85% LT4 dissolved in 60 min might be considered as biorelevant dissolution specification criteria for LT4 IR tablets. Copyright

An Experimental Design Approach to Selecting the Optimum HPLC Conditions for the Determination of 2-Arylimidazoline Derivatives

Abstract In order to improve the chromatographic resolution (Rs) with a good analysis time, experimental designs were applied for multivariate optimization of the experimental conditions of an isocratic reversed phase high performance liquid chromatographic (RP-HPLC) method used for the simultaneous determination of seven 2-arylimidazoline derivatives, acting as vasoconstrictors and antihypertensives. Optimal conditions for the separation of the seven 2-arylimidazolines were obtained using a mixture of acetonitrile–triethylamine phosphate buffer (pH 4.0; 25 mM) (30:70, v/v) as mobile phase at 25°C. Here the 23 full factorial experimental design was employed to optimize RP-HPLC separation of the 2-arylimidazolines. The suggested RP-HPLC method is applicable for routine analysis of the 2-arylimidazoline derivatives under the same chromatographic conditions, which can shorten the time and the costs of the analysis as well. Detailed description of the method development and optimization given in this paper will enhance the reproducibility of the established experimental conditions and simplify the process of some future methods developments.

Population Pharmacokinetic Approach of Immunosuppressive Therapy in Kidney Transplant Patients

Immunosuppressive therapy is the cornerstone of successful kidney transplantation. Frequently used immunosuppressives are cyclosporine, tacrolimus, sirolimus and mycophenolic acid. These drugs have narrow therapeutic index and show high pharmacokinetic variability. In order to maintain the balance between efficacy and safety, dosing is based on measured drug concentrations. Proper identification, quantification and understanding the sources of variability in measured concentrations facilitate routine dose adjustment in clinical practice. Classical pharmacokinetic studies have limited use in transplant patients attributable to design with intense sampling in a small, relatively homogenous population, and identification of only single variability factor per study. Population approach is a powerful tool for analysing sparse data, identifying factors that influence drug pharmacokinetics and estimating variability. In this report we reviewed available population pharmacokinetic models for cyclosporine, tacrolimus, sirolimus and mycophenolic acid in adult kidney transplant patients. The major focus was to describe various demographic factors, biochemical parameters, genetic polymorphisms of metabolic enzymes and transporters and drug-drug interactions, which have been identified as an important concern of pharmacokinetic variability in kidney transplant patients.

Population Pharmacokinetic Analysis of Therapeutic Drug Monitoring Data in Optimizing Pharmacotherapy of Antiepileptic Drugs

Katarina Vucicevic1, Branislava Miljkovic1, Sandra Vezmar Kovacevic1, Zoran Todorovic2, Milica Prostran2 and Iztok Grabnar3 1Department of Pharmacokinetics and Clinical Pharmacy, Faculty of Pharmacy, University of Belgrade, 2Department of Pharmacology, Clinical Pharmacology and Toxicology, School of Medicine, University of Belgrade, 3Chair of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, 1,2Serbia 3Slovenia

Expectations, concerns, and needs of patients who start drugs for chronic conditions. A prospective observational study among community pharmacies in Serbia

Abstract Background: During the initiation of treatment of a chronic disease, patients may have varying interests, expectations, concerns, and reasons to stop treatment, influencing compliance with prescribed treatment. Thus, healthcare professionals are expected to integrate these needs into medicines management. Objectives: To determine what information is important to patients; assess predictors of patients’ interests, expectations, concerns, reasons to stop therapy; evaluate drug-related problems following initiation of therapy and summarize how pharmacists resolve them during patient–pharmacist counselling. Methods: In 2014, a four-month study was performed in Serbian community pharmacies, as part of the Pharmaceutical Care Quality Indicators Project led by the European Directorate for the Quality of Medicines & Healthcare. Seventy community pharmacists were asked to participate in the study. Pharmacists recruited adult patients who consented to participate in the study and who initiated treatment, lasting at least six months. Patients completed an open-ended questions form. After two-to-four weeks, a patient–pharmacist consultation was performed. Results: Forty-four community pharmacists (response rate 62.9%) sent back the completed forms from 391 patients (response rate 67.1%). The total number of dispensed drugs was 403. In terms of drug safety, 29.4% of patients sought information, 32.5% expressed concerns, and 28.1% of patients cited it as a reason to discontinue treatment. During the first weeks of therapy, 18% of patients experienced practical problems, while 27.3% reported adverse drug reactions. Conclusion: Safety issues are a major focus of patients’ prescribed new medicines for long-term treatment.