Skip to main content
SpringerLink
Log in

Dose Adaptation of Antineoplastic Drugs in Patients with Liver Disease

  • Review Article
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Dose adaptation for liver disease is important in patients treated with antineoplastic drugs because of the high prevalence of impaired liver function in this population and the dose-dependent, frequently serious adverse effects of these drugs. We classified the antineoplastic drugs marketed in Switzerland at the end of 2004 according to their bioavailability and/or hepatic extraction to predict their kinetic behaviour in patients with decreased liver function. This prediction was compared with kinetic studies carried out with these drugs in patients with liver disease. The studies were identified by a structured, computer-based literature search.

Of the 69 drugs identified, 52 had a predominant extrarenal (in most cases hepatic) metabolism and/or excretion. For 49 drugs, hepatic extraction could be calculated and/or bioavailability data were available, allowing classification according to hepatic extraction. For 18 drugs, kinetic studies have been reported in patients with impaired liver function, with the findings generally resulting in quantitative recommendations for adaptation of the dosage. In particular, recommendations are precise for 16 drugs excreted by the bile (e.g. doxorubicin and derivatives and vinca alkaloids). Validation studies comparing such recommendations with kinetics and/or dynamics of antineoplastic drugs in patients with decreased liver function have not been published.

We conclude that there are currently not enough data for safe use of cyctostatics in patients with liver disease. Pharmaceutical companies should be urged to provide kinetic data (especially hepatic extraction data) for the classification of such drugs and to conduct kinetic studies for drugs with primarily hepatic metabolism in patients with impaired liver function to allow quantitative advice to be given for dose adaptation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Table III
Table IV

Similar content being viewed by others

References

  1. Delco F, Tchambaz L, Schlienger R, et al. Dose adjustment in patients with liver disease. Drug Saf 2005; 28(6): 529–45

    Article  PubMed  CAS  Google Scholar 

  2. Herbert MF. Guide to drug dosage in hepatic disease. In: Holford NHG, editor. Drug data handbook. 3rd ed. Auckland: Adis International, 1998: 179

    Google Scholar 

  3. Bass NM, Williams RL. Guide to drug dosage in hepatic disease. Clin Pharmacokinet 1988; 15(6): 396–420

    Article  PubMed  CAS  Google Scholar 

  4. Westphal JF, Brogard JM. Drug administration in chronic liver disease. Drug Saf 1997; 17(1): 47–73

    Article  PubMed  CAS  Google Scholar 

  5. Verbeeck RK, Horsmans Y. Effect of hepatic insufficiency on pharmacokinetics and drug dosing. Pharm World Sci 1998; 20(5): 183–92

    Article  PubMed  CAS  Google Scholar 

  6. Reichen J. Assessment of hepatic function with xenobiotics. Semin Liver Dis 1995; 15(3): 189–201

    Article  PubMed  CAS  Google Scholar 

  7. Chawla Y, Santa N, Dhiman RK, et al. Portal hemodynamics by duplex Doppler sonography in different grades of cirrhosis. Dig Dis Sci 1998; 43(2): 354–7

    Article  PubMed  CAS  Google Scholar 

  8. Iwao T, Toyonaga A, Oho K, et al. Value of Doppler ultrasound parameters of portal vein and hepatic artery in the diagnosis of cirrhosis and portal hypertension. Am J Gastroenterol 1997; 92(6): 1012–7

    PubMed  CAS  Google Scholar 

  9. Pare P, Talbot J, Hoefs JC. Serum-ascites albumin concentration gradient: a physiologic approach to the differential diagnosis of ascites. Gastroenterology 1983; 85(2): 240–4

    PubMed  CAS  Google Scholar 

  10. Albillos A, Cuervas-Mons V, Millan I, et al. Ascitic fluid polymorphonuclear cell count and serum to ascites albumin gradient in the diagnosis of bacterial peritonitis. Gastroenterology 1990; 98(1): 134–40

    PubMed  CAS  Google Scholar 

  11. George J, Liddle C, Murray M, et al. Pre-translational regulation of cytochrome P450 genes is responsible for disease-specific changes of individual P450 enzymes among patients with cirrhosis. Biochem Pharmacol 1995; 49(7): 873–81

    Article  PubMed  CAS  Google Scholar 

  12. George J, Murray M, Byth K, et al. Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease. Hepatology 1995; 21(1): 120–8

    PubMed  CAS  Google Scholar 

  13. Marcellin P, de Bony F, Garret C, et al. Influence of cirrhosis on lamotrigine pharmacokinetics. Br J Clin Pharmacol 2001; 51(5): 410–4

    Article  PubMed  CAS  Google Scholar 

  14. Macdonald JI, Wallace SM, Mahachai V, et al. Both phenolic and acyl glucuronidation pathways of diflunisal are impaired in liver cirrhosis. Eur J Clin Pharmacol 1992; 42(5): 471–4

    Article  PubMed  CAS  Google Scholar 

  15. Sonne J, Andreasen PB, Loft S, et al. Glucuronidation of oxazepam is not spared in patients with hepatic encephalopathy. Hepatology 1990; 11(6): 951–6

    Article  PubMed  CAS  Google Scholar 

  16. Huet PM, Villeneuve JP. Determinants of drug disposition in patients with cirrhosis. Hepatology 1983; 3(6): 913–8

    Article  PubMed  CAS  Google Scholar 

  17. Shand DG. Hepatic circulation and drug disposition in cirrhosis. Gastroenterology 1979; 77(1): 185–6

    PubMed  CAS  Google Scholar 

  18. Theodor E. Portal hypertension complicating liver involvement in metastatic carcinoma: a case report. Isr J Med Sci 1979; 15(3): 285–7

    PubMed  CAS  Google Scholar 

  19. Huang JF, Little JM. Malignant jaundice. Aust N Z J Surg 1987; 57(12): 905–9

    Article  PubMed  CAS  Google Scholar 

  20. Donelli MG, Zucchetti M, Munzone E, et al. Pharmacokinetics of anticancer agents in patients with impaired liver function. Eur J Cancer 1998; 34(1): 33–46

    Article  PubMed  CAS  Google Scholar 

  21. Benichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol 1990; 11(2): 272–6

    Article  PubMed  CAS  Google Scholar 

  22. Morant J. Arzneimittelkompendium der Schweiz. Basel: Documed AG, 2004

    Google Scholar 

  23. Sifton DW. Physicians’ desk reference. 58th ed.] Montvale (NJ): Medical Economics Company, 2004

    Google Scholar 

  24. Dollery C, Boobis A, Rawlins M, et al. Therapeutic Drugs, 2 ed. Edinburgh: Churchill Livingstone, 1999

    Google Scholar 

  25. Zimmerman HJ. Hepatotoxicity. 2 ed. Philadelphia (PA): Lippincott Williams & Wilkins, 1999

    Google Scholar 

  26. Koren G, Beatty K, Seto A, et al. The effects of impaired liver function on the elimination of antineoplastic agents. Ann Pharmacother 1992; 26(3): 363–71

    PubMed  CAS  Google Scholar 

  27. Chlebowski RT, Bulcavage L, Henderson IC, et al. Mitoxantrone use in breast cancer patients with elevated bilirubin. Breast Cancer Res Treat 1989; 14(3): 267–74

    Article  PubMed  CAS  Google Scholar 

  28. Smyth JF, Macpherson JS, Warrington PS, et al. The clinical pharmacology of mitozantrone. Cancer Chemother Pharmacol 1986; 17(2): 149–52

    Article  PubMed  CAS  Google Scholar 

  29. Pendyala L, Creaven PJ. In vitro cytotoxicity, protein binding, red blood cell partitioning, and biotransformation of oxaliplatin. Cancer Res 1993; 53(24): 5970–6

    PubMed  CAS  Google Scholar 

  30. Rowinsky EK, Cazenave LA, Donehower RC. Taxol: a novel investigational antimicrotubule agent. J Natl Cancer Inst 1990; 82(15): 1247–59

    Article  PubMed  CAS  Google Scholar 

  31. Chao Y, Chan WK, Birkhofer MJ, et al. Phase II and pharmacokinetic study of paclitaxel therapy for unresectable hepatocellular carcinoma patients. Br J Cancer 1998; 78(1): 34–9

    Article  PubMed  CAS  Google Scholar 

  32. Payne JY, Holmes F, Cohen PR, et al. Paclitaxel: severe mucocutaneous toxicity in a patient with hyperbilirubinemia. South Med J 1996; 89(5): 542–5

    Article  PubMed  CAS  Google Scholar 

  33. Venook AP, Egorin MJ, Rosner GL, et al. Phase I and pharmacokinetic trial of paclitaxel in patients with hepatic dysfunction: Cancer and Leukemia Group B 9264. J Clin Oncol 1998; 16(5): 1811–9

    PubMed  CAS  Google Scholar 

  34. Panday VR, Huizing MT, Willemse PH, et al. Hepatic metabolism of paclitaxel and its impact in patients with altered hepatic function. Semin Oncol 1997; 24(4 Suppl. 11): S11–34-S11-38

    PubMed  CAS  Google Scholar 

  35. Clarke SJ, Zalcberg J, Olver I, et al. Open label, multi-centre phase II study of raltitrexed (‘Tomudex’) in patients with inoperable squamous-cell carcinoma of head and neck. Ann Oncol 2000; 11(2): 239–41

    Article  PubMed  CAS  Google Scholar 

  36. Raderer M, Fiebiger W, Wrba F, et al. Fatal liver failure after the administration of raltitrexed for cancer chemotherapy: a report of two cases. Cancer 2000; 89(4): 890–2

    Article  PubMed  CAS  Google Scholar 

  37. Maruyama S, Hirayama C, Abe J, et al. Chronic active hepatitis and liver cirrhosis in association with combined tamoxifen/tegafur adjuvant therapy. Dig Dis Sci 1995; 40(12): 2602–7

    Article  PubMed  CAS  Google Scholar 

  38. Pinto HC, Baptista A, Camilo ME, et al. Tamoxifen-associated steatohepatitis-report of three cases. J Hepatol 1995; 23(1): 95–7

    Article  PubMed  CAS  Google Scholar 

  39. Pratt DS, Knox TA, Erban J. Tamoxifen-induced steatohepatitis. Ann Intern Med 1995; 123(3): 236

    PubMed  CAS  Google Scholar 

  40. Floren LC, Hebert MF, Venook AP, et al. Tamoxifen in liver disease: potential exacerbation of hepatic dysfunction. Ann Oncol 1998; 9(10): 1123–6

    Article  PubMed  CAS  Google Scholar 

  41. Martinez Cerezo FJ, Tomas A, Donoso L, et al. Controlled trial of tamoxifen in patients with advanced hepatocellular carcinoma. J Hepatol 1994; 20(6): 702–6

    Article  PubMed  CAS  Google Scholar 

  42. van Maanen MJ, Huitema AD, Beijen JH. Influence of comedicated drugs on the biotransformation of thioTEPA to TEPA and thioTEPA-mercapturate. Anticancer Res 2000; 20(3A): 1711–6

    PubMed  Google Scholar 

  43. Lazarus HM, Reed MD, Spitzer TR, et al. High-dose i.v. thiotepa and cryopreserved autologous bone marrow transplantation for therapy of refractory cancer. Cancer Treat Rep 1987; 71(7-8): 689–95

    PubMed  CAS  Google Scholar 

  44. Lee JL, Gooley T, Bensinger W, et al. Veno-occlusive disease of the liver after busulfan, melphalan, and thiotepa conditioning therapy: incidence, risk factors, and outcome. Biol Blood Marrow Transplant 1999; 5 (5): 306–15

    Article  Google Scholar 

  45. Przepiorka D, Khouri I, Thall P, et al. Thiotepa, busulfan and cyclophosphamide as a preparative regimen for allogeneic transplantation for advanced chronic myelogenous leukemia. Bone Marrow Transplant 1999; 23(10): 977–81

    Article  PubMed  CAS  Google Scholar 

  46. Herben VM, Schoemaker E, Rosing H, et al. Urinary and fecal excretion of topotecan in patients with malignant solid tumours. Cancer Chemother Pharmacol 2002; 50(1): 59–64

    Article  PubMed  CAS  Google Scholar 

  47. O’Reilly S, Rowinsky E, Slichenmyer W, et al. Phase I and pharmacologic studies of topotecan in patients with impaired hepatic function. J Natl Cancer Inst 1996; 88(12): 817–24

    Article  PubMed  Google Scholar 

  48. Wall JG, Benedetti JK, O’Rourke MA, et al. Phase II trial to topotecan in hepatocellular carcinoma: a Southwest Oncology Group study. Invest New Drugs 1997; 15(3): 257–60

    Article  PubMed  CAS  Google Scholar 

  49. Anttila M, Laakso S, Nylanden P, et al. Pharmacokinetics of the novel antiestrogenic agent toremifene in subjects with altered liver and kidney function. Clin Pharmacol Ther 1995; 57(6): 628–35

    Article  PubMed  CAS  Google Scholar 

  50. Muller FO, Terblanche J, Schall R, et al. Pharmacokinetics of triptorelin after intravenous bolus administration in healthy males and in males with renal or hepatic insufficiency. Br J Clin Pharmacol 1997; 44(4): 335–41

    Article  PubMed  CAS  Google Scholar 

  51. Van den Berg HW, Desai ZR, Wilson R, et al. The pharmacokinetics of vincristine in man: reduced drug clearance associated with raised serum alkaline phosphatase and dose-limited elimination. Cancer Chemother Pharmacol 1982; 8(2): 215–9

    Article  PubMed  Google Scholar 

  52. Desai ZR, Van den Berg HW, Bridges JM, et al. Can severe vincristine neurotoxicity be prevented? Cancer Chemother Pharmacol 1982; 8(2): 211–4

    Article  PubMed  CAS  Google Scholar 

  53. Leveque D, Jehl F. Clinical pharmacokinetics of vinorelbine. Clin Pharmacokinet 1996; 31(3): 184–97

    Article  PubMed  CAS  Google Scholar 

  54. Robieux I, Sorio R, Borsatti E, et al. Pharmacokinetics of vinorelbine in patients with liver metastases. Clin Pharmacol Ther 1996; 59(1): 32–40

    Article  PubMed  CAS  Google Scholar 

  55. Hardman JG, Limbird LE, Gilman AG. The pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill, 2001

    Google Scholar 

  56. Taeschner W, Vozeh S. Pharmacokinetic drug data. In: Holford NHG, editor. Drug data handbook. 3rd ed. Auckland: Aids International, 1998: 48

  57. Reynolds NA, Wagstaff AJ. Cetuximab: in the treatment of metastatic colorectal cancer. Drugs 2004; 64(1): 109–18; discussion 119-21

    Article  PubMed  CAS  Google Scholar 

  58. Balis FM, Holcenberg JS, Bleyer WA. Clinical pharmacokinetics of commonly used anticancer drugs. Clin Pharmacokinet 1983; 8(3): 202–32

    Article  PubMed  CAS  Google Scholar 

  59. Boddy AV, Yule SM. Metabolism and pharmacokinetics of oxazaphosphorines. Clin Pharmacokinet 2000; 38(4): 291–304

    Article  PubMed  CAS  Google Scholar 

  60. Camaggi CM, Strocchi E, Comparsi R, et al. Biliary excretion and pharmacokinetics of 4’epidoxorubicin (epirubicin) in advanced cancer patients. Cancer Chemother Pharmacol 1986; 18(1): 47–50

    Article  PubMed  CAS  Google Scholar 

  61. Gunnarsson PO, Andersson SB, Johansson SA, et al. Pharmacokinetics of estramustine phosphate (Estracyt) in prostatic cancer patients. Eur J Clin Pharmacol 1984; 26(1): 113–9

    Article  PubMed  CAS  Google Scholar 

  62. Clemett D, Lamb HM. Exemestane: a review of its use in postmenopausal women with advanced breast cancer. Drugs 2000; 59(6): 1279–96

    Article  Google Scholar 

  63. Katchen B, Buxbaum S. Disposition of a new, nonsteroid, antiandrogen, alpha, alpha, alpha-trifluoro-2-methyl-4’-nitrom-propionotoluidide (Flutamide), in men following a single oral 200mg dose. J Clin Endocrinol Metab 1975; 41(2): 373–9

    Article  PubMed  CAS  Google Scholar 

  64. Gillies HC, Herriott D, Liang R, et al. Pharmacokinetics of idarubicin (4-demethoxydaunorubicin; IMI-30; NSC 256439) following intravenous and oral administration in patients with advanced cancer. Br J Clin Pharmacol 1987; 23(3): 303–10

    Article  PubMed  CAS  Google Scholar 

  65. Lokiec F, du Sorbier BM, Sanderink GJ. Irinotecan (CPT-11) metabolites in human bile and urine. Clin Cancer Res 1996; 2(12): 1943–9

    PubMed  CAS  Google Scholar 

  66. Tamassia V, Pacciarini MA, Moro E, et al. Pharmacokinetic study of intravenous and oral idarubicin in cancer patients. Int J Clin Pharmacol Res 1987; 7(5): 419–26

    PubMed  CAS  Google Scholar 

  67. Lee FY, Workman P, Roberts JT, et al. Clinical pharmacokinetics of oral CCNU (lomustine). Cancer Chemother Pharmacol 1985; 14(2): 125–31

    Article  PubMed  CAS  Google Scholar 

  68. Chodak GW. Bicalutamide-associated fulminant hepatic failure. Urology 1997; 50(6): 1027

    Article  PubMed  CAS  Google Scholar 

  69. Umezawa H, Ishizuka M, Maeda K, et al. Studies on bleomycin. Cancer 1967; 20(5): 891–5

    Article  PubMed  CAS  Google Scholar 

  70. Morris LE, Guthrie TH. Busulfan-induced hepatitis. Am J Gastroenterol 1988; 83(6): 682–3

    PubMed  CAS  Google Scholar 

  71. Underwood JC, Shahani RT, Blackburn EK. Jaundice after treatment of leukemia with busulphan. BMJ 1971; 1(5748): 556–7

    Article  PubMed  CAS  Google Scholar 

  72. Blum JL. The role of capecitabine, an oral, enzymatically activated fluoropyrimidine, in the treatment of metastatic breast cancer. Oncologist 2001; 6(1): 56–64

    Article  PubMed  CAS  Google Scholar 

  73. Robert F, Ezekiel MP, Spencer SA, et al. Phase I study of antiepidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer. J Clin Oncol 2001; 1(13): 3234–43

    Google Scholar 

  74. Patel SP, Nast CC, Adler SG. Chlorambucil-induced acute hepatic failure in a patient with membranous nephropathy. Am J Kidney Dis 2000; 36(2): 401–4

    Article  PubMed  CAS  Google Scholar 

  75. Mok CC, Wong WM, Shek TW, et al. Cumulative hepatotoxicity induced by continuous low-dose cyclophosphamide therapy. Am J Gastroenterol 2000; 95(3): 845–6

    Article  PubMed  CAS  Google Scholar 

  76. Gustafsson LL, Eriksson LS, Dahl ML, et al. Cyclophosphamide-induced acute liver failure requiring transplantation in a patient with genetically deficient debrisoquine metabolism: a causal relationship? J Intern Med 1996; 240(5): 311–4

    Article  PubMed  CAS  Google Scholar 

  77. Goldberg JW, Lidsky MD. Cyclophosphamide-associated hepatotoxicity. South Med J 1985; 78(2): 222–3

    Article  PubMed  CAS  Google Scholar 

  78. Blake JC, Sawyer Am, Dooley JS et al. Severe hepatitis caused by cyproterone acetate. Gut 1990; 31: 556–7

    Article  PubMed  CAS  Google Scholar 

  79. Pinganaud G, Chaslerie A, Bourdel Marchasson I, et al. Cyproterone-induced hepatotoxicity. Ann Pharmacother 1995; 29(6): 634

    PubMed  CAS  Google Scholar 

  80. Pu YS, Liu CM, Kao JH, et al. Antiandrogen hepatotoxicity in patients with chronic viral hepatitis. Eur Urol 1999; 36(4): 293–7

    Article  PubMed  CAS  Google Scholar 

  81. Migliari R, Muscas G, Murru M, et al. Antiandrogens: a summary review of pharmacodynamic properties and tolerability in prostate cancer therapy. Arch Ital Urol Androl 1999; 71(5): 293–302

    PubMed  CAS  Google Scholar 

  82. Rollins BJ. Hepatic veno-occlusive disease. Am J Med 1986; 81(2): 297–306

    Article  PubMed  CAS  Google Scholar 

  83. Houghton AN, Shafi N, Rickles FR. Acute hepatic vein thrombosis occurring during therapy for Hodgkin’s disease: a case report. Cancer 1979; 44(6): 2324–9

    Article  PubMed  CAS  Google Scholar 

  84. Roila F, Crino L, Carloni G, et al. Cyproterone acetate: hepatotoxicity and prostatic cancer treatment. Ann Oncol 1993; 4(8): 701

    PubMed  CAS  Google Scholar 

  85. Tran A, Housset C, Boboc B, et al. Etoposide (VP 16-213) induced hepatitis. Report of three cases following standarddose treatments. J Hepatol 1991; 12(1): 36–9

    Article  PubMed  CAS  Google Scholar 

  86. Cuevas Campos MA, Pareja Llorens G, Garcia Romero E, et al. Toxic hepatitis caused by flutamide [in Spanish]. Gastroenterol Hepatol 1998; 21(10): 499–500

    PubMed  CAS  Google Scholar 

  87. Dourakis SP, Alexopoulou AA, Hadziyannis SJ. Fulminant hepatitis after flutamide treatment. J Hepatol 1994; 20(3): 350–3

    Article  PubMed  CAS  Google Scholar 

  88. Moller S, Iversen P, Franzmann MB. Flutamide-induced liver failure. J Hepatol 1990; 10(3): 346–9

    Article  PubMed  CAS  Google Scholar 

  89. Okaneya T, Murata Y, Kinebuchi Y. Fatal hepatic failure following hepatitis caused by flutamide: a case report [in Japanese]. Nippon Hinyokika Gakkai Zasshi 1999; 90(5): 590–3

    PubMed  CAS  Google Scholar 

  90. Pontiroli L, Sartori M, Pittau S, et al. Flutamide-induced acute hepatitis: investigation on the role of immunoallergic mechanisms. Ital J Gastroenterol Hepatol 1998; 30(3): 310–4

    PubMed  CAS  Google Scholar 

  91. Wada T, Ueda M, Abe K, et al. Risk factor of liver disorders caused by flutamide—statistical analysis using multivariate logistic regression analysis [in Japanese]. Hinyokika Kiyo 1999; 45(8): 521–6

    PubMed  CAS  Google Scholar 

  92. Satoh T, Egawa S, Katsuta M, et al. A case of fulminant hepatitis caused by antiandrogen, flutamide in a patient with prostate cancer. Nippon Hinyokika Gakkai Zasshi 1997; 88(7): 694–6

    PubMed  CAS  Google Scholar 

  93. Wietzke P, Munke H, Hartmann H, et al. Hepatotoxicity of flutamide. Z Gastroenterol 1997; 35(8): 631–5

    PubMed  CAS  Google Scholar 

  94. Chapoutot C, Perney P, Le Bricquir Y, et al. Acute cytolytic hepatitis caused by hydroxycarbamide. Gastroenterol Clin Biol 1997; 21(1): 87–9

    PubMed  CAS  Google Scholar 

  95. Gross R, Scapa E. Hepatotoxicity of 6-mercaptopurine in Crohn’s disease. Am J Gastroenterol 1992; 87(12): 1885–6

    PubMed  CAS  Google Scholar 

  96. Gross R. Hepatotoxicity of 6-mercaptopurine and azathioprine. Mayo Clin Proc 1994; 69(5): 498

    PubMed  CAS  Google Scholar 

  97. Laidlaw ST, Reilly JT, Suvarna SK. Fatal hepatotoxicity associated with 6-mercaptopurine therapy. Postgrad Med J 1995; 71(840): 639

    Article  PubMed  CAS  Google Scholar 

  98. Berkovitch M, Matsui D, Zipursky A, et al. Hepatotoxicity of 6-mercaptopurine in childhood acute lymphocytic leukemia: pharmacokinetic characteristics. Med Pediatr Oncol 1996; 26(2): 85–9

    Article  PubMed  CAS  Google Scholar 

  99. Gilbert SC, Klintmalm G, Menter A, et al. Methotrexate-induced cirrhosis requiring liver transplantation in three patients with psoriasis. A word of caution in light of the expanding use of this ‘steroid-sparing’ agent. Arch Intern Med 1990; 150(4): 889–91

    Article  PubMed  CAS  Google Scholar 

  100. Hakim NS, Kobienia B, Benedetti E, et al. Methotrexate-induced hepatic necrosis requiring liver transplantation in a patient with rheumatoid arthritis. Int Surg 1998; 83(3): 224–5

    PubMed  CAS  Google Scholar 

  101. Malatjalian DA, Ross JB, Williams CN, et al. Methotrexate hepatotoxicity in psoriatics: report of 104 patients from Nova Scotia, with analysis of risks from obesity, diabetes and alcohol consumption during long term follow-up. Can J Gastroenterol 1996; 10(6): 369–75

    PubMed  CAS  Google Scholar 

  102. Shergy WJ, Polisson RP, Caldwell DS, et al. Methotrexate-associated hepatotoxicity: retrospective analysis of 210 patients with rheumatoid arthritis. Am J Med 1988; 85(6): 771–4

    Article  PubMed  CAS  Google Scholar 

  103. ter Borg EJ, Seldenrijk CA, Timmer R. Liver cirrhosis due to methotrexate in a patient with rheumatoid arthritis. Neth J Med 1996; 49(6): 244–6

    Article  PubMed  Google Scholar 

  104. West SG. Methotrexate hepatotoxicity. Rheum Dis Clin North Am 1997; 23(4): 883–915

    Article  PubMed  CAS  Google Scholar 

  105. Whiting-O’Keefe QE, Fye KH, Sack KD. Methotrexate and histologic hepatic abnormalities: a meta-analysis. Am J Med 1991; 90(6): 711–6

    Article  PubMed  Google Scholar 

  106. Soh LT, Ang PT, Sng I, et al. Fulminant hepatic failure in non-Hodgkin lymphoma patients treated with chemotherapy. Eur J Cancer 1992; 28A(8-9): 1338–9

    Article  PubMed  CAS  Google Scholar 

  107. Farrow AC, Buchanan GR, Zwiener RJ, et al. Serum aminotransferase elevation during and following treatment of childhood acute lymphoblastic leukemia. J Clin Oncol 1997; 15(4): 1560–6

    PubMed  CAS  Google Scholar 

  108. Exadaktylos P, Reiss T, Schobess R, et al. Acute hepatotoxicity with intermediate-dose methotrexate in children with leukemia and non-Hodgkin’s lymphoma [in German]. Klin Padiatr 1994; 206(4): 315–8

    Article  PubMed  CAS  Google Scholar 

  109. Fabbri A, Motta E, Ferrari S, et al. High-dose methotrexate treatment and liver function in patients with osteosarcoma. J Intern Med 1994; 236(2): 209–14

    Article  PubMed  CAS  Google Scholar 

  110. Wagner T, Heydrich D, Bartels H, et al. Effect of damaged liver parenchyma, renal insufficiency and hemodialysis on the pharmacokinetics of cyclophosphamide and its activated metabolites [in German]. Arzneimittelforschung 1980; 30(9): 1588–92

    PubMed  CAS  Google Scholar 

  111. Twelves C, Glynne-Jones R, Cassidy J, et al. Effect of hepatic dysfunction due to liver metastases on the pharmacokinetics of capecitabine and its metabolites. Clin Cancer Res 1999; 5(7): 1696–702

    PubMed  CAS  Google Scholar 

  112. Twelves CJ, O’Reilly SM, Coleman RE, et al. Weekly epirubicin for breast cancer with liver metastases and abnormal liver biochemistry. Br J Cancer 1989; 60(6): 938–41

    Article  Google Scholar 

  113. Juma FD. Effect of liver failure on the pharmacokinetics of cyclophosphamide. Eur J Clin Pharmacol 1984; 26(5): 591–3

    Article  PubMed  CAS  Google Scholar 

  114. Benjamin RS. Pharmacokinetics of adriamycin (NSC-123127) in patients with sarcomas. Cancer Chemother Rep 1974; 58(2): 271–3

    PubMed  CAS  Google Scholar 

  115. Chan KK, Chlebowski RT, Tong M, et al. Clinical pharmacokinetics of adriamycin in hepatoma patients with cirrhosis. Cancer Res 1980; 40(4): 1263–8

    PubMed  CAS  Google Scholar 

  116. Johnson PJ, Dobbs N, Kalayci C, et al. Clinical efficacy and toxicity of standard dose adriamycin in hyperbilirubinaemic patients with hepatocellular carcinoma: relation to liver tests and pharmacokinetic parameters. Br J Cancer 1992; 65(5): 751–5

    Article  PubMed  CAS  Google Scholar 

  117. Preiss R, Matthias M, Sohr R, et al. Pharmacokinetics of adriamycin, adriamycinol, and antipyrine in patients with moderate tumor involvement of the liver. J Cancer Res Clin Oncol 1987; 113(6): 593–8

    Article  PubMed  CAS  Google Scholar 

  118. Piscitelli SC, Rodvold KA, Rushing DA, et al. Pharmacokinetics and pharmacodynamics of doxorubicin in patients with small cell lung cancer. Clin Pharmacol Ther 1993; 53(5): 555–61

    Article  PubMed  CAS  Google Scholar 

  119. Morris RG, Reece PA, Dale BM, et al. Alteration in doxorubicin and doxorubicinol plasma concentrations with repeated courses to patients. Ther Drug Monit 1989; 11(4): 380–3

    PubMed  CAS  Google Scholar 

  120. Mross K, Maessen P, van der Vijgh WJ, et al. Pharmacokinetics and metabolism of epidoxorubicin and doxorubicin in humans. J Clin Oncol 1988; 6(3): 517–26

    PubMed  CAS  Google Scholar 

  121. Dobbs NA, Twelves CJ. Anthracycline doses in patients with liver dysfunction: do UK oncologists follow current recommendations? Br J Cancer 1998; 77(7): 1145–8

    Article  PubMed  CAS  Google Scholar 

  122. Camaggi CM, Strocchi E, Tamassia V, et al. Pharmacokinetic studies of 4’-epi-doxorubicin in cancer patients with normal and impaired renal function and with hepatic metastases. Cancer Treat Rep 1982; 66(10): 1819–24

    PubMed  CAS  Google Scholar 

  123. Jakobsen P, Bastholt L, Dalmark M, et al. A randomized study of epirubicin at four different dose levels in advanced breast cancer. Feasibility of myelotoxicity prediction through single blood-sample measurement. Cancer Chemother Pharmacol 1991; 28(6): 465–9

    Article  PubMed  CAS  Google Scholar 

  124. Speth PA, Linssen PC, Beex LV, et al. Cellular and plasma pharmacokinetics of weekly 20-mg 4’-epi-adriamycin bolus injection in patients with advanced breast carcinoma. Cancer Chemother Pharmacol 1986; 18(1): 78–82

    Article  PubMed  CAS  Google Scholar 

  125. Dobbs NA, Twelves CJ, Rizzi P, et al. Epirubicin in hepatocellular carcinoma: pharmacokinetics and clinical activity. Cancer Chemother Pharmacol 1994; 34(5): 405–10

    Article  PubMed  CAS  Google Scholar 

  126. Twelves CJ, Richards MA, Smith P, et al. Epirubicin in breast cancer patients with liver metastases and abnormal liver biochemistry: initial weekly treatment followed by rescheduling and intensification. Ann Oncol 1991; 2(9): 663–6

    PubMed  CAS  Google Scholar 

  127. Twelves CJ, Dobbs NA, Michael Y, et al. Clinical pharmacokinetics of epirubicin: the importance of liver biochemistry tests. Br J Cancer 1992; 66 (4): 765–9

    Article  Google Scholar 

  128. D’Incalci M, Rossi C, Zucchetti M, et al. Pharmacokinetics of etoposide in patients with abnormal renal and hepatic function. Cancer Res 1986; 46(5): 2566–71

    PubMed  Google Scholar 

  129. Hande KR, Wolff SN, Greco FA, et al. Etoposide kinetics in patients with obstructive jaundice. J Clin Oncol 1990; 8(6): 1101–7

    PubMed  CAS  Google Scholar 

  130. Joel SP, Shah R, Clark PI, et al. Predicting etoposide toxicity: relationship to organ function and protein binding. J Clin Oncol 1996; 14(1): 257–67

    PubMed  CAS  Google Scholar 

  131. Aita P, Robieux I, Sorio R, et al. Pharmacokinetics of oral etoposide in patients with hepatocellular carcinoma. Cancer Chemother Pharmacol 1999; 43(4): 287–94

    Article  PubMed  CAS  Google Scholar 

  132. Fleming RA, Milano GA, Etienne MC, et al. No effect of dose, hepatic function, or nutritional status on 5-FU clearance following continuous (5-day), 5-FU infusion. Br J Cancer 1992; 66(4): 668–72

    Article  PubMed  CAS  Google Scholar 

  133. Lu K, Savaraj N, Kavanagh J, et al. Clinical pharmacology of 4-demethoxydaunorubicin (DMDR). Cancer Chemother Pharmacol 1986; 17(2): 143–8

    Article  PubMed  CAS  Google Scholar 

  134. Camaggi CM, Strocchi E, Carisi P, et al. Idarubicin metabolism and pharmacokinetics after intravenous and oral administration in cancer patients: a crossover study. Cancer Chemother Pharmacol 1992; 30(4): 307–16

    Article  PubMed  CAS  Google Scholar 

  135. Raymond E, Boige V, Faivre S, et al. Dosage adjustment and pharmacokinetic profile of irinotecan in cancer patients with hepatic dysfunction. J Clin Oncol 2002; 20(21): 4303–12

    Article  PubMed  CAS  Google Scholar 

  136. Skoglund KA, Soderhall S, Beck O, et al. Plasma and urine levels of methotrexate and 7-hydroxymethotrexate in children with ALL during maintenance therapy with weekly oral methotrexate. Med Pediatr Oncol 1994; 22(3): 187–93

    Article  PubMed  CAS  Google Scholar 

  137. Savaraj N, Lu K, Manuel V, et al. Pharmacology of mitoxantrone in cancer patients. Cancer Chemother Pharmacol 1982; 8(1): 113–7

    Article  PubMed  CAS  Google Scholar 

  138. O’Reilly SM, Richards MA, Rubens RD. Liver metastases from breast cancer: the relationship between clinical, biochemical and pathological features and survival. Eur J Cancer 1990; 26(5): 574–7

    Article  PubMed  Google Scholar 

  139. Sato T, Kato J, Kawanishi J, et al. Acute exacerbation of hepatitis due to reactivation of hepatitis B virus with mutations in the core region after chemotherapy for malignant lymphoma. J Gastroenterol 1997; 32(5): 668–71

    Article  PubMed  CAS  Google Scholar 

  140. Yoshiba M, Sekiyama K, Sugata F, et al. Reactivation of precore mutant hepatitis B virus leading to fulminant hepatic failure following cytotoxic treatment. Dig Dis Sci 1992; 37(8): 1253–9

    Article  PubMed  CAS  Google Scholar 

  141. Yeo W, Steinberg JL, Tam JS, et al. Lamivudine in the treatment of hepatitis B virus reactivation during cytotoxic chemotherapy. J Med Virol 1999; 59(3): 263–9

    Article  PubMed  CAS  Google Scholar 

  142. Dai MS, Lu JJ, Chen YC, et al. Reactivation of precore mutant hepatitis B virus in chemotherapy-treated patients. Cancer 2001; 92(11): 2927–32

    Article  PubMed  CAS  Google Scholar 

  143. Faggioli P, De Paschale M, Tocci A, et al. Acute hepatic toxicity during cyclic chemotherapy in non Hodgkin’s lymphoma. Haematologica 1997; 82(1): 38–42

    PubMed  CAS  Google Scholar 

  144. Lok AS, Liang RH, Chiu EK, et al. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study. Gastroenterology 1991; 100(1): 182–8

    PubMed  CAS  Google Scholar 

  145. Yoshiba M, Sekiyama K, Iwabuchi S, et al. Recurrent fulminant hepatic failure in an HB carrier after intensive chemotherapy. Dig Dis Sci 1993; 38(9): 1751–5

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The review was supported by a grant from the Swiss National Science Foundation to Professor Stephan Krahenbuhl (3100-59812-03/1).

The authors have no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

  1. Division of Clinical Pharmacology & Toxicology, University Hospital, Basel, 4031, Switzerland

    Lydia Tchambaz, Chantal Schlatter, Max Jakob, Anita Krâhenbûhl &  Stephan Krâhenbûhl

  2. Hospital Library, University Hospital, Basel, Switzerland

    Peter Wolf

Authors
  1. Lydia Tchambaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chantal Schlatter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Max Jakob
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anita Krâhenbûhl
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Stephan Krâhenbûhl
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephan Krâhenbûhl.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tchambaz, L., Schlatter, C., Jakob, M. et al. Dose Adaptation of Antineoplastic Drugs in Patients with Liver Disease. Drug-Safety 29, 509–522 (2006). https://doi.org/10.2165/00002018-200629060-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002018-200629060-00004

Keywords

Search

Navigation