Permeability of Gemcitabine and PBPK Modeling to Assess Oral Administration

Abstract

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™, 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.

The Role of “Physiologically Based Pharmacokinetic Model (PBPK)” New Approach Methodology (NAM) in Pharmaceuticals and Environmental Chemical Risk Assessment

“…For instance, a gemcitabine PBPK model was developed using Gastroplus software with IV and oral routes of administration to evaluate the plasma-concentration time profile. The author showed that the drug Cmax was lower, but AUC (area under curve) was higher for the tablet dosage regimens (1000 mg, three/day and 1500 mg 2–3 times a day) compared to the IV infusion [ 47 ]. Often, the availability of the compound in systemic circulation is dependent on multiple factors.…”

“…The inhalation route is quite successful in respiratory diseases and also for rapid systemic drug delivery. A PBPK model was built for inhaled nemirasalib, consisting of extra-thoracic, thoracic, bronchiolar and alveolar tissues for evaluating pulmonary drug absorption [ 47 ]. For environmental chemical such as xylene, PBPK with lungs as a route for inhalation and exhalation was modeled for reconstructing the human exposure [ 52 ].…”

The Role of “Physiologically Based Pharmacokinetic Model (PBPK)” New Approach Methodology (NAMs) in Pharmaceuticals and Environmental Chemical Risk Assessment

“…For instance, gemcitabine PBPK model was developed using Gastroplus software with IV and oral route of administration to evaluate plasma-concentration time profile. Author showed that the drug Cmax was lower, but AUC was higher for the tablet dosage regimens (1000 mg, three*/day and 1500 mg 2-3*/day) compared to the IV infusion (Ferreira et al, 2021) Often the availability of the compound in systemic circulation is dependent on multiple factors. For instance, absorption is often considered the critical parameter for oral route along with influence from fasting or fed state.…”

“…Inhalation route of exposure is quite successful in respiratory diseases and also for rapid systemic drug delivery. PBPK model was built for inhaled nemirasalib consisting of extra-thoracic, thoracic, bronchiolar and alveolar tissues for evaluating pulmonary drug absorption (Ferreira et al, 2021). For environmental chemical like xylene, PBPK with lungs as a route for inhalation and exhalation was modeled for reconstructing the human exposure (McNally et al, 2012).…”

Prediction of Drug Synergism between Peptides and Antineoplastic Drugs Paclitaxel, 5-Fluorouracil, and Doxorubicin Using In Silico Approaches

“…The generic GastroPlus ® ACAT model provided reasonable predictions especially for biopharmaceutical classification system (BCS) class 1 compounds [20]. In addition, the ability of PBPK models to predict oral PK will also improve, providing a better tool for the discovery and development of new medicines [21][22][23][24], as drug combinations or drug synergism.…”