DHP23002 as a next generation oral paclitaxel formulation for pancreatic cancer therapy


Autoři: Eunseo Jang aff001;  Minhee Son aff002;  Junhee Jang aff002;  In-Hyun Lee aff002;  Sol Kim aff002;  Taejun Kwon aff001;  Yong-hyun Jeon aff001;  Woo-Suk Koh aff001;  Kil-Soo Kim aff001;  Sang Kyoon Kim aff001
Působiště autorů: Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, South Korea aff001;  Dae Hwa Pharmaceutical Co. Ltd., Pangyo Research Laboratory, Sungnam City, South Korea aff002;  College of Veterinary Medicine, Kyungpook National University, Daegu, South Korea aff003
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225095

Souhrn

Objective

This study aimed to develop a new oral paclitaxel formulation (DHP23002) and to evaluate its absorption and antitumor effects in a pancreatic tumor mouse model.

Methods

To investigate the oral absorption of DHP23002, a newly developed lipid-based orally active paclitaxel formulation, a pharmacokinetic study of DHP23002, was conducted in mice (62.5 and 125 mg/kg). Moreover, to evaluate the antitumor effect of DHP23002 in pancreatic cancer treatment, the drug was administered to female athymic nude mice at 0 (vehicle), 25, 62.5, and 125 mg/kg on alternate days; the efficacy of the agent was compared with the efficacy of intravenous Taxol® injections at 10 mg/kg once per week. After 3 weeks of administration, tumor growth in mice belonging to each group was further monitored for 4 weeks after discontinuing medication. Moreover, to examine paclitaxel (DHP23002) accumulation in the tumor tissue, the amount of paclitaxel in tumor/blood was quantified using liquid chromatography with quadruple-TOF mass spectrometry.

Results

In the mouse pharmacokinetic study, oral Taxol® showed a negligible absorption, whereas DHP23002 showed a high absorption rate dependent on dosage, with a bioavailability of approximately 40% at a dose of 62.5 mg/kg. In efficacy-related studies, DHP23002 administration at a dose of 25, 62.5, or 125 mg/kg on alternate days for 3 weeks showed a superior tumor inhibitory effect of 80%, 92%, and 97% in a xenograft mouse model, respectively, after 7 weeks. Paclitaxel accumulation in tumors persisted for >24 h in mice, when orally administered once at doses of 25, 62.5, and 125 mg/kg DHP23002.

Conclusion

Oral chemotherapy with DHP23002 showed excellent absorption in animals owing to a strong antitumor activity in a pancreatic cancer mouse model. This demonstrates that paclitaxel is largely distributed and persists for a prolonged period at the tumor site owing to oral DHP23002 administration.

Klíčová slova:

Apoptosis – Blood – Cancer treatment – Drug administration – Mouse models – Oral administration – Pancreatic cancer – Drug absorption


Zdroje

1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136: E359–E386. doi: 10.1002/ijc.29210 25220842

2. Malvezzi M, Bertuccio P, Levi F, La Vecchia C, Negri E. European cancer mortality predictions for the year 2014. Ann Oncol. 2014;25(8): 1650–1656. doi: 10.1093/annonc/mdu138 24759568

3. Malvezzi M, Bertuccio P, Rosso T, Rota M, Levi F, La Vecchia C, et al. European cancer mortality predictions for the year 2015: does lung cancer have the highest death rate in EU women?. Ann Oncol. 2015;26(4): 779–786. doi: 10.1093/annonc/mdv001 25623049

4. Ilic M, Ilic I. Epidemiology of pancreatic cancer. World J Gastroenterol. 2016:22(44): 9694–9705. doi: 10.3748/wjg.v22.i44.9694 27956793

5. Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15(6): 2403–13. doi: 10.1200/JCO.1997.15.6.2403 9196156

6. Conroy T, Desseigne F, Ychou M, Ducreux M, Bouche O, Guimbaud R, et al. Randomized phase III trial comparing FOLFIRINOX (F: 5FU/leucovorin [LV], irinotecan [I], and oxaliplatin [O]) versus gemcitabine (G) as first-line treatment for metastatic pancreatic adenocarcinoma (MPA): Preplanned interim analysis results of the PRODIGE 4/ACCORD 11 trial. J Clin Oncol. 2010;28: 303s.

7. Lambert A, Gavoille C, and Conroy T. Current status on the place of FOLFIRINOX in metastatic pancreatic cancer and future directions. Therap Adv Gastroenterol. 2017;10(8): 631–645. doi: 10.1177/1756283X17713879 28835777

8. Woodcock DM, Jefferson S, Linsenmeyer ME, Crowther PJ, Chojnowski GM, Williams B, et al. Reversal of the multidrug resistance phenotype with Cremophor EL, a common vehicle for water-insoluble vitamins and drugs. Cancer Res. 1990;50(14): 4199–4203. 2364376

9. Sparreboom A, van Tellingen O, Nooijen W, Beijnen JH. Nonlinear pharmacokinetics of paclitaxel in mice results from the pharmaceutical vehicle Cremophor EL. Cancer Res. 1996; 56(9): 2112–2115. 8616858

10. Sparreboom A, van Zuylen L, Brouwer E, Loos WJ, de Bruijn P, Gelderblom H, et al. Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications. Cancer Res 1999;59(7): 1454–1457. 10197613

11. Miele E, Spinelli G. P, Miele E, Tomao F, and Tomao S. Albumin-bound formulation of paclitaxel (Abraxane® ABI-007) in the treatment of breast cancer. Int J Nanomedicine. 2009; 4: 99–105. doi: 10.2147/ijn.s3061 19516888

12. Hidalgo M, Plaza C, Illei P, Brachmann C, Heise C, Pierce D, et al. SPARC analysis in the phase III MPACT trial of NAB-Paclitaxel (NAB-P) plus gemcutabine (GEM) vs gem alone for patients with metastatic pancreatic cancer (PC). Annual Oncology. 2014 June 01. Pii:106. doi: 10.1093/annonc/mdu193.4

13. Ryu MH, Ryoo BY, Kim TW, Kim SB, Lim HS, et al. A Phase I/IIa Study of DHP107, a Novel Oral Paclitaxel Formulation, in Patients with Advanced Solid Tumors or Gastric Cancer. Oncologist. 2017;22(2): 129–e8. doi: 10.1634/theoncologist.2016-0273 28196905

14. Hong JW, Lee IH, Kwak YH, Park YT, Sung HC, Kwon IC, et al. Efficacy and tissue distribution of DHP107, an oral paclitaxel formulation. Mol Cancer Ther. 2007;6: 3239–47. doi: 10.1158/1535-7163.MCT-07-0261 18089717

15. Lee IH, Son MH, Park YT, Lee HK, Pharmaceutical Composition for oral administration comprising high concentration Taxane. PCT No. WO 2017/018635 (02.02.2017 Gazette 2017/05)

16. Andrew D, Seidman MD. One-hour paclitaxel via weekly infusion: dose-density with enhanced therapeutic index. Oncology (Williston Park). 1998;12: 19–22.

17. Lee HJ, Heo DS, Cho JY, Han SW, Chang HJ, Yi HG, et al. A Phase I Study of Oral Paclitaxel with a Novel P-Glycoprotein Inhibitor, HM30181A, in Patients with Advanced Solid Cancer. Cancer Res Treat. 2014; 46(3): 234–242. doi: 10.4143/crt.2014.46.3.234 25038758

18. Lee IH, Hong JW, Jang Y, Park YT, Chung H. Development, Optimization and Absorption Mechanism of DHP107, Oral Paclitaxel Formulation for Single-Agent Anticancer Therapy. In Brzozowski T editor, InTech: New Advances in the Basic and Clinical Gastroenterology; 2012. pp. 357–374


Článek vyšel v časopise

PLOS One


2019 Číslo 11