Title (srp)

Primena tehnika za naprednu analizu podataka u biofarmaceutskoj karakterizaciji lekova: identifikacija, klasifikacija i predviđanje faktora koji utiču na intestinalnu apsorpciju lekovitih supstanci: doktorska disertacija

Author

Gatarić, Biljana, 1988-, 68092681

Contributor

Parojčić, Jelena, 1968-, 12768615
Cvijić, Sandra, 1976-, 13848167
Gagić, Žarko, 1985-, 66649865

Description (eng)

The absorption of drugs from gastrointestinal tract depends on a number of interrelated physicochemical, physiological, biopharmaceutical and formulation factors. The application of modern advanced data analysis techniques can contribute to a mechanistic understanding of the phenomena involved in drug absorption and the identification of the factors on which it depends. The main goal of the research was to evaluate the possibility of applying different advanced data analysis techniques in biopharmaceutical characterization of drugs through the development and validation of models for predicting permeability, identification of critical values of factors on which absorption depends and the possibility of predicting food effects. Advanced data analysis was performed on a sample of 128 model drug substances grouped into three data sets based on the extensive analysis of the available data on their physicochemical, biopharmaceutical and pharmacokinetic characteristics. The application of hierarchical clustering on principal components has shown that permeability is the most important factor for predicting the absorption of drugs after oral administration. Two values of the permeability coefficient, 1 × 10-4 and 2.7 × 10-4 cm/s, were identified as the basis for classification, which indicates the ternary classification system and the existence of a separate group of drugs with moderate permeability. Using a random forest algorithm, the model was developed and validated that showed a moderate ability to predict the effect of food on absorption (kappa value > 0.4). Four drugs reported in the literature to show low solubility and low permeability (acyclovir, furosemide, valsartan and norfloxacin) were characterized using physiologically based pharmacokinetic models in combination with the results of in vitro dissolution studies. The obtained results indicate that the existing criteria on which the solubility assessment is based within the Biopharmaceutical Classification System are too conservative and would need to be modified in order to establish biorelevant limit values and criteria for drug classification.

Description (srp)

Apsorpcija lekovite supstance iz gastrointestinalnog trakta zavisi od brojnih meĎusobno povezanih fizičkohemijskih, fizioloških, biofarmaceutskih i farmaceutsko-tehnoloških faktora. Primena savremenih tehnika za naprednu analizu podataka moţe da doprinese mehanističkom razumevanju fenomena uključenih u apsorpciju lekova i identifikaciji faktora od kojih ona zavisi. Osnovni cilj istraţivanja bio je procena mogućnosti primene različitih tehnika za naprednu analizu podataka u biofarmaceutskoj karakterizaciji lekova kroz razvoj i validaciju modela za predviĎanje permeabilnosti, identifikaciju kritičnih vrednosti faktora od kojih zavisi apsorpcija i mogućnost predviĎanje uticaja hrane. Napredna analiza podataka sprovedena je na uzorku od 128 model supstanci grupisanih u tri seta podataka na osnovu opseţne analize dostupnih informacija o njihovim fizičkohemijskim, biofarmaceutskim i farmakokinetičkim karakteristikama. Primenom hijerarhijskog klasterovanja na glavnim komponentama pokazano je da je permeabilnost najvaţniji faktor za predviĎanje apsorpcije lekovitih supstanci nakon oralne primene. Kao osnov za klasifikaciju identifikovane su dve vrednosti koeficijenta permeabilnosti, 1 × 10-4 i 2,7 × 10-4 cm/s, što ukazuje na ternerni sistem klasifikacije i postojanje posebne grupe lekovitih supstanci sa umerenom permeabilnošću. Primenom algoritma slučajnih šuma razvijen je i validiran model koje je pokazao umerenu sposobnost predviĎanja efekta hrane na apsorpciju (kappa vrednost > 0,4). Četiri lekovite supstance za koje se u literaturi navodi da pokazuju nisku rastvorljivost i nisku permeabilnost (aciklovir, furosemid, valsartan i norfloksacin) su okarakterisane primenom fiziološki zasnovanih farmakokinetičkih modela u kombinaciji sa rezultatima in vitro ispitivanja brzine rastvaranja. Dobijeni rezultati ukazuju da su postojeći kriterijumi na kojima se zasniva procena rastvorljivosti u okviru Biofarmaceutskog sistema klasifikacije previše strogi i da ih je potrebno modifikovati kako bi se uspostavile biorelevantne granične vrednosti i kriterijumi za klasifikaciju lekova.

Description (srp)

Farmacija - Farmaceutska tehnologija / Pharmacy - Pharmaceutical technology Datum odbrane: 29.09.2021.

Object languages

Serbian

Date

2021

Rights

Creative Commons License
This work is licensed under a
CC BY-NC-ND 2.0 AT - Creative Commons Attribution - Non-Commercial - No Derivative Works 2.0 Austria License.

CC BY-NC-ND 2.0 AT

http://creativecommons.org/licenses/by-nc-nd/2.0/at/

Subject

advanced data analysis techniques, biopharmaceutical characterization of drugs, drug absorption, permeability, solubility, food effect, physiologically based pharmacokinetic modeling

OSNO - Opšta sistematizacija nau?nih oblasti -- Farmacija (32) -- Farmaceutska tehnologija i kozmetologija (3215)

Identifiers