Bioequivalence study of 2.5 mg film-coated bisoprolol tablets in healthy volunteers

Wstęp: Bisoprolol jest jednym z najczęściej stosowanych beta-adrenolityków cechujących się kardioselektywnością i pozbawionym wewnętrznej aktywności sympatykomimetycznej. Jest powszechnie stosowany w leczeniu choroby niedokrwiennej serca czy niewydolności serca. Cel: Celem pracy była ocena równoważności biologicznej tabletek powlekanych zawierających bisoprolol w dawce 2,5 mg (Bisocard® — lek badany) w odniesieniu do oryginalnego produktu leczniczego (Concor Cor 2.5® — lek referencyjny). Metody: Przeprowadzono badanie otwarte z randomizacją w schemacie krzyżowym, po pojedynczym podaniu na czczo zdrowym ochotnikom rasy białej bisolprololu w dawce 10 mg (4 tabletki po 2,5 mg). Próbki krwi pobierano do 60. godziny po podaniu leku. Stężenie bisoprololu w osoczu oznaczono zwalidowaną metodą LC-MS/MS. Produkty lecznicze uznano za równoważne biologicznie, gdy 90-procentowe przedziały ufności (CI) stosunków średnich geometrycznych (produkt badany/referencyjny) dla zlogarytmowanych AUC(0–t), AUC(0–∞) i Cmax mieściły się w granicach 80–125%. Działania niepożądane monitorowano na podstawie parametrów klinicznych i zgłoszeń ochotników. Wyniki: Dwudziestu sześciu zdrowych ochotników obu płci (średnia wieku ok. 29 lat, wskaźnik masy ciała 22,7 kg/m2) zostało włączonych do badania, a 24 z nich ukończyło część kliniczną badania. Otrzymano następujące stosunki średnich geometrycznych (produkt badany/referencyjny): AUC(0–t) 95,16% (90% CI 92,52–97,87%), AUC(0–∞) 95,08% (90% CI 92,40–97,83%) oraz Cmax 100,00% (90% CI 94,83–105,45%). Nie zaobserwowano istotnych statystycznie różnic w ocenianych parametrach farmakokinetycznych między produktami badanym i referencyjnym. Nie stwierdzono poważnych zdarzeń niepożądanych w badanej populacji. Wnioski: W badanej populacji stwierdzono równoważność biologiczną leku generycznego (Bisocard®) z produktem referencyjnym (Concor Cor 2.5®). Oba produkty cechują się porównywalną, dobrą tolerancją i bezpieczeństwem.Background: Bisoprolol is one of the most widely used beta-blockers characterised by cardioselectivity, and it has no intrinsic sympathomimetic activity. It is commonly used in the treatment of coronary heart disease and heart failure.   Aim: The aim of study was to assess the bioequivalence of the film-coated tablets containing 2.5 mg of bisoprolol (Bisocard® — the medicinal product) to the original medicinal product (Concor Cor 2.5® — the reference).   Methods: A randomised, open-label, two-period, crossover, single-dose, relative bioavailability study was conducted in fasted healthy Caucasian volunteers. A single 10-mg oral dose (four tablets of 2.5 mg) of the test or reference product was followed by a 14-day wash-out period, after which the subjects received the alternative product. Blood was sampled within a period of 60 h post administration in pre-specified time points. Bisoprolol concentrations were determined by a validated LC-MS/MS method. The products were considered bioequivalent if the 90% confidence interval (CI) of the log-transformed geometric mean ratios (test vs. reference) for AUC(0–t), AUC(0–∞), and Cmax were within 80–125% limits. Adverse events were monitored during the study based on the subject claims and clinical parameters.   Results: Twenty-six healthy male and female volunteers (mean age ca. 29 years; body mass index 22.7 kg/m2) were in­cluded in the study, and 24 completed the clinical part. The geometric mean ratios (test/reference) for the log-transformed AUC(0–t), AUC(0–∞), and Cmax were 95.16% (90% CI 92.52–97.87%), 95.08% (90% CI 92.40–97.83%), and 100.00% (90% CI 94.83–105.45%), respectively. There were no significant differences in the pharmacokinetic parameters between the test and reference formulations. No serious adverse events were reported.   Conclusions: The results of this single-dose study in healthy Caucasian volunteers indicate that Bisocard®; 2.5 mg film-coated tablets are bioequivalent to the reference product — Concor Cor 2.5®; 2.5 mg film-coated tablets. Both products had similar safety profile and have been well tolerated.  

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Abstract: A sensitive liquid chromatographic-single quadrupole mass spectrometric method was developed and validated for the determination of lapatinib in human plasma. Following a liquid-liquid extraction with methyl t-butyl ether, lapatinib and isotope labelled lapatinib, used as an internal standard (IS), were separated from the endogenous compounds on a Zorbax SB-C18 (150 ◊ 3 mm, 3.5 µm) column. An isocratic elution with the mobile phase consisting of formic buffer and the mixture of acetonitrile, methanol and formic acid was used. Mass spectrometry with positive electrospray ionization in a single ion monitoring mode was applied. The proposed method provides the satisfactory recovery of lapatinib from human plasma and a sensitivity comparable to numerous tandem mass spectrometric methods, with a lower limit of quantification of 5 ng/mL. The validated method may be applied to pharmacokinetic studies in humans following a single 250 mg oral dose

Replicates Number for Drug Stability Testing during Bioanalytical Method Validation—An Experimental and Retrospective Approach

Background: The stability of a drug or metabolites in biological matrices is an essential part of bioanalytical method validation, but the justification of its sample size (replicates number) is insufficient. The international guidelines differ in recommended sample size to study stability from no recommendation to at least three quality control samples. Testing of three samples may lead to results biased by a single outlier. We aimed to evaluate the optimal sample size for stability testing based on 90% confidence intervals. Methods: We conducted the experimental, retrospective (264 confidence intervals for the stability of nine drugs during regulatory bioanalytical method validation), and theoretical (mathematical) studies. We generated experimental stability data (40 confidence intervals) for two analytes—tramadol and its major metabolite (O-desmethyl-tramadol)—in two concentrations, two storage conditions, and in five sample sizes (n = 3, 4, 5, 6, or 8). Results: The 90% confidence intervals were wider for low than for high concentrations in 18 out of 20 cases. For n = 5 each stability test passed, and the width of the confidence intervals was below 20%. The results of the retrospective study and the theoretical analysis supported the experimental observations that five or six repetitions ensure that confidence intervals fall within 85–115% acceptance criteria. Conclusions: Five repetitions are optimal for the assessment of analyte stability. We hope to initiate discussion and stimulate further research on the sample size for stability testing

"Pharmaceutical Strategy for Europe" : synthesis of active pharmaceutical ingredients as a Polish brand?

Correct diagnosis and appropriate selection of pharmacotherapy will not upgrade patient’s health if the drug is not available in the pharmacy. Pharmaceutical supply chain breakdown may occur due to epidemiological or political reasons. Then, the finished drug form factories located in Poland will not secure the drug supply. Thus, cooperation of the scientific community with the pharmaceutical and chemical industries is necessary to boost the domestic manufacturing of active pharmaceutical substances and substrates. Due to number of substances needed, the scale of national demand and the investments, the problem needs to be solved at European level. The Pharmaceutical Strategy for Europe is an important guidance in this regard. The aim of our paper is to review the current state, indicate solutions and initiate a discussion on the development of the synthesis of active pharmaceutical substances in Poland. We focused on small-molecular compounds, the national perspective and the relationship between the synthesis of active substances and protection of the natural environment. Point actions for investments in infrastructure as well as research and development are not enough. Thus, we propose to create a system supporting synthesis of active pharmaceutical substances in Poland.Publication considered as an additional result of the collaboration established as a consequence of the ORBIS project (H2020-MSCA-RISE) implementatio