Journal
CURRENT ISSUES IN MOLECULAR BIOLOGY
Volume 43, Issue 3, Pages 2189-2198Publisher
MDPI
DOI: 10.3390/cimb43030153
Keywords
gemcitabine; cancer therapy; in silico study; PBPK modeling; GastroPlus (TM)
Categories
Funding
- Fundo Europeu de Desenvolvimento Regional through the COMPETE 2020 (FEDER) Operational Programme for Competitiveness and Internationalization (POCI), Portugal 2020
- Portuguese funds through Fundacao para a Ciencia e a Tecnologia (FCT) [UIDB/4255/2020]
- FCT [UID/QUI/50006/2019]
- FEDER (European Union) [IF/00092/2014/CP1255/CT0004]
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Gemcitabine, a nucleoside analog used for solid tumors, is limited by factors like metabolic inactivation and rapid clearance. Research aims to improve therapy efficacy and enhance oral bioavailability. Modeling and analysis suggest oral administration may be a viable alternative to traditional IV infusions, with potential for personalized health care and new drug delivery systems.
Gemcitabine is a nucleoside analog effective against several solid tumors. Standard treatment consists of an intravenous infusion over 30 min. This is an invasive, uncomfortable and often painful method, involving recurring visits to the hospital and costs associated with medical staff and equipment. Gemcitabine's activity is significantly limited by numerous factors, including metabolic inactivation, rapid systemic clearance of gemcitabine and transporter deficiency-associated resistance. As such, there have been research efforts to improve gemcitabine-based therapy efficacy, as well as strategies to enhance its oral bioavailability. In this work, gemcitabine in vitro and clinical data were analyzed and in silico tools were used to study the pharmacokinetics of gemcitabine after oral administration following different regimens. Several physiologically based pharmacokinetic (PBPK) models were developed using simulation software GastroPlus (TM), predicting the PK parameters and plasma concentration-time profiles. The integrative biomedical data analyses presented here are promising, with some regimens of oral administration reaching higher AUC in comparison to the traditional IV infusion, supporting this route of administration as a viable alternative to IV infusions. This study further contributes to personalized health care based on potential new formulations for oral administration of gemcitabine, as well nanotechnology-based drug delivery systems.
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