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

• Type: Article in International Scientific Journal
• Date: 2021

Authors

Correia, C (Author) Other; Ferreira, A (Author) Other; Santos, J (Author) Other; Lapa, RAS (Author) FFUP; Yliperttula, M (Author) Other; Urtti, A (Author) Other; Nuno Vale (Author) FMUP

Journal

Title: Molecules

Vol. 26 No. 17

Final page: 4257

ISSN: 1420-3049

Publisher: MDPI

Indexing

ISI Web of Knowledge - 1 Citation

Other information

Authenticus ID: P-00V-6Y6

DOI: 10.3390/molecules26144257

Abstract (EN): 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 (AUC(effect)) 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 AUC(effect) are powerful tools to study relationships between tissue drug concentration and the percentage of cell growth inhibition over time.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 24