Mariana Pereira; Nuno Vale
School of Medicine and Biomedical Sciences of the University of Porto (ICBAS); Faculty of Medicine of the University of Porto (FMUP)
Objectives: Drug repurposing is an emerging strategy in the quest for new cancer therapies, offering distinct advantages such as leveraging drugs already deemed safe for human use, accelerating the drug development process, and reducing costs [1]. Efavirenz (EFV) and etravirine (ETV) are first and second-generation non-nucleoside reverse transcriptase inhibitors that are approved for the treatment of human immunodeficiency virus (HIV) patients [2,3] and have been shown to have repurposing possibilities for other diseases [4]. Our group has recently published an in vitro work demonstrating the potential of ETV repurposing in bladder cancer treatment [5]. Combining repurposed drugs, either with each other or with traditional anticancer medications, can enhance their efficacy, reduce individual dosages, minimize side effects, and even overcome drug resistance [6]. A combination of ETV and EFV can emerge as a new cancer treatment regimen, but their drug-drug interaction (DDI) needs to be studied to guarantee the safety of this combination before repurposing. The objective of this work was to develop a Physiologically Based Pharmacokinetic (PBPK) model of ETV, using literature and computational data, and perform DDI studies between ETV and EFV at relevant concentrations.
Methods: Literature and ADMET Predictor® (version 11) data of ETV were used in combination to develop a PBPK model using GastroPlus® software (version 9.8.3) from Simulation Plus (Simulation Plus Inc., Lancaster, CA, USA). The model was constructed using a fed state and based on the physiology of a male American of 30 years old and 70 kg. Tablets were used as dosage form and two dosage regimens were tested, 100 mg once and two 200 mg doses 12 h apart. Pharmacokinetic values were obtained and compared with the literature [7,8]. Afterward, the DDI module of GastroPlus was used to make dynamic simulations of interactions between ETV (200 mg two times a day) and EFV at a single dose of both 400 mg and 600 mg, using a PBPK model already validated and included in the software.
Results: For 100 mg single dose the maximum plasma concentration (Cmax), the time required to maximum plasma concentration (Tmax), and the area under the curve from administration to the last time point with a measurable concentration after dosing (AUC0-T) for a 96 h simulation where of 0.131 µg/mL, 3.28 h and 2.592 µg.h/mL, respectively. These values fit with the ones obtained in literature in the same conditions (0.129 ± 0.064 µg/mL, 4 h and 1.417 ± 1.140 µg.h/mL) [7]. Further validation of the model was obtained with a 24 h simulation of 200 mg ETV every 12 h, with a simulated Cmax of 0.329 vs 0.363 ± 0.207 µg/mL and a simulated AUC0-T of 4.374 µg.h/mL vs 4.005 ± 2.346 µg.h/mL in the literature [8]. After this was obtained, the DDI study was performed with ETV as a victim and EFV as the perpetrator, with induction kinetic constants of its CYP enzymes 3A4 and 2B6 already integrated into the GastroPlus-validated EFV model. Ratios between ETV/EFV alone (baseline) and in combination for fraction absorbed (Fa), fraction of the drug concentration in the portal vein (FDp), fraction of the drug concentration in blood (F), Cmax, Tmax, AUC0-T, and area under the curve extrapolated to infinity (AUC0-∞) were obtained. For 400 mg of EFV, the ratios were mostly around the 0.9-1 mark, with the lowest being for ETV Cmax at a ratio of 0.878, which translates to a decrease of Cmax from 0.329 to 0.289 µg/mL, and AUC0-∞ of EFV with 0.773, which is a decrease from 97600 to 75400 µg.h/mL. However, none of these values are significant decreases. For 600 mg EFV the situation was comparable, with the same not significant decreases noted in ETV Cmax (ratio 0.875, 0.329 to 0.288 µg/mL) and EFV AUC0-∞ (ratio 0.72, 150000 vs 108000 µg.h/mL). It is also important to note that there were no significant changes between the pharmacokinetic parameters of the same concentration of ETV when compared between combinations with 400 mg or 600 mg of EFV.
Conclusions: This study demonstrates a successful attempt at creating a PBPK model of ETV with pharmacokinetic values comparable to those obtained previously in literature. It also demonstrates that there is no drug-drug interaction between ETV and EFV, two potential repurposing drugs that have shown potential for cancer treatment, which indicates that this is a viable combination to start performing in vitro testing and possibly develop a new anticancer therapy.
References:
[1] Pushpakom, S.; Iorio, F.; Eyers, P.A.; Escott, K.J.; Hopper, S.; Wells, A.; Doig, A.; Guilliams, T.; Latimer, J.; McNamee, C.; et al. Drug repurposing: progress, challenges and recommendations. Nature Reviews Drug Discovery 2019, 18, 41-58.
[2] Costa, B.; Vale, N. Efavirenz: History, Development and Future. Biomolecules 2022, 13, doi:10.3390/biom13010088.
[3] Etravirine. In LiverTox: Clinical and Research Information on Drug-Induced Liver Injury; National Institute of Diabetes and Digestive and Kidney Diseases: Bethesda (MD), 2012.
[4] Marima, R.; Hull, R.; Dlamini, Z.; Penny, C. Efavirenz and Lopinavir/Ritonavir Alter Cell Cycle Regulation in Lung Cancer. Front Oncol 2020, 10, 1693, doi:10.3389/fonc.2020.01693.
[5] Pereira, M.; Vale, N. Exploring Darunavir, Rilpivirine and Etravirine as Potential Therapies for Bladder Cancer: Efficacy and Synergistic Effects. Biomedicines 2024, 12, 647.
[6] Sun, W.; Sanderson, P.E.; Zheng, W. Drug combination therapy increases successful drug repositioning. Drug Discov Today 2016, 21, 1189-1195, doi:10.1016/j.drudis.2016.05.015.
[7] Schöller-Gyüre, M.; Boffito, M.; Pozniak, A.L.; Leemans, R.; Kakuda, T.N.; Woodfall, B.; Vyncke, V.; Peeters, M.; Vandermeulen, K.; Hoetelmans, R.M. Effects of different meal compositions and fasted state on the oral bioavailability of etravirine. Pharmacotherapy 2008, 28, 1215-1222, doi:10.1592/phco.28.10.1215.
[8] Siccardi, M.; Olagunju, A.; Curley, P.; Hobson, J.; Khoo, S.; Back, D.; Owen, A. Prediction of Etravirine Pharmacogenetics Using a Physiologically Based Pharmacokinetic Approach; 2013.
Reference: PAGE 32 (2024) Abstr 10878 [www.page-meeting.org/?abstract=10878]
Poster: Methodology - Other topics