izpis_h1_title_alt

Kombiniran pristop k študiju kemizma razgradnje venetoklaksa z in silico orodji in načrtovanimi stresnimi testi : doktorska disertacija
ID Žigart, Nina (Author), ID Časar, Zdenko (Mentor) More about this mentor... This link opens in a new window, ID Ilaš, Janez (Comentor)

.pdfPDF - Presentation file, Download (9,64 MB)
MD5: 06475670F52A3435053A3787743A24FC

Abstract
Stabilnost zdravilne učinkovine vpliva na njeno varnost in učinkovitost, zato je ključna pri razvoju zdravil. Pri razvoju zdravil je potrebno testiranje stabilnosti in identifikacija znatnih razgradnih produktov zdravilne učinkovine. Za poglobljeno razumevanje stabilnosti zdravilne učinkovine se izvaja dolgoročno in pospešeno testiranje stabilnosti. Pospešeno testiranje traja 6 mesecev dolgoročno pa 12 mesecev, kar znatno podaljšuje razvoj zdravila. Zgodnje napovedovanje in identifikacija možnih nečistot v zdravilu je zato pomembna pri farmacevtskem razvoju. Stresni testi zdravilne učinkovine lahko pomagajo pri zgodnji identifikaciji možnih razgradnih produktov, kar pripomore pri določevanju razgradnih poti in intrinzične stabilnosti molekule. S stresnimi testi si pomagamo tudi pri razvoju analiznih metod za testiranje stabilnosti zdravilne učinkovine. Pred izvedbo stresnih testov navadno skušamo napovedati razgradne produkte, pri čemer si pomagamo z literaturnimi podatki in kemijskim znanjem. Vedno bolj se uporabljajo tudi napovedna orodja oz. in silico orodja, ki napovedujejo razgradne produkte in nam dajo začetno sliko glede stabilnosti molekule pod različnimi pogoji. Taka orodja so lahko v pomoč tudi pri identifikaciji razgradnih produktov, pridobljenih s stresnim testiranjem. Venetoklaks je selektiven zaviralec anti-apoptotične beljakovine limfoma celic B (Bcl)-2. Je prva registrirana zdravilna učinkovina s to proteinsko tarčo. Leta 2016 je bil odobren za zdravljenje bolnikov s kronično limfocitno levkemijo v Združenih državah Amerike. Ker je venetoklaks relativno nova zdravilna učinkovina, v literaturi še ni bilo veliko znanega glede njegove stabilnosti. Prav tako ni bilo moč najti analiznih metod za testiranje stabilnosti venetoklaksa. Kot edina zdravilna učinkovina v skupini zaviralcev proteina Bcl-2 ima strukturo, ki se razlikuje od drugih znanih zdravilnih učinkovin. Tako je tudi stabilnost molekule na prvi pogled težje napovedljiva. Namen našega dela je bila določitev razgradnih produktov venetoklaksa z uporabo kombiniranega pristopa z in silico orodji in stresnimi testi ter razvoj analizne metode za spremljanje venetoklaksa in njegovih razgradnih produktov. Na podlagi struktur razgradnih produktov smo nato želeli določiti kemizme razgradnje venetoklaksa. Cilj je bil tudi vključitev principa razvoja analizne metode z vgrajeno kakovostjo (AQbD) in s tem izboljšanje robustnosti analizne metode in boljše razumevanje vplivov posameznih parametrov analizne metode na ključne odzive analizne metode.

Language:Slovenian
Keywords:razvoj zdravil, venetoklaks, in silico orodja, stresni testi, kemizem razgradnje venetoklaksa
Work type:Dissertation
Typology:2.08 - Doctoral Dissertation
Organization:FFA - Faculty of Pharmacy
Place of publishing:Ljubljana
Publisher:[N. Žigart]
Year:2021
Number of pages:131 str.
PID:20.500.12556/RUL-137073 This link opens in a new window
UDC:615.015+66.022.362(043.3)
COBISS.SI-ID:64108547 This link opens in a new window
Publication date in RUL:01.06.2022
Views:738
Downloads:32
Metadata:XML DC-XML DC-RDF
:
Copy citation
Share:Bookmark and Share

Secondary language

Language:English
Title:A combined approach to the study of venetoclax degradation pathways using in silico tools and designed stress testing
Abstract:
Drug stability is crucial in drug development since it affects the safety and efficiency of the drug product. Stability testing and identification of significant degradation products of the active pharmaceutical ingredient (API) are required during drug development. Long-term and accelerated stability testing is performed to provide an in-depth understanding of the stability of the active substance. Accelerated testing lasts 6 months and long-term testing lasts 12 months, which significantly prolongs the development of the drug product. Therefore, early prediction and identification of possible impurities in drug product is important in pharmaceutical development. Stress tests of the active substance can help in the early identification of possible degradation products, which helps to determine degradation pathways and intrinsic stability of the molecule. Stress tests also help to develop stability-indicating analytical methods. Before performing stress tests, we usually try to predict degradation products, using literature data and chemical knowledge. Increasingly, in silico tools that predict degradation products are used, which give us an initial picture of the stability of the molecule under different conditions. Such tools can also be helpful in identifying degradation products obtained in stress testing. Venetoclax is a selective inhibitor of the anti-apoptotic B-cell lymphoma (Bcl)-2 protein, a first of its kind. It was approved for the treatment of patients with chronic lymphocytic leukemia in the United States in 2016. Because venetoclax is a relatively new active substance, not much is known about its stability in the literature and no stability-indicating analytical method for venetoclax could be found. As the only Bcl-2 protein inhibitor on the market, it has a structure that differs from other known active substances. Thus, the stability of the molecule is also more difficult to predict at first glance. The purpose of our work was to determine the degradation products of venetoclax using a combined approach with in silico tools and stress tests, as well as to develop an analytical method for monitoring venetoclax and its degradation products. Additionally, we wanted to determine the degradation pathways and degradation chemistry of venetoclax based on the structures of degradation products. The aim was also to include the principles of Analytical Quality by Design (AQbD) in analytical method development, thus improve the robustness of the analytical method, and better understand the effects of critical method parameters on the critical method attributes.


Similar documents

Similar works from RUL:
Similar works from other Slovenian collections:

Back