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

Abstract

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.

Two Possible Strategies for Drug Modification of Gemcitabine and Future Contributions to Personalized Medicine

“…In a study from our group, gemcitabine and 5-fluorouracil (5-FU), which is another traditional anticancer drug, were combined with three repurposed drugs, itraconazole, verapamil, and tacrine to assess their joined effect on cancerous cells. The main objective was to predict the effect of these combinations in humans using in vitro and in silico techniques [ 27 ].…”

“…The results showed that combinations with verapamil and tacrine had no effects on all types of cells, with the effects being the same as the ones with the anticancer drug alone, while combination with itraconazole improved the overall effect with 5-FU in all cell types and with gemcitabine in A549 cells. However, when looking at the effects of gemcitabine in PNT2 and PC-3 cells, the increase was only noticeable for smaller concentrations of this drug, matching with the control at higher concentrations of gemcitabine [ 27 ].…”

“…The dose-response curves obtained for the first study showed that, at higher concentrations of itraconazole, the inhibition of cell growth for the gemcitabine-itraconazole combination is higher than for either drug alone, while for 5-FU-itraconazole, no improvement was obtained. In the second study, for both combinations, despite itraconazole not affecting the highest cell growth inhibition percentage, which is entirely dependent on the anticancer drugs, it had a great impact on the lowest cell growth inhibition percentage (from 0 to 13% and 33%), which seems to be dependent on itraconazole [ 27 ].…”

“…The results from these simulations showed that AUC effect increased with higher concentrations of itraconazole combined with both anticancer drugs. Gemcitabine also had higher AUC effect values since it has a higher dose and exposure time compared with 5-FU [ 27 ].…”

“…It was shown that the % effect was higher in the gemcitabine-itraconazole combination (73% vs. 59% of cell growth inhibition) and it also maintained the high levels for a longer period (260 min vs. 70 min) before it started to drop abruptly. This type of relationship is important for dose regimen assessment [ 27 ].…”