Primena metode prilagođenog indirektnog poređenja u proceni biološke ekvivalnetnosti i zamenjivosti generičkih lekova – primer klopidogrela

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. Beogra

Investigation to Explain Bioequivalence Failure in Pravastatin Immediate-Release Products

Abstract: The purpose of this work is to explore the predictive ability of the biopharmaceutics classification system (BCS) biowaiver based on the dissolution methods for two pravastatin test products,where one of themshowedbioequivalence (BE)while the other test failed(non-bioequivalence, or NBE), and to explore the reasons for the BE failure. Experimental solubility and permeability data confirmed that pravastatin is a BCS class III compound. The permeability experiments confirmed that the NBE formulation significantly increased pravastatin permeability, and could explain its higher absorption rate and higher Cmax. This finding highlights the relevance of requiring similar excipients for BCS class III drugs. The BCS-based biowaiver dissolution tests at pH 1.2, 4.5, and 6.8, with the paddle apparatus at 50 rpm in 900 mL media, were not able to detect differences in pravastatin products, although the NBE formulation exhibited a more rapid dissolution at earlier sampling times. Dissolution tests conducted in 500 mL did not achieve complete dissolution, and both formulations were dissimilar because the amount dissolved at 15 min was less than 85%. The difference was less than 10% at pH 1.2 and 4.5, while at pH 6.8 f 2, results reflected the Cmax rank order

One and Two-Step In Vitro-In Vivo Correlations Based on USP IV Dynamic Dissolution Applied to Four Sodium Montelukast Products

Montelukast is a weak acid drug characterized by its low solubility in the range of pH 1.2 to 4.5, which may lead to dissolution-limited absorption. The aim of this paper is to develop an in vivo predictive dissolution method for montelukast and to check its performance by establishing a level-A in vitro-in vivo correlation (IVIVC). During the development of a generic film-coated tablet formulation, two clinical trials were done with three different experimental formulations to achieve a similar formulation to the reference one. A dissolution test procedure with a flow-through cell (USP IV) was used to predict the in vivo absorption behavior. The method proposed is based on a flow rate of 5 mL/min and changes of pH mediums from 1.2 to 4.5 and then to 6.8 with standard pharmacopoeia buffers. In order to improve the dissolution of montelukast, sodium dodecyl sulfate was added to the 4.5 and 6.8 pH mediums. Dissolution profiles in from the new method were used to develop a level-A IVIVC. One-step level-A IVIVC was developed from dissolution profiles and fractions absorbed obtained by the Loo–Riegelman method. Time scaling with Levy’s plot was necessary to achieve a linear IVIVC. One-step differential equation-based IVIVC was also developed with a time-scaling function. The developed method showed similar results to a previously proposed biopredictive method for montelukast, and the added value showed the ability to discriminate among different release rates in vitro, matching the in vivo clinical bioequivalence results