New In Vitro-In Silico Approach for the Prediction of In Vivo Performance of Drug Combinations

Autor: Nuno Vale, Arto Urtti, Joana Santos, Rui A. S. Lapa, Abigail Ferreira, Cristiana V. Correia, Marjo Yliperttula
Přispěvatelé: Division of Pharmaceutical Biosciences, Biopharmaceutics Group, Drug Research Program, Drug Delivery Unit, Drug Delivery
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Pharmaceutical Science
in vitro-in silico approach
Pharmacology
Deoxycytidine
Analytical Chemistry
QD241-441
0302 clinical medicine
ANTIFUNGAL
Neoplasms
Antineoplastic Combined Chemotherapy Protocols
Drug Discovery
media_common
drug repurposing
In vitro toxicology
CHEMOTHERAPY
3. Good health
Drug Combinations
Drug repositioning
Chemistry (miscellaneous)
317 Pharmacy
030220 oncology & carcinogenesis
SIMULATION
Molecular Medicine
GROWTH
CLINICAL PHARMACOKINETICS
Fluorouracil
pharmacokinetics
medicine.drug
Drug
Itraconazole
media_common.quotation_subject
In silico
INHIBITION
drug combination
Antineoplastic Agents
Context (language use)
VERAPAMIL
Models
Biological
Article
ITRACONAZOLE
03 medical and health sciences
Pharmacokinetics
In vivo
Cell Line
Tumor
medicine
Humans
Computer Simulation
Physical and Theoretical Chemistry
cell growth inhibition
Cell Proliferation
business.industry
Organic Chemistry
Gemcitabine
030104 developmental biology
business
RESISTANCE
Zdroj: Molecules
Volume 26
Issue 14
Molecules, Vol 26, Iss 4257, p 4257 (2021)
ISSN: 1420-3049
DOI: 10.3390/molecules26144257
Popis: Pharmacokinetic (PK) studies improve the design of dosing regimens in preclinical and clinical settings. In complex diseases like cancer, single-agent approaches are often insufficient for an effective treatment, and drug combination therapies can be implemented. In this work, in silico PK models were developed based on in vitro assays results, with the goal of predicting the in vivo performance of drug combinations in the context of cancer therapy. Combinations of reference drugs for cancer treatment, gemcitabine and 5-fluorouracil (5-FU), and repurposed drugs itraconazole, verapamil or tacrine, were evaluated in vitro. Then, two-compartment PK models were developed based on the previous in vitro studies and on the PK profile reported in the literature for human patients. Considering the quantification parameter area under the dose-response-time curve (AUCeffect) for the combinations effect, itraconazole was the most effective in combination with either reference anticancer drugs. In addition, cell growth inhibition was itraconazole-dose dependent and an increase in effect was predicted if itraconazole administration was continued (24-h dosing interval). This work demonstrates that in silico methods and AUCeffect are powerful tools to study relationships between tissue drug concentration and the percentage of cell growth inhibition over time.
Databáze: OpenAIRE
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