Hepatic Artery and Peripheral Vein Pharmacokinetics of Raltitrexed in Swine After the Administration of a Hepatic Arterial Infusion

Author(s): Linzhong Zhu, Nan Zheng*, Xingang Li, Xiaofeng Zhang

Journal Name: Current Drug Metabolism

Volume 20 , Issue 7 , 2019

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Abstract:

Background: Hepatic Arterial Infusion (HAI) with raltitrexed has become an effective treatment for hepatocellular cancer and colorectal cancer liver metastases. However, traditional Body Surface Area (BSA)-based dosing is unsafe or ineffective, and a more accurate model-based approach is required.

Methods: In this study, domestic swine were given 1 mg or 4 mg raltitrexed administered by an HAI with infusion times of 30, 60 and 120 min. Hepatic Artery (HA) and Peripheral Vein (PV) samples were collected, and a twocompartment model with an elimination pathway was established to describe the in vivo behavior of raltitrexed.

Results: The clearance was 0.27 L/min, and the volumes of distribution were 0.35 and 6.65 L for the HA and PV compartments, respectively. The goodness-of-fit plots and visual predictive checks suggested that the proposed pharmacokinetic model agreed well with the observations.

Conclusion: The pharmacokinetic model could be helpful in quantitatively describing the detailed processes of raltitrexed activity administered by HAI and determining an appropriate dosing regimen for preclinical and clinical studies.

Keywords: Raltitrexed, hepatic arterial infusion, hepatic artery, peripheral vein, pharmacokinetics, two-compartmental model, swine.

[1]
Llovet, J.M.; Real, M.I.; Montaña, X.; Planas, R.; Coll, S.; Aponte, J.; Ayuso, C.; Sala, M.; Muchart, J.; Solà, R.; Rodés, J.; Bruix, J. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet, 2002, 359(9319), 1734-1739.
[http://dx.doi.org/10.1016/S0140-6736(02)08649-X] [PMID: 12049862]
[2]
Suzuki, E.; Chiba, T.; Ooka, Y.; Ogasawara, S.; Tawada, A.; Motoyama, T.; Kanogawa, N.; Saito, T.; Yoshikawa, M.; Yokosuka, O. Transcatheter arterial infusion for advanced hepatocellular carcinoma: Who are candidates? World J. Gastroenterol., 2015, 21(29), 8888-8893.
[http://dx.doi.org/10.3748/wjg.v21.i29.8888] [PMID: 26269678]
[3]
Kanat, O.; Gewirtz, A.; Kemeny, N. What is the potential role of hepatic arterial infusion chemo-therapy in the current armamentorium against colorectal cancer. J. Gastrointest. Oncol., 2012, 3(2), 130-138.
[PMID: 22811880]
[4]
Whisenant, J.; Venook, A. Defining the role of hepatic arterial infusion chemotherapy in metastatic colorectal cancer. Oncology (Williston Park), 2004, 18(6), 762-768.
[PMID: 15214595]
[5]
Wilson, K.S.; Malfair Taylor, S.C. Raltitrexed: Optimism and reality. Expert Opin. Drug Metab. Toxicol., 2009, 5(11), 1447-1454.
[http://dx.doi.org/10.1517/17425250903307455] [PMID: 19863453]
[6]
Guo, J-H.; Zhang, H-Y.; Gao, S.; Zhang, P-J.; Li, X-T.; Chen, H.; Wang, X-D.; Zhu, X. Hepatic artery infusion with raltitrexed or 5-fluorouracil for colorectal cancer liver metastasis. World J. Gastroenterol., 2017, 23(8), 1406-1411.
[http://dx.doi.org/10.3748/wjg.v23.i8.1406] [PMID: 28293087]
[7]
Yoshikawa, M.; Ono, N.; Yodono, H.; Ichida, T.; Nakamura, H. Phase II study of hepatic arterial infusion of a fine-powder formulation of cisplatin for advanced hepatocellular carcinoma. Hepatol. Res., 2008, 38(5), 474-483.
[http://dx.doi.org/10.1111/j.1872-034X.2008.00338.x] [PMID: 18430093]
[8]
Gurney, H. How to calculate the dose of chemotherapy. Br. J. Cancer, 2002, 86(8), 1297-1302.
[http://dx.doi.org/10.1038/sj.bjc.6600139] [PMID: 11953888]
[9]
Ratain, M.J. Body-surface area as a basis for dosing of anticancer agents: Science, myth, or habit? J. Clin. Oncol., 1998, 16(7), 2297-2298.
[http://dx.doi.org/10.1200/JCO.1998.16.7.2297] [PMID: 9667242]
[10]
Budman, D.R.; Berry, D.A.; Cirrincione, C.T.; Henderson, I.C.; Wood, W.C.; Weiss, R.B.; Ferree, C.R.; Muss, H.B.; Green, M.R.; Norton, L.; Frei, E., III Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. J. Natl. Cancer Inst., 1998, 90(16), 1205-1211.
[http://dx.doi.org/10.1093/jnci/90.16.1205] [PMID: 9719081]
[11]
Price, G.S.; Frazier, D.L. Use of Body Surface Area (BSA)-based dosages to calculate chemotherapeutic drug dose in dogs: I. Potential problems with current BSA formulae. J. Vet. Intern. Med., 1998, 12(4), 267-271.
[http://dx.doi.org/10.1111/j.1939-1676.1998.tb02121.x] [PMID: 9686386]
[12]
Khouri, C.; Guiu, B.; Cercueil, J.P.; Chauffert, B.; Ladoire, S.; Ghiringhelli, F. Raltitrexed and oxaliplatin hepatic arterial infusion for advanced colorectal cancer: A retrospective study. Anticancer Drugs, 2010, 21(6), 656-661.
[http://dx.doi.org/10.1097/CAD.0b013e328337d469] [PMID: 20216061]
[13]
Euteneuer, J.C.; Kamatkar, S.; Fukuda, T.; Vinks, A.A.; Akinbi, H.T. Suggestions for model-informed precision dosing to optimize neonatal drug therapy. J. Clin. Pharmacol., 2019, 59(2), 168-176.
[http://dx.doi.org/10.1002/jcph.1315] [PMID: 30204236]
[14]
Kern, W.; Beckert, B.; Lang, N.; Stemmler, J.; Beykirch, M.; Stein, J.; Goecke, E.; Waggershauser, T.; Braess, J.; Schalhorn, A.; Hiddemann, W. Phase I and pharmacokinetic study of hepatic arterial infusion with oxaliplatin in combination with folinic acid and 5-fluorouracil in patients with hepatic metastases from colorectal cancer. Ann. Oncol., 2001, 12(5), 599-603.
[http://dx.doi.org/10.1023/A:1011186708754] [PMID: 11432616]
[15]
Lévi, F.; Karaboué, A.; Etienne-Grimaldi, M-C.; Paintaud, G.; Focan, C.; Innominato, P.; Bouchahda, M.; Milano, G.; Chatelut, E. Pharmacokinetics of irinotecan, oxaliplatin and 5-fluorouracil during hepatic artery chronomodulated infusion: A translational European OPTILIV study. Clin. Pharmacokinet., 2017, 56(2), 165-177.
[http://dx.doi.org/10.1007/s40262-016-0431-2] [PMID: 27393140]
[16]
Clarke, S.J.; Beale, P.J.; Rivory, L.P. Clinical and preclinical pharmacokinetics of raltitrexed. Clin. Pharmacokinet., 2000, 39(6), 429-443.
[http://dx.doi.org/10.2165/00003088-200039060-00004] [PMID: 11192475]
[17]
Dedrick, R.L. Arterial drug infusion: Pharmacokinetic problems and pitfalls. J. Natl. Cancer Inst., 1988, 80(2), 84-89.
[http://dx.doi.org/10.1093/jnci/80.2.84] [PMID: 3278123]
[18]
Gupta, S.; Wright, K.C.; Ensor, J.; Van Pelt, C.S.; Dixon, K.A.; Kundra, V. Hepatic arterial embolization with doxorubicin-loaded superabsorbent polymer microspheres in a rabbit liver tumor model. Cardiovasc. Intervent. Radiol., 2011, 34(5), 1021-1030.
[http://dx.doi.org/10.1007/s00270-011-0154-6] [PMID: 21479746]
[19]
Kelley, K.W.; Curtis, S.E.; Marzan, G.T.; Karara, H.M.; Anderson, C.R. Body surface area of female swine. J. Anim. Sci., 1973, 36(5), 927-930.
[http://dx.doi.org/10.2527/jas1973.365927x] [PMID: 4703721]
[20]
Dreher, M.R.; Sharma, K.V.; Woods, D.L.; Reddy, G.; Tang, Y.; Pritchard, W.F.; Chiesa, O.A.; Karanian, J.W.; Esparza, J.A.; Donahue, D.; Levy, E.B.; Willis, S.L.; Lewis, A.L.; Wood, B.J. Radiopaque drug-eluting beads for transcatheter embolotherapy: experimental study of drug penetration and coverage in swine. J. Vasc. Interv. Radiol., 2012, 23(2), 257-64.e4.
[http://dx.doi.org/10.1016/j.jvir.2011.10.019] [PMID: 22178039]
[21]
Curley, S.A.; Byrd, D.R.; Newman, R.A.; Ellis, H.J.; Chase, J.; Carrasco, C.H.; Cleary, K.; Bodden, W.; Hohn, D.C. Reduction of systemic drug exposure after hepatic arterial infusion of doxorubicin with complete hepatic venous isolation and extracorporeal chemofiltration. Surgery, 1993, 114(3), 579-585.
[PMID: 8367814]
[22]
Goodwin, S.C.; Bittner, C.A.; Peterson, C.L.; Wong, G. Single-dose toxicity study of hepatic intra-arterial infusion of doxorubicin coupled to a novel magnetically targeted drug carrier. Toxicol. Sci., 2001, 60(1), 177-183.
[http://dx.doi.org/10.1093/toxsci/60.1.177] [PMID: 11222884]
[23]
Vaupel, P.; Kallinowski, F.; Okunieff, P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: A review. Cancer Res., 1989, 49(23), 6449-6465.
[PMID: 2684393]
[24]
Gunasekara, N.S.; Faulds, D. Raltitrexed. A review of its pharmacological properties and clinical efficacy in the management of advanced colorectal cancer. Drugs, 1998, 55(3), 423-435.
[http://dx.doi.org/10.2165/00003495-199855030-00012] [PMID: 9530547]
[25]
Wilson, K.S.; Malfair Taylor, S.C. Raltitrexed: Optimism and reality. Expert Opin. Drug Metab. Toxicol., 2009, 5(11), 1447-1454.
[http://dx.doi.org/10.1517/17425250903307455] [PMID: 19863453]
[26]
Fleck, C.; Hilger, R.; Jurkutat, S.; Karge, E.; Merkel, U.; Schimske, A.; Schubert, J. Ex vivo stimulation of renal transport of the cytostatic drugs methotrexate, cisplatin, topotecan (Hycamtin) and raltitrexed (Tomudex) by dexamethasone, T3 and EGF in intact human and rat kidney tissue and in human renal cell carcinoma. Urol. Res., 2002, 30(4), 256-262.
[http://dx.doi.org/10.1007/s00240-002-0265-2] [PMID: 12202944]


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Article Details

VOLUME: 20
ISSUE: 7
Year: 2019
Page: [601 - 608]
Pages: 8
DOI: 10.2174/1389200220666190618100847
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