Journal of Veterinary Science

The Korean Society of Veterinary Science (대한수의학회)
권호 표지
DOI QR코드

DOI QR Code

Pharmacokinetics of thalidomide in dogs: can feeding affect it? A preliminary study

  • Received : 2020.02.22
  • Accepted : 2020.04.12
  • Published : 2020.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Tumor-associated neoangiogenesis is a crucial target for antitumor therapies. Thalidomide (TAL) is a promising anti-neoangiogenetic drug that has recently been used in the treatment of several malignancies in dogs. Objectives: The aim of the study was to assess the pharmacokinetics of TAL after single oral administration in dogs. Additionally, the influence of feeding on the pharmacokinetic profile of TAL in dogs has been preliminarily investigated. Methods: Six healthy adult female Labradors were enrolled according to a randomized single-dose, 2-treatment, 2-phase, paired 2 × 2 cross-over study design. The dogs were administered a single 400 mg capsule of TAL in fasted and fed conditions. Blood was collected from 15 min to 48 h after dosing, and TAL quantified in plasma by a validated high-performance liquid chromatography method. The pharmacokinetics of TAL were analyzed using a non-compartmental approach. Results: TAL concentration was quantifiable up to 10 h and 24 h after fasted and fed conditions, respectively. Cmax (fasted, 1.34 ± 0.12 ㎍/mL; fed, 2.47 ± 0.19 ㎍/mL) and Tmax (fasted, 3 h; fed, 10 h) differed substantially between the 2 groups. AUC and t1/2λz were significantly higher in fed (42.46 ± 6.64 mg × h/L; 17.14 ± 4.68 h) compared to fasted (12.38 ± 1.13 mg × h/L; 6.55 ± 1.25 h) dogs. The relative oral bioavailability of TAL for the fasted group was low (36.92% ± 3.28%). Conclusions: Feeding affects the pharmacokinetics of oral TAL in dogs, showing a delayed, but higher absorption with different rate of elimination. These findings are of importance in clinical veterinary settings, and represent a starting point for further related studies.

Keywords

Acknowledgement

The authors sincerely thank Dr. Victoria Llewelyn (Flinders University, Australia) for manuscript grammar correction and the ThothPro LLC (Gdansk, Poland) team for software supply. This work was supported by University of Pisa grant (ex 60% 2018).

References

  1. Somers GF. Pharmacological properties of thalidomide (α-phthalimido glutarimide), a new sedative hypnotic drug. Br J Pharmacol Chemother. 1960;15(1):111-116. https://doi.org/10.1111/j.1476-5381.1960.tb01217.x
  2. Teo SK, Colburn WA, Tracewell WG, Kook KA, Stirling DI, Jaworsky MS, et al. Clinical pharmacokinetics of thalidomide. Clin Pharmacokinet. 2004;43(5):311-327. https://doi.org/10.2165/00003088-200443050-00004
  3. Sheskin J. Thalidomide in the treatment of lepra reaction. Clin Pharmacol Ther. 1965;6(3):303-306. https://doi.org/10.1002/cpt196563303
  4. Calabrese L, Fleischer AB Jr. Thalidomide: current and potential clinical applications. Am J Med. 2000;108(6):487-495. https://doi.org/10.1016/S0002-9343(99)00408-8
  5. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341(21):1565-1571. https://doi.org/10.1056/NEJM199911183412102
  6. Govindarajan R, Heaton KM, Broadwater R, Zeitlin A, Lang NP, Hauer-Jensen M. Effect of thalidomide on gastrointestinal toxic effects of irinotecan. Lancet. 2000;356(9229):566-567. https://doi.org/10.1016/S0140-6736(00)02586-1
  7. Marx GM, Pavlakis N, McCowatt S, Boyle FM, Levi JA, Bell DR, et al. Phase II study of thalidomide in the treatment of recurrent glioblastoma multiforme. J Neurooncol. 2001;54(1):31-38. https://doi.org/10.1023/A:1012554328801
  8. Patt YZ, Hassan MM, Lozano RD, Nooka AK, Schnirer II, Zeldis JB, et al.. Thalidomide in the treatment of patients with hepatocellular carcinoma: a phase II trial. Cancer. 2005;103(4):749-755. . https://doi.org/10.1002/cncr.20821
  9. Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet. 2006;367(9513):825-831. https://doi.org/10.1016/S0140-6736(06)68338-4
  10. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674. https://doi.org/10.1016/j.cell.2011.02.013
  11. Murdoch C, Muthana M, Coffelt SB, Lewis CE. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer. 2008;8(8):618-631. https://doi.org/10.1038/nrc2444
  12. D'Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A. 1994;91(9):4082-4085. https://doi.org/10.1073/pnas.91.9.4082
  13. Verheul HM, Panigrahy D, Yuan J, D'Amato RJ. Combination oral antiangiogenic therapy with thalidomide and sulindac inhibits tumour growth in rabbits. Br J Cancer. 1999;79(1):114-118. https://doi.org/10.1038/sj.bjc.6690020
  14. Kenyon BM, Browne F, D'Amato RJ. Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization. Exp Eye Res. 1997;64(6):971-978. https://doi.org/10.1006/exer.1997.0292
  15. Dunzendorfer S, Schratzberger P, Reinisch N, Kahler CM, Wiedermann CJ. Effects of thalidomide on neutrophil respiratory burst, chemotaxis, and transmigration of cytokine- and endotoxin-activated endothelium. Naunyn Schmiedebergs Arch Pharmacol. 1997;356(5):529-535. https://doi.org/10.1007/PL00005087
  16. Corral LG, Haslett PA, Muller GW, Chen R, Wong LM, Ocampo CJ, et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol. 1999;163(1):380-386.
  17. Finotello R, Henriques J, Sabattini S, Stefanello D, Felisberto R, Pizzoni S, et al. A retrospective analysis of chemotherapy switch suggests improved outcome in surgically removed, biologically aggressive canine haemangiosarcoma. Vet Comp Oncol. 2017;15(2):493-503. https://doi.org/10.1111/vco.12193
  18. Bray JP, Orbell G, Cave N, Munday JS. Does thalidomide prolong survival in dogs with splenic haemangiosarcoma? J Small Anim Pract. 2018;59(2):85-91. https://doi.org/10.1111/jsap.12796
  19. Polton G, Finotello R, Sabattini S, Rossi F, Laganga P, Vasconi ME, et al. Survival analysis of dogs with advanced primary lung carcinoma treated by metronomic cyclophosphamide, piroxicam and thalidomide. Vet Comp Oncol. 2018;16(3):399-408. https://doi.org/10.1111/vco.12393
  20. De Campos CB, Lavalle GE, Monteiro LN, Pegas GR, Fialho SL, Balabram D, et al. Adjuvant thalidomide and metronomic chemotherapy for the treatment of canine malignant mammary gland neoplasms. In Vivo. 2018;32(6):1659-1666. https://doi.org/10.21873/invivo.11429
  21. Teo SK, Evans MG, Brockman MJ, Ehrhart J, Morgan JM, Stirling DI, et al. Safety profile of thalidomide after 53 weeks of oral administration in beagle dogs. Toxicol Sci. 2001;59(1):160-168. https://doi.org/10.1093/toxsci/59.1.160
  22. Jankowski M, Fulton L, Sheafor S, Prescott D, Khanna C. Ongoing Evaluation of Single Agent Thalidomide in Dogs with Measurable Cancer. Veterinary Cancer Society 19th Annual Meeting; 1999 Nov 13-Nov 16; Woods Hole, USA. Woods Hole: Veterinary Cancer Society Conference; 1999.
  23. Woods JP, Mathews KA, Binnington AG. Thalidomide for the treatment of hemangiosarcoma in dogs. Vet Comp Oncol. 2004;2(2):108-109.
  24. Torano JS, Verbon A, Guchelaar HJ. Quantitative determination of thalidomide in human serum with high-performance liquid chromatography using protein precipitation with trichloroacetic acid and ultraviolet detection. J Chromatogr B Biomed Sci Appl. 1999;734(2):203-210. https://doi.org/10.1016/S0378-4347(99)00345-X
  25. Saccomanni G, Turini V, Manera C, Placanica G, Sale EO, Jemos C, et al. High performance liquid chromatographic determination of thalidomide in patients affected by hepatocellular carcinoma. J Pharm Biomed Anal. 2008;48(2):447-451. https://doi.org/10.1016/j.jpba.2008.01.003
  26. Guideline on Bioanalytical Method Validation. EMEA/CHMP/EWP/192217/2009. EMA Committee for Medicinal Products for Human Use (CHMP) Rev. 1 Corr. 2** [Internet]. Amsterdam: European Medicines Agency; http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/08/WC500109686.pdf. Updated 2011. Accessed 2017 Apr 18.
  27. Teo SK, Colburn WA, Thomas SD. Single-dose oral pharmacokinetics of three formulations of thalidomide in healthy male volunteers. J Clin Pharmacol. 1999;39(11):1162-1168. https://doi.org/10.1177/009127009903901108
  28. Teo SK, Scheffler MR, Kook KA, Tracewell WG, Colburn WA, Stirling DI, et al. Effect of a high-fat meal on thalidomide pharmacokinetics and the relative bioavailability of oral formulations in healthy men and women. Biopharm Drug Dispos. 2000;21(1):33-40. https://doi.org/10.1002/1099-081X(200001)21:1<33::AID-BDD213>3.0.CO;2-R
  29. Teo SK, Scheffler MR, Kook KA, Tracewell WG, Colburn WA, Stirling DI, et al. Thalidomide dose proportionality assessment following single doses to healthy subjects. J Clin Pharmacol. 2001;41(6):662-667. https://doi.org/10.1177/00912700122010555
  30. Singh BN. Effects of food on clinical pharmacokinetics. Clin Pharmacokinet. 1999;37(3):213-255. https://doi.org/10.2165/00003088-199937030-00003
  31. Chen LX, Ni XL, Zhang H, Wu M, Liu J, Xu S, et al. Preparation, characterization, in vitro and in vivo antitumor effect of thalidomide nanoparticles on lung cancer. Int J Nanomedicine. 2018;13:2463-2476. https://doi.org/10.2147/IJN.S159327
  32. Crounse RG. Human pharmacology of griseofulvin: the effect of fat intake on gastrointestinal absorption. J Invest Dermatol. 1961;37(6):529-533. https://doi.org/10.1038/jid.1961.154
  33. Walther FM, Allan MJ, Roepke RK, Nuernberger MC. The effect of food on the pharmacokinetics of oral fluralaner in dogs. Parasit Vectors. 2014;7(1):84. https://doi.org/10.1186/1756-3305-7-84
  34. Welling PG. Effects of food on drug absorption. Annu Rev Nutr. 1996;16(1):383-415. https://doi.org/10.1146/annurev.nu.16.070196.002123
  35. Lebkowska-Wieruszewska B, Stefanelli F, Chericoni S, Owen H, Poapolathep A, Lisowski A, et al. Pharmacokinetics of Bedrocan®, a cannabis oil extract, in fasting and fed dogs: an explorative study. Res Vet Sci. 2019;123:26-28. https://doi.org/10.1016/j.rvsc.2018.12.003
  36. Abiru H, Sarna SK, Condon RE. Contractile mechanisms of gallbladder filling and emptying in dogs. Gastroenterology. 1994;106(6):1652-1661. https://doi.org/10.1016/0016-5085(94)90423-5
  37. Ferguson L, Wennogle SA, Webb CB. Bilious vomiting syndrome in dogs: retrospective study of 20 cases (2002-2012). J Am Anim Hosp Assoc. 2016;52(3):157-161. https://doi.org/10.5326/jaaha-ms-6300
  38. Toutain PL, Bousquet-Melou A. Plasma terminal half-life. J Vet Pharmacol Ther. 2004;27(6):427-439. https://doi.org/10.1111/j.1365-2885.2004.00600.x
  39. Baidas SM, Winer EP, Fleming GF, Harris L, Pluda JM, Crawford JG, et al. Phase II evaluation of thalidomide in patients with metastatic breast cancer. J Clin Oncol. 2000;18(14):2710-2717. https://doi.org/10.1200/JCO.2000.18.14.2710
  40. Fine HA, Figg WD, Jaeckle K, Wen PY, Kyritsis AP, Loeffler JS, et al. Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol. 2000;18(4):708-715. https://doi.org/10.1200/JCO.2000.18.4.708
  41. Figg WD, Raje S, Bauer KS, Tompkins A, Venzon D, Bergan R, et al. Pharmacokinetics of thalidomide in an elderly prostate cancer population. J Pharm Sci. 1999;88(1):121-125. https://doi.org/10.1021/js980172i
  42. Chen W, Xiao Y, Chen J, Liu J, Shao J, Li T, et al. Sex-related pharmacokinetic differences and mechanisms of metapristone (RU486 metabolite). Sci Rep. 2017;7(1):17190. https://doi.org/10.1038/s41598-017-17225-0
  43. Fleischer S, Sharkey M, Mealey K, Ostrander E, Martinez M. Pharmacogenetic and metabolic differences between dog breeds: their impact on canine medicine and the use of the dog as a preclinical animal model. AAPS J. 2008;10(1):110-119. https://doi.org/10.1208/s12248-008-9011-1
  44. Martinez M, Mahmood I, Hunter RP. Allometric scaling of clearance in dogs. J Vet Pharmacol Ther. 2009;32(5):411-416. https://doi.org/10.1111/j.1365-2885.2009.01062.x
  45. Middleton RP, Lacroix S, Scott-Boyer MP, Dordevic N, Kennedy AD, Slusky AR, et al. Metabolic differences between dogs of different body sizes. J Nutr Metab. 2017;2017:4535710. https://doi.org/10.1155/2017/4535710
  46. Court MH, Hay-Kraus BL, Hill DW, Kind AJ, Greenblatt DJ. Propofol hydroxylation by dog liver microsomes: assay development and dog breed differences. Drug Metab Dispos. 1999;27(11):1293-1299.
  47. Hay Kraus BL, Greenblatt DJ, Venkatakrishnan K, Court MH. Evidence for propofol hydroxylation by cytochrome P4502B11 in canine liver microsomes: breed and gender differences. Xenobiotica. 2000;30(6):575-588. https://doi.org/10.1080/004982500406417
  48. Zoran DL, Riedesel DH, Dyer DC. Pharmacokinetics of propofol in mixed-breed dogs and greyhounds. Am J Vet Res. 1993;54(5):755-760.
  49. KuKanich B, Lascelles BD, Papich MG. Use of a von Frey device for evaluation of pharmacokinetics and pharmacodynamics of morphine after intravenous administration as an infusion or multiple doses in dogs. Am J Vet Res. 2005;66(11):1968-1974. https://doi.org/10.2460/ajvr.2005.66.1968
  50. KuKanich B, Coetzee JF, Gehring R, Hubin M. Comparative disposition of pharmacologic markers for cytochrome P-450 mediated metabolism, glomerular filtration rate, and extracellular and total body fluid volume of Greyhound and Beagle dogs. J Vet Pharmacol Ther. 2007;30(4):314-319. https://doi.org/10.1111/j.1365-2885.2007.00875.x
  51. Gunn HM. The proportions of muscle, bone and fat in two different types of dog. Res Vet Sci. 1978;24(3):277-282. https://doi.org/10.1016/s0034-5288(18)33033-9