Generic placeholder image

Current Pharmaceutical Biotechnology

Editor-in-Chief

ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Research Article

Simultaneously Inhibiting P-gp Efflux and Drug Recrystallization Enhanced the Oral Bioavailability of Nintedanib

Author(s): Jiandong Wang, Shujuan Zhang, Chunli Tan, Qi Wei and Subin Xiong*

Volume 24, Issue 15, 2023

Published on: 12 May, 2023

Page: [1972 - 1982] Pages: 11

DOI: 10.2174/1389201024666230417091625

Price: $65

Abstract

Introduction: Nintedanib (NDNB) is a novel triple-angiokinase inhibitor for the treatment of lung cancer. However, the oral bioavailability of NDNB is only 4.7% owing to the poor solubility and the efflux of P-glycoprotein (P-gp).

Aim: The aim was to explore the potential applications of a hydrogel of NDNB/hydroxypropyl-β- cyclodextrin (HP-β-CD) complex combined with a strong P-gp inhibitor Itraconazole (ITZ) for augmenting the oral delivery of NDNB.

Methods: The NDNB/HP-β-CD complex was prepared and characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and molecular simulation and was subjected to in vitro and in situ studies. Then the NDNB/HP-β-CD complex was dispersed in carbopol 934 hydrogel and the gel was evaluated for pharmacokinetic and pharmacodynamics studies.

Results: The HP-β-CD and NDNB formed complex by van der Waals and hydrogen bonding interaction forces by XRD, FT-IR, and molecular simulation studies. When the molar ratio of NDNB/HP-β-CD was 1:20, the complex exhibited high drug inclusion efficiency and excellent stability. The in situ perfusion results revealed that the permeability of the combination of complex and ITZ enhanced about 3.0-fold compared with the NDNB solution. The oral bioavailability of the sequential administration of ITZ and NDNB/HP-β-CD complex gels was increased 3.5-fold by preventing recrystallization, extending the residence time in the gastrointestinal tract, and inhibiting P-gp in comparison with NDNB soft capsules. The co-therapy with NDNB/HP-β-CD complex gels and ITZ exerted a strong anti-tumor effect.

Conclusion: In conclusion, NDNB/HP-β-CD complex gels combined with P-gp inhibitor were a potential strategy for enhancing the oral bioavailability and anti-tumor effect of NDNB.

Keywords: Nintedanib, hydroxypropyl-β-cyclodextrin, itraconazole, complex, gels, bioavailability.

Graphical Abstract
[1]
Wadowska, K.; Bil-Lula, I.; Trembecki, Ł.; Śliwińska-Mossoń, M. Genetic markers in lung cancer diagnosis: A review. Int. J. Mol. Sci., 2020, 21(13), 4569.
[http://dx.doi.org/10.3390/ijms21134569] [PMID: 32604993]
[2]
Hirsch, F.R.; Scagliotti, G.V.; Mulshine, J.L.; Kwon, R.; Curran, W.J., Jr; Wu, Y.L.; Paz-Ares, L. Lung cancer: Current therapies and new targeted treatments. Lancet, 2017, 389(10066), 299-311.
[http://dx.doi.org/10.1016/S0140-6736(16)30958-8] [PMID: 27574741]
[3]
Blandin, K.S.; Crosbie, P.A.; Balata, H.; Chudziak, J.; Hussell, T.; Dive, C. Progress and prospects of early detection in lung cancer. Open Biol., 2017, 7(9), 170070.
[http://dx.doi.org/10.1098/rsob.170070]
[4]
Zhu, Y.; Liang, X.; Lu, C.; Kong, Y.; Tang, X.; Zhang, Y.; Yin, T.; Gou, J.; Wang, Y.; He, H. Nanostructured lipid carriers as oral delivery systems for improving oral bioavailability of nintedanib by promoting intestinal absorption. Int. J. Pharm., 2020, 586, 119569.
[http://dx.doi.org/10.1016/j.ijpharm.2020.119569] [PMID: 32592899]
[5]
Reck, M.; Syrigos, K.; Miliauskas, S.; Zöchbauer-Müller, S.; Fischer, J.R.; Buchner, H.; Kitzing, T.; Kaiser, R.; Radonjic, D.; Kerr, K. Non-interventional LUME-BioNIS study of nintedanib plus docetaxel after chemotherapy in adenocarcinoma non-small cell lung cancer: A subgroup analysis in patients with prior immunotherapy. Lung Cancer, 2020, 148, 159-165.
[http://dx.doi.org/10.1016/j.lungcan.2020.08.004] [PMID: 32927350]
[6]
Xu, Y.; Liu, Y.; He, T.; Zhang, Y.; Wang, M.; Yuan, H.; Yang, M. Biguanides decorated albumin nanoparticles loading nintedanib for synergic enhanced hepatocellular carcinoma therapy. Colloids Surf. B Biointerfaces, 2021, 207, 112020.
[http://dx.doi.org/10.1016/j.colsurfb.2021.112020] [PMID: 34403984]
[7]
Eisen, T.; Loembé, A-B.; Shparyk, Y.; MacLeod, N.; Jones, R.J.; Mazurkiewicz, M.; Temple, G.; Dressler, H.; Bondarenko, I. A randomised, phase II study of nintedanib or sunitinib in previously untreated patients with advanced renal cell cancer: 3-year results. Br. J. Cancer, 2015, 113(8), 1140-1147.
[http://dx.doi.org/10.1038/bjc.2015.313] [PMID: 26448178]
[8]
Van Cutsem, E.; Yoshino, T.; Lenz, H.J.; Lonardi, S.; Falcone, A.; Limón, M.L.; Saunders, M.; Sobrero, A.; Park, Y.S.; Ferreiro, R.; Hong, Y.S.; Tomasek, J.; Taniguchi, H.; Ciardiello, F.; Stoehr, J.; Oum’Hamed, Z.; Vlassak, S.; Studeny, M.; Argiles, G. Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): A phase III, international, randomized, placebo-controlled study. Ann. Oncol., 2018, 29(9), 1955-1963.
[http://dx.doi.org/10.1093/annonc/mdy241] [PMID: 30010751]
[9]
Yamanaka, T.; Harimoto, N.; Yokobori, T.; Muranushi, R.; Hoshino, K.; Hagiwara, K.; Gantumur, D.; Handa, T.; Ishii, N.; Tsukagoshi, M.; Igarashi, T.; Tanaka, H.; Watanabe, A.; Kubo, N.; Araki, K.; Shirabe, K. Nintedanib inhibits intrahepatic cholangiocarcinoma aggressiveness via suppression of cytokines extracted from activated cancer-associated fibroblasts. Br. J. Cancer, 2020, 122(7), 986-994.
[http://dx.doi.org/10.1038/s41416-020-0744-7] [PMID: 32015511]
[10]
Liu, H.; Mei, J.; Xu, Y.; Tang, L.; Chen, D.; Zhu, Y.; Huang, S.; Webster, T.J.; Ding, H. Improving the oral absorption of nintedanib by a self-microemulsion drug delivery system: Preparation and in vitro/in vivo evaluation. Int. J. Nanomed., 2019, 14, 8739-8751.
[http://dx.doi.org/10.2147/IJN.S224044] [PMID: 31806968]
[11]
Vaidya, B.; Shukla, S.K.; Kolluru, S.; Huen, M.; Mulla, N.; Mehra, N.; Kanabar, D.; Palakurthi, S.; Ayehunie, S.; Muth, A.; Gupta, V. Nintedanib-cyclodextrin complex to improve bio-activity and intestinal permeability. Carbohydr. Polym., 2019, 204, 68-77.
[http://dx.doi.org/10.1016/j.carbpol.2018.09.080] [PMID: 30366544]
[12]
Wind, S.; Schmid, U.; Freiwald, M.; Marzin, K.; Lotz, R.; Ebner, T.; Stopfer, P.; Dallinger, C. Clinical pharmacokinetics and pharmacodynamics of nintedanib. Clin. Pharmacok., 2019, 58(9), 1131-1147.
[http://dx.doi.org/10.1007/s40262-019-00766-0] [PMID: 31016670]
[13]
Veerman, G.D.M.; van der Werff, S.C.; Koolen, S.L.W.; Miedema, J.R.; Oomen-de Hoop, E.; van der Mark, S.C.; Chandoesing, P.P.; de Bruijn, P.; Wijsenbeek, M.S.; Mathijssen, R.H.J. The influence of green tea extract on nintedanib’s bioavailability in patients with pulmonary fibrosis. Biomed. Pharmacother., 2022, 151, 113101.
[http://dx.doi.org/10.1016/j.biopha.2022.113101] [PMID: 35594703]
[14]
Zhou, Z.M.; Wang, Y.K.; Yan, D.M.; Fang, J.H.; Xiao, X.R.; Zhang, T.; Cheng, Y.; Xu, K.P.; Li, F.; Cheng, Y.; Xu, K.P.; Li, F. Metabolic profiling of tyrosine kinase inhibitor nintedanib using metabolomics. J. Pharm. Biomed. Anal., 2020, 180, 113045.
[http://dx.doi.org/10.1016/j.jpba.2019.113045] [PMID: 31887668]
[15]
Luedtke, D.; Marzin, K.; Jungnik, A.; von Wangenheim, U.; Dallinger, C. Effects of ketoconazole and rifampicin on the pharmacokinetics of nintedanib in healthy subjects. Eur. J. Drug Metab. Pharmacok., 2018, 43(5), 533-541.
[http://dx.doi.org/10.1007/s13318-018-0467-9] [PMID: 29500603]
[16]
Zhang, L.; Liu, Z.; Yang, K.; Kong, C.; Liu, C.; Chen, H.; Huang, J.; Qian, F. Tumor progression of non-small cell lung cancer controlled by albumin and micellar nanoparticles of itraconazole, a multitarget angiogenesis inhibitor. Mol. Pharm., 2017, 14(12), 4705-4713.
[http://dx.doi.org/10.1021/acs.molpharmaceut.7b00855] [PMID: 29068216]
[17]
Lee, W.H.; Loo, C.Y.; Ghadiri, M.; Leong, C.R.; Young, P.M.; Traini, D. The potential to treat lung cancer via inhalation of repurposed drugs. Adv. Drug Deliv. Rev., 2018, 133, 107-130.
[http://dx.doi.org/10.1016/j.addr.2018.08.012] [PMID: 30189271]
[18]
Karuppasamy, R.; Veerappapillai, S.; Maiti, S.; Shin, W.H.; Kihara, D. Current progress and future perspectives of polypharmacology: From the view of non-small cell lung cancer. Semin. Cancer Biol., 2021, 68, 84-91.
[http://dx.doi.org/10.1016/j.semcancer.2019.10.019] [PMID: 31698087]
[19]
Dirix, L.; Swaisland, H.; Verheul, H.M.W.; Rottey, S.; Leunen, K.; Jerusalem, G.; Rolfo, C.; Nielsen, D.; Molife, L.R.; Kristeleit, R.; Vos-Geelen, J.; Mau-Sørensen, M.; Soetekouw, P.; van Herpen, C.; Fielding, A.; So, K.; Bannister, W.; Plummer, R. Effect of itraconazole and rifampin on the pharmacokinetics of olaparib in patients with advanced solid tumors: Results of two phase I open-label studies. Clin. Ther., 2016, 38(10), 2286-2299.
[http://dx.doi.org/10.1016/j.clinthera.2016.08.010] [PMID: 27745744]
[20]
Ghadi, M.; Hosseinimehr, S.J.; Amiri, F.T.; Mardanshahi, A.; Noaparast, Z. Itraconazole synergistically increases therapeutic effect of paclitaxel and 99mTc-MIBI accumulation, as a probe of P-gp activity, in HT-29 tumor-bearing nude mice. Eur. J. Pharmacol., 2021, 895, 173892.
[http://dx.doi.org/10.1016/j.ejphar.2021.173892] [PMID: 33497608]
[21]
Miyazaki, N.; Misaka, S.; Ogata, H.; Fukushima, T.; Kimura, J. Effects of itraconazole, dexamethasone and naringin on the pharmacokinetics of nadolol in rats. Drug Metab. Pharmacok., 2013, 28(4), 356-361.
[http://dx.doi.org/10.2133/dmpk.DMPK-12-RG-111] [PMID: 23419354]
[22]
Rudin, C.M.; Brahmer, J.R.; Juergens, R.A.; Hann, C.L.; Ettinger, D.S.; Sebree, R.; Smith, R.; Aftab, B.T.; Huang, P.; Liu, J.O. Phase 2 study of pemetrexed and itraconazole as second-line therapy for metastatic nonsquamous non-small-cell lung cancer. J. Thorac. Oncol., 2013, 8(5), 619-623.
[http://dx.doi.org/10.1097/JTO.0b013e31828c3950] [PMID: 23546045]
[23]
Wu, W.; Xue, W. Evaluation of anticancer activity of honokiol by complexation with hydroxypropyl-β-cyclodextrin. Colloids Surf. B Biointerfaces, 2020, 196, 111298.
[http://dx.doi.org/10.1016/j.colsurfb.2020.111298] [PMID: 32798987]
[24]
Corina, D.; Florina, B.; Iulia, P.; Cristina, D.; Rita, A.; Alexandra, P.; Virgil, P.; Hancianu, M.; Daliana, M.; Codruta, S. Rutin and its cyclodextrin inclusion complexes: Physico-chemical evaluation and in vitro activity on B164A5 murine melanoma cell line. Curr. Pharm. Biotechnol., 2018, 18(13), 1067-1077.
[http://dx.doi.org/10.2174/1389201019666180209165523] [PMID: 29437003]
[25]
Jansook, P.; Ogawa, N.; Loftsson, T. Cyclodextrins: structure, physicochemical properties and pharmaceutical applications. Int. J. Pharm., 2018, 535(1-2), 272-284.
[http://dx.doi.org/10.1016/j.ijpharm.2017.11.018] [PMID: 29138045]
[26]
Xu, R.R.; Hu, R.; Chen, L.; Pan, B.; Wang, X.C.; Wu, H.H.; Song, X.H.; Hu, R. Preparation, characterization, toxicity and pharmacodynamics of the inclusion complex of brucea javanica oil with beta-cyclodextrin polymers. Curr. Pharm. Biotechnol., 2018, 18(10), 855-861.
[http://dx.doi.org/10.2174/1389201019666171211153209] [PMID: 29231135]
[27]
Garg, A.; Ahmad, J.; Hassan, M.Z. Inclusion complex of thymol and hydroxypropyl-β-cyclodextrin (HP-β-CD) in polymeric hydrogel for topical application: Physicochemical characterization, molecular docking, and stability evaluation. J. Drug Deliv. Sci. Technol., 2021, 64, 102609.
[http://dx.doi.org/10.1016/j.jddst.2021.102609]
[28]
Gao, Y.; Carr, R.A.; Spence, J.K.; Wang, W.W.; Turner, T.M.; Lipari, J.M.; Miller, J.M. A pH-dilution method for estimation of biorelevant drug solubility along the gastrointestinal tract: Application to physiologically based pharmacokinetic modeling. Mol. Pharm., 2010, 7(5), 1516-1526.
[http://dx.doi.org/10.1021/mp100157s] [PMID: 20715778]
[29]
Higuchi, T.; Connoras, K.A. Phase-solubility techniques. Adv. Anal. Chem. Instrum., 1965, 4, 117-212.
[30]
Krzak, A.; Bilewicz, R. Voltammetric/UV–Vis study of temozolomide inclusion complexes with cyclodextrin derivatives. Bioelectrochemistry, 2020, 136, 107587.
[http://dx.doi.org/10.1016/j.bioelechem.2020.107587] [PMID: 32645568]
[31]
Patel, R.P.; Patel, M.M. Preparation and evaluation of inclusion complex of the lipid lowering drug lovastatin with β- cyclodextrin. Dhaka. Dhaka Univ. J. Pharm. Sci., 1970, 6(1), 25- 36.
[http://dx.doi.org/10.3329/dujps.v6i1.340]
[32]
Saokham, P.; Muankaew, C.; Jansook, P.; Loftsson, T. Solubility of cyclodextrins and drug/cyclodextrin complexes. Molecules, 2018, 23(5), 1161.
[http://dx.doi.org/10.3390/molecules23051161] [PMID: 29751694]
[33]
Litou, C.; Psachoulias, D.; Vertzoni, M.; Dressman, J.; Reppas, C. Measuring pH and buffer capacity in fluids aspirated from the fasted upper gastrointestinal tract of healthy adults. Pharm. Res., 2020, 37(3), 42.
[http://dx.doi.org/10.1007/s11095-019-2731-3] [PMID: 31989335]
[34]
Zhang, S.; Cui, D.; Xu, J.; Wang, J.; Wei, Q.; Xiong, S. Bile acid transporter mediated STC/Soluplus self-assembled hybrid nanoparticles for enhancing the oral drug bioavailability. Int. J. Pharm., 2020, 579, 119120.
[http://dx.doi.org/10.1016/j.ijpharm.2020.119120] [PMID: 32035254]
[35]
Qin, Y.; Xiao, C.; Li, X.; Huang, J.; Si, L.; Sun, M. Enteric polymer-based amorphous solid dispersions enhance oral absorption of the weakly basic drug nintedanib via stabilization of supersaturation. Pharmaceutics, 2022, 14(9), 1830.
[http://dx.doi.org/10.3390/pharmaceutics14091830] [PMID: 36145578]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy