Mehanističko modelovanje i mogućnost predviđanja brzine rastvaranja lekovite supstance iz tableta in vitro i in vivo
Mechanistic modeling and predictability of in vitro and in vivo drug dissolution from tablets
Докторанд
Beloica, SofijaМентор
Parojčić, JelenaЧланови комисије
Ibrić, SvetlanaCvijić, Sandra
Gatarić, Biljana
Метаподаци
Приказ свих података о дисертацијиСажетак
Ispitivanje brzine rastvaranja lekovite supstance iz preparata prepoznato je kao najznačajnija in
vitro metoda u biofarmaceutskoj karakterizaciji lekova. Adekvatno osmišljenim in vitro testom moguće je
simulirati ponašanje lekovite supstance in vivo, te na taj način uočiti eventualne probleme vezane za njenu
biološku raspoloživost. Dobijeni profili mogu se koristiti kao ulazni parametri za in silico simulacije, a
ovakav integrisani pristup ima za cilj da ubrza razvoj efikasnih i bezbednih lekova u skladu sa potrebama
i očekivanjima pacijenata. Osnovni cilj ovog rada je procena mogućnosti primene mehanističkog in vitro-
in vivo-in silico modelovanja u razvoju in vitro metode za ispitivanje brzine rastvaranja lekovite
supstance iz preparata koja omogućava predviđanje in vivo ponašanja leka i identifikaciju klinički
značajnih specifikacija za lekovite supstance koje pokazuju različite biofarmaceutske karakteristike i
pripadaju različitim klasama Biofarmaceutskog sistema klasifikacije.
U i...straživanju je ispitivan uticaj fiziološki zasnovanih medijuma i dinamičkih uređaja na brzinu
rastvaranja lekovitih susptanci iz ispitivanih preparata. Kod najvećeg broja ispitivanih preparata nije
zabeležen značajan uticaj fizioloških surfaktanata na brzinu rastvaranja. Takođe, u slučaju preparata sa
trenutnim oslobađanjem, primena dinamičkih uređaja za ispitivanje brzine rastvaranja nije pokazala
prednost u odnosu na aparaturu sa lopaticom. Dobijeni rezultati ukazuju da se za najveći broj ispitivanih
preparata ispitivanje brzine rastvaranja u aparaturi sa lopaticom uz korišćenje medijuma koji simulira
sadržaj tankog creva na gladno bez dodatka fizioloških surfaktanata može usvojiti kao bioprediktivna
metoda za ispitivanje brzine rastvaranja. Ovakav zaključak podržan je i visokim stepenom in vitro-in vivo
korelacije između ispitivanih profila.
Fiziološki zasnovano biofarmaceutsko modelovanje uz primenu Simcyp® i GastroPlusTM
programskih paketa omogućilo je uspešno predviđanje apsorpcije ispitivanih model supstanci na osnovu
odgovarajućeg seta ulaznih podataka. Ipak, u najvećem broju slučajeva, bilo je neophodno primeniti
optimizaciju parametara kako bi se postiglo slaganje simuliranog i in vivo profila koncentracije lekovite
supstance u plazmi (tzv. „middle out“ pristup). Analiza osteljivosti parametara pokazala se vrlo korisnom
alatkom koja može ukazati na kritične parametre koji značajno utiču na obim i brzinu apsorpcije. Na
primeru model supstance ibuprofena dokazana je i generalizaciona sposobnost razvijenog modela za
predviđanje apsorpcije lekovite supstance iz različitih farmaceutskih oblika. Iako su prisutne izvesne
razlike, pre svega u pogledu obima apsorpcije, profili dobijeni Simcyp® i GastroPlusTM simulacijama su,
generalno, bili međusobno slični. Pokazano je da se gastrointestinalna simulacija može koristiti kao
metoda izbora za predviđanje apsorpcije lekovitih supstanci, kao i za mehanističko proučavanje procesa
apsorpcije u slučajevima kada primena konvencionalnih farmakokinetičkih metoda nije moguća (lekovite
supstance klase 2 i 4 BCS koje se zbog niske rastvorljivosti ne mogu primeniti u obliku rastvora za
intravensku primenu i/ili u slučajevima kada lekovita supstanca pokazuje nelinearnu kinetiku usled
izraženog presistemskog metabolizma, uticaja transportera i td.). Rezultati dobijeni primenom
gastrointestinalne simulacije bili su, generalno, u saglasnosti sa rezultatima dobijenim primenom
konvencionalne farmakokinetičke analize.
Dissolution test for solid oral dosage forms has been recognized as the most important in
vitro method in biopharmaceutical drug characterization. With the right choice of experimental
conditions, it is possible to simulate the in vivo drug behavior, and in that way to identify
possible problems related to its bioavailability. Experimentally obtained in vitro drug dissolution
profiles can be used as input parameters for in silico simulations, and this integrated approach
aims to accelerate development of effective and safe drugs in accordance with patients needs and
expectations. The main objective of this work was to assess the possibility of applying
mechanistic in vitro-in vivo-in silico modeling in the development of an in vitro drug dissolution
method, that enables prediction of in vivo behavior of the drug and identification of clinically
significant specifications for drug substances that show different biopharmaceutical properties
and belong to different classes of the Biopharm...aceutical Classification System.
In this research we examined the influence of physiologically based dissolution media and
dynamic dissolution devices on the dissolution rate of drug substances from selected
preparations. No significant influence of physiological surfactants on the dissolution rate was
recorded for the majority of tested preparations. Also, in the case of immediate release
preparations, the dynamic dissolution devices did not show an adventage over the compandial
paddle apparatus. The obtained results indicate that, for the majority of tested preparations,
paddle apparatus using fasted state simulated intestinal fluid without addition of physiological
surfactants can be adopted as biopredictive dissolution method. This conclusion is also supported
by the high level of in vitro-in vivo correlation between the examined profiles.
Physiologically based biopharmaceutics modeling using Simcyp® and GastroPlusTM
software packages enabled to successfully predict absorption of selected drugs based on the
appropriate set of input data. However, in the majority of cases, it was necessary to apply
parameter optimization in order to achieve agreement between the simulated and the in vivo drug
substance plasma profile (the so-called „middle out“ approach). Parameter sensitivity analysis
proved to be a very useful tool that can indicate critical parameters that significantly affect the
extent and rate of absorption. Using the example of model substance ibuprofen, the
generalization ability of the developed model for predicting drug absorption from different
dosage forms was proven. Although there are some differences, primarly regarding the extent of
absorption, the profiles obtained by Simcyp® and GastroPlusTM simulations were, in general,
similar to each other. It has been shown that gastrointestinal simulations can be used as method
of choice for predicting drug absorption, as well as for mechanistic study of drug absorption
process in cases where application of conventional pharmacokinetic methods is not possible
(drug substances of BCS class 2 and 4 which due to low solubility cannot be administered in the
form of intravenous solution and/or in cases when drug substance shows non-linear kinetics due
to pronounced pre-systemic metabolism, influence of transporteres, etc.). The results obtained
using gastrointestinal simulation were, in general, in agreement with the results obtained using
conventional pharmacokinetic analysis.