Dušan Jovanović

Influence of dissolution media composition on drug release and in‐vitro/in‐vivo correlation for paracetamol matrix tablets prepared with novel carbomer polymers

The influence of dissolution media composition on drug release kinetics and in‐vitro/in‐vivo correlation (IVIVC) for hydrophilic matrix tablets based on Carbopol 971P and Carbopol 71G was investigated. A number of buffered and unbuffered media differing with respect to their pH value, ionic strength and ionic species was evaluated. The observed in‐vitro drug release profiles were compared with the hypothetical drug release profiles in‐vivo calculated by numerical deconvolution from the results of an in‐vivo study. The obtained IVIVC plots were examined using linear and non‐linear (proportional odds, proportional hazards and proportional reversed hazards) mathematical models. Although the studied sustained release agents were chemically identical, they exhibited pronounced differences in drug product behaviour both in‐vitro and in‐vivo. The use of non‐linear modelling resulted in an improved level of correlation, especially in the case of Carbopol 71G matrices. The obtained results indicated the susceptibility of drug release kinetics and hence IVIVC in the case of anionic polymer matrices to media composition, and emphasized the need for thorough evaluation of applied media during the development of biorelevant dissolution methodology. Although the use of non‐linear modelling could be advantageous, the need for a simple and meaningful nonlinear relationship is pointed out.

Justification of metformin hydrochloride biowaiver criteria based on bioequivalence study

The Biopharmaceutics Classification System (BCS) represents the framework for predicting the intestinal drug absorption based on its solubility and intestinal permeability. Recent research has lead to the use of in vitro tests to waive additional in vivo bioequivalence studies for some pharmaceutical products (i.e., biowaiver). The current regulations permit waivers for BCS Class I (highly soluble/highly permeable) drug substances, which represent up to 25% of the drugs. Efforts in both the science and regulatory bodies are being made to extend biowaivers to certain Class II and III products, which would represent more than 50% of all drugs coming to the market. The aim of this study was to investigate the influence of experimental conditions on metformin hydrochloride (CAS 1115-70-4) release from two immediate-release tablet formulations with proven bioequivalence and justify the biowaiver request for dissolution profile similarity in three pH media. The results obtained indicate that differences in drug dissolution observed in vitro were not reflected in vivo. Such data support the existing idea that BCS Class III drugs are eligible biowaiver candidates, even if a very rapid dissolution criterion is not fulfilled.

A near-fatal case of acute poisoning by amitraz/xylene showing atrial fibrillation

Amitraz has become a significant cause of acute poisoning because of its wide use in veterinary medicine during the last decade. The majority of published cases of amitraz poisoning have dealt with children, while severe life-threatening poisoning in adults is very rare. In this report, the clinical and laboratory features in a case of acute poisoning by amitraz and xylene in an adult are presented. A 72-year-old man accidentally swallowed about 40 g of Mitac 20, a commercial formulation of amitraz dissolved in xylene. The ingested dose was estimated to be about 10 g of amitraz and 35 g of xylene. Initial symptoms were dizziness and nausea, followed by coma, respiratory insufficiency, miosis, and hyperglycemia. As an α2-adrenergic agonist, amitraz usually causes bradycardia, but the present patient showed atrial fibrillation with rapid ventricular response, which was successfully treated by digoxin. Amitraz itself and xylene metabolites were confi rmed in his blood and urine, respectively, by instrumental analysis. Supportive and symptomatic measures were taken over 3 days, and the patient recovered fully despite the significant ingested amounts of amitraz and xylene.

Bioequivalence assessment of the two brands of glimepiride tablets.

BACKGROUND/AIM Glimepiride, as an antidiabetic from the group of sulfonylurea, is administered perorally in the treatment of diabetes mellitus. The aim of this study was to compare pharmacokinetic profiles and relative bioavailabilities of the two oral formulations of glimepiride, generic and innovator tablets, after a single dose of the active drug. METHODS An oral dose of 6 mg glimepiride was given under fasting conditions to 24 healthy volunteers. A one-week washout period was applied between the two consecutive periods. The serum samples obtained before dosing, and at various time points up to 48 hours, were analyzed for glimepiride concentration using the validated high-performance liquid chromatographic method with ultraviolet detection. Pharmacokinetic parameters representing early (maximal concentration, time to reach maximal concentration) and total exposure (area under the curve from the time 0 to the infinite time) to glimepiride were obtained and further analyzed using the multifactorial analysis of variance and the non-parametric Wilcoxon signed ranks test. Comparison of the secondary kinetic variables was only descriptive. RESULTS The point estimates of the ratios of geometric means (test/reference) of maximal concentrations and areas under the curve were 1.046 (90% confidence interval: 0.906-1.208) and 1.022 (90% confidence interval: 0.856-1.220), respectively, while the median values of times to reach maximal concentration, at 5% level of significance, did not differ significantly. Both formulations were well tolerated. Transient mild hypoglycaemia, which had been noted in 6 participants, resolved spontaneously within 30-60 minutes. CONCLUSION Since all the parametric 90% confidence intervals for the log-transformed main variables of glimepiride were within the 0.80 and 1.25 interval, accepted as the definition of bioequivalence, and the differences in times to reach maximal concentration also did not reach statistical significance, studied tablets were considered bioequivalent.

Biopharmaceutical characterization of sustained release matrix tablets based on novel carbomer polymers: formulation and in vivo investigation.

SummaryWith the increased interest in modified release dosage forms and drug delivery systems, there is an increasing concern for biopharmaceutical characterization of the formulation in the early stages of drug product development. The main objectives of biopharmaceutical characterization are the in vitro and in vivo evaluation of the selected formulations in order to identify the factors influencing drug release; define the in vitro test methodology that would be predictive of drug products in vivo behavior and develop quantitative in vitro — in vivo correlation. The purpose of this study was to assess the potential of novel carbomer polymers, Carbopol 971P and Carbopol 71G, as a sustained release agents in matrix tablets containing high dosage drug substance. Although chemically identical, the two polymers exhibited substantially different drug release properties in vitro. Hypothetical in vivo drug release profiles were calculated by numerical deconvolution from cumulative urinary excretion data observed in vivo. The obtained results indicated that sound and reliable in vivo drug release profiles could be obtained from urinary excretion data and also, emphasized the need for in vitro testing under a range of experimental conditions in order to develop the biorelevant drug release methodology.

[Magnetic resonance imaging and bone scintigraphy in bone metastasis detection: a comparative study].

BACKGROUND/AIM Bone scintigraphy is well-known method for the detection of neoplastic lesions with a high sensitivity and, at the same time, a lower specificity. On the other hand magnetic resonance imaging (MRI) is previously established noninvasive imaging method regar ding its diagnostic specificity. The aim of this study was to determine the possibilities and to correlate two different diagnostic methods--bone scintigraphy and MRI in the detection of bone metastasis in the spine and pelvic bones. METHODS A total of 123 patients who underwent both bone scintigraphy and spine and pelvic MRI on 1.5 T MR imager were enrolled in this study. Scans were subsequently analyzed in total and divided in regions of interest (cervical, upper, middle and lower thoracic, upper and lower lumbar and pelvic region, which includes sacral spinal segment); afterwards the total number of 585 mat ching regions were compared and statistically analyzed. RESULTS The statistical analysis demonstrated significant correlation between the findings of both methods in total. Divided by regions of interest, significant degrees of correlation were demonstrated in all of them, except in the cervical spine region where the r-value was in the range of low correlation. CONCLUSION Having a high mutual correlation, bone scintigraphy and MRI are to be considered as the complementary diagnostic methods in the detection of bone metastases. Still, increased diagnostic potential of MRI may highlights negative bone scintigraphy findings in the patients with solitary metastatic lesions or diffuse vertebral infiltration. Advances in the bone scintigraphy (single photon emission tomography--SPECT, SPECT-computed tomography--SPECT-CT) and MRI (whole body MRI, diffusion MRI), make it possible the diagnostic potential of both methods will result in a further improvement in bone metastasis detection.

A Pharmacokinetic Comparison of Generic Tablets Containing Bisoprolol With the Innovator Formulation in Healthy Volunteers

B is a cardioselective beta-blocker, devoid of intrinsic sympathomimetic and membrane-stabilizing properties. As a fumarate salt, in doses ranging between 5 mg and 20 mg of bisoprolol, it is used in the management of hypertension and angina pectoris. Sometimes, it is also employed as an adjunct to standard therapy in patients with stable chronic heart failure. When given orally, bisoprolol was almost completely absorbed from the gastrointestinal tract and underwent only minimal first-pass metabolism, resulting in an oral bioavailability of about 90%. Peak plasma concentrations were reached 2 to 4 hours after the oral administration, with an elimination half-life of 10–12 hours. About 30% to 35% of bisoprolol was bound to plasma proteins; it was also reported to be moderately lipid soluble and rapidly and widely distributed in the body (Vd was about 2.9 L/kg in healthy subjects). Mean total body clearance was calculated to be 14.2 L/h in healthy individuals and 7.8 L/h in patients with impaired renal function. Approximately 50% of the dose was metabolized in the liver to pharmacologically inactive polar metabolites. Both the unchanged drug and metabolites were eliminated by the kidneys, whereas less than 2% of the dose was excreted in feces. Obesity, pathologic conditions (eg, renal or hepatic failure), or interactions with concurrently used drugs might affect the pharmacokinetic profile of bisoprolol and thereby contribute to the changes in therapeutic efficacy or in the adverse events profile. Therapeutic failure might also occur when the patient is switched between an innovator drug and a nonbioequivalent generic formulation. Having in mind that pharmacokinetic studies investigating the bioequivalence of generic and innovator drugs could minimize such risks, the aim of this study was to evaluate the bioequivalence of 2 tablet formulations of bisoprolol, each containing 10 mg of active drug. As a secondary objective, the tolerability of both formulations was also assessed.

A pharmacokinetic comparison of three pharmaceutical formulations of nimesulide in healthy volunteers.

BACKGROUND/AIM Switching the patient from one pharmaceutical formulation of the same drug to another, may lead to therapeutic inadequancy in some cases. To minimize the risk, careful pharmacokinetic studies are desired in the pre-registration period and afterwards. METHODS A randomized, crossover design with one-week wash-out period between each dose was applied. Serum samples, obtained before dosing and at various appropriate time points up to 15 hours, were analyzed for nimesulide content by a high-performance liquid chromatographic method with ultraviolet (LU) detection. The pharmacokinetics and relative bioavailability of three different pharmaceutical formulations containing nimesulide, manufactured by the same pharmaceutical factory, were studied prospectively in 12 healthy subjects of both sexes. A single 100-mg oral dose of nimesulide was given to the volunteers in the form of conventional tablets, mouth dissolving tablets or as a suspension. Analysis of variance, power analysis, 90% confidence intervals, and two one-sided tests were used for the statistical analysis of pharmacokinetic parameters. RESULTS The tolerability of all preparations was excellent. The respective confidence intervals of the ratios of geometric means of C(max) and AUC(0-infinity) of nimesulide were out of acceptable limits either for conventional tablets in comparison with suspension or for mouth dissolving tablets when compared with conventional tablets. A comparison of mouth dissolving tablets with suspension showed a statistically significant difference between C(max) values (suprabioavailability of mouth dissolving tablets), while the point estimate of the ratio of geometric means of AUC(0-infinity) was 0.945 with the corresponding 90% confidence interval of 0.902-0.991. At the 5% level of significance, there were no differences between the formulations under the study in times elapsed to peak serum concentrations, as revealed by the non-parametric Wilcoxon signed ranks test. CONCLUSION Only a 90% confidence interval for the relative differences of log-transformed AUC(0-infinity) values of nimesulide absorbed from mouth dissolving tablets vs. suspension was included in the 80% to 125% interval proposed by the Food and Drug Administration (FDA). On that basis, mouth dissolving tablets (Nimulid-MD) were considered bioequivalent to Nimulid suspension according to the extent of drug absorption. Concerning the comparable amounts of nimesulide available in the systemic circulation after application of these formulations the one might not expect therapeutic failure after switching the patient from one to another.

Bioequivalence testing of a new tablet formulation of generic fluoxetine

SummaryThe pharmacokinetics and relative bioavailability of fluoxetine capsules (reference) and tablets (test) were compared in 24 healthy subjects of both sexes after a single 20 mg oral dose of fluoxetine (as a hydrochloride salt).A randomized, crossover design with a 2-week wash-out period between each dose was applied. Serum samples, obtained before dosing and at various appropriate time points up to 192 hours, were analyzed for fluoxetine and norfluoxetine content by a simple, accurate and precise HPLC method. ANOVA, power analysis, 90% confidence intervals (CI), and two one-sided tests were used for the statistical analysis of pharmacokinetic parameters.The tolerability of the preparations was good. The respective point estimates of the ratios of the geometric means of log-Cmax and log-AUC0−∞ of fluoxetine were 0.912 and 0.935 with 90% of 0.838–0.992 and 0.857–1.020. The corresponding point estimates of norfluoxetine were 0.952 (90% CI=0.843−1.075) and 0.904 (90% CI=0.807−1.013), respectively.Since both 90% CI for the AUC0−∞ and Cmax geometric mean ratios of fluoxetine and norfluoxetine were included in the 80% to 125% interval proposed by the FDA the test drug (fluoxetine tablets) was considered bioequivalent to the reference one (Prozac® capsules) according both to the rate and extent of absorption.

Acute poisoning by cardiovascular agents

In order to determine the frequency, severity of poisoning, and the efficacy of the applied therapeutic measures, retrospective study of 391 patients treated for acute drug poisoning was performed during one-year period at the Clinic for Emergency and Clinical Toxicology and Pharmacology. In 49 (12.5%) patients cardiovascular agents were the cause of poisoning, most frequently beta-blockers and calcium antagonists (77.5%). Poisoning with antihypertensive agents was registered in 12.2% of patients, antiarrhythmics in 8.2%, and cardiotonics in 2.1%. Beta-blockers and calcium antagonists caused severe poisoning in over 40% of cases. Predominant clinical manifestations were registered on cardiovascular system, while central nervous system effects occurred secondary to cardiotoxicity. Symptomatic and supportive measures were performed most frequently, while specific agents, glucagon, calcium salts, and others, were used less often.