Skip to main content
SpringerLink
Log in

Pharmacokinetic Optimisation of Cancer Chemotherapy

Effect on Outcomes

  • Review Article
  • Disease Management
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Summary

Cancer chemotherapy doses are empirical in that the majority are administered at a fixed dose (mg/m2 or mg/kg). One reason for this is the intrinsic sensitivity of the tumour or host cells to one particular chemotherapy agent is unknown. Therefore, the likelihood of response or toxicity is unpredictable a priori. This contrasts with antimicrobial chemotherapy where sensitivity (minimum inhibitory concentration) can be determined for a specific bacterium. The pharmacokinetics of cancer chemotherapy agents is also highly variable between patients. In addition, the small therapeutic index of these drugs, combined with the lack of good surrogate markers of toxicity or response, adds to the empiricism of the administration of cancer chemotherapy.

In the past few years, numerous studies have established good relationships between systemic exposure to cancer chemotherapy and both response and toxicity. These relationships have been used to individualise chemotherapy dose administration a priori and a posteriori. Some examples of drugs which are individualised based on their pharmacokinetics are methotrexate, busulfan and carboplatin. Other examples of antineoplastic agents which may eventually be individualised based on their pharmacokinetics are mercaptopurine, fluorouracil, etoposide and teniposide, topotecan and suramin.

New strategies are being investigated to improve the therapeutic index of cancer chemotherapy agents such as biomodulation, pharmacogenetics, circadian administration and the modification of drug scheduling. Pharmacokinetic studies have also played a major role in these areas.

Thus, despite the empiricism associate with cancer chemotherapy administration, some progress has been made and shown to have an impact on outcome. However, more studies are needed to improve cancer chemotherapy administra-tion.

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

Similar content being viewed by others

References

  1. National Cancer Institute of Canada. Toronto: Canadian Statistics on Cancer, 1996: 1–55

  2. Rivera GK, Pinkel D, Simone JV, et al. Treatment of acute lymphoblastic leukemia: 30 years’ experience at St. Jude Children’s Research Hospital. N Engl J Med 1993; 329(18): 1289–95

    PubMed  CAS  Google Scholar 

  3. Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol 1992; 43: 329–39

    PubMed  CAS  Google Scholar 

  4. Bertino JR. Karnofsky memorial lecture: ode to methotrexate. J Clin Oncol 1993; 11(1): 5–14

    PubMed  CAS  Google Scholar 

  5. Pui CH, Relling MV, Masson E, et al. Pharmacokinetic resistance in childhood leukemia. In: Pieters R, Kaspers GJL, Veerman AJP, editors. Drug resistance in leukemia and lymphoma. London: Harwood Academic Publishers; 1995: 1–16

    Google Scholar 

  6. Peck CC, D’Argenio DZ, Rodman JH. Analysis of pharmacokinetic data for individualizing drug dosage regimens. In: Evans WE, Schentag JJ, Jusko WJ, editors. Applied pharmacokinetics-principles of therapeutic drug monitoring. 3rd ed. Vancouver (WA): Applied Therapeutics, Inc., 1992: 3.1–3.31

    Google Scholar 

  7. Newell DR. Can pharmacokinetic and pharmacodynamic studies improve cancer chemotherapy. Ann Oncol 1994; 5 Suppl. 4: 9–15

    PubMed  Google Scholar 

  8. Liliemark J, Peterson C. Pharmacokinetic optimisation of anti-cancer therapy. Clin Pharmacokinet 1991; 21(3): 213–31

    PubMed  CAS  Google Scholar 

  9. Rodman JH, Relling MV, Stewart CF, et al. Clinical pharmacokinetics and pharmacodynamics of anticancer drugs in children. Sem Oncol 1993; 20(1): 18–29

    CAS  Google Scholar 

  10. Evans WE, Relling MV. Clinical pharmacokinetics-pharmaco-dynamics of anticancer drugs. Clin Pharmacokinet 1989; 16: 327–36

    PubMed  CAS  Google Scholar 

  11. Petros WP, Evans WE. Pharmacokinetics and pharmacodynamics of anticancer agents: contributions to the therapy of childhood cancer. Pharmacotherapy 1990; 10(5): 313–25

    PubMed  CAS  Google Scholar 

  12. Chabot G. Factors involved in clinical pharmacology variability in oncology. Anticancer Res 1994; 14: 2269–72

    PubMed  CAS  Google Scholar 

  13. Hryniuk WM. More is better [editorial]. J Clin Oncol 1988; 6(9): 1365–7

    PubMed  CAS  Google Scholar 

  14. DeVita VT, Molloy Hubbard S, Longo DL. The chemotherapy of lymphomas: looking back, moving forward — the Richard and Hinda Rosenthal Foundation Award Lecture. Cancer Res 1987; 47: 5810–24

    Google Scholar 

  15. Tannock IF, Boyd NF, DeBoer G, et al. A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil: chemotherapy for patients with metastatic breast cancer. J Clin Oncol 1988; 6: 1377–87

    PubMed  CAS  Google Scholar 

  16. Hryniuk WM, Figueredo A, Goodyear M. Applications of dose intensity to problems in chemotherapy of breast and colorectal cancer. Semin Oncol 1987; 14(4): 3–11

    PubMed  CAS  Google Scholar 

  17. Reilly JJ, Workman P. Normalisation of anti-cancer drug dosage using body weight and surface area: Is it worthwhile? Cancer Chemother Pharmacol 1993; 32: 411–8

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  19. Evans WE, Crom WR, Abromowitch M, et al. Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia. N Engl J Med 1986; 314: 471–7

    PubMed  CAS  Google Scholar 

  20. Graf N, Winkler K, Betlemovic M, et al. Methotrexate pharmacokinetics and prognosis in osteosarcoma. J Clin Oncol 1994; 12: 1443–51

    PubMed  CAS  Google Scholar 

  21. Saeter G, Alvegard TA, Elomaa I, et al. Treatment of osteosarcoma of the extremities with the T-10 protocol, with emphasis on the effects of preoperative chemotherapy with single-agent high-dose methotrexate: a Scandinavian sarcoma group study. J Clin Oncol 1991; 9: 1766–75

    PubMed  CAS  Google Scholar 

  22. Patte C, Philip T, Rodary C, et al. High survival rate in advanced-stage B-cell lymphomas and leukemias without CNS involvement with a short intensive polychemotherapy: results from the French Pediatric Oncology Society of a randomized trial of 216 children. J Clin Oncol 1991; 9: 123–32

    PubMed  CAS  Google Scholar 

  23. Relling MV, Fairclough D, Ayers D, et al. Patient characteristics associated with high-risk methotrexate concentrations and toxicity. J Clin Oncol 1994; 12: 1667–72

    PubMed  CAS  Google Scholar 

  24. Masson E, Relling MV, Synold TW, et al. Accumulation of methotrexate polyglutamates in lymphoblasts is a determinant of antileukemic effects in vivo. J Clin Invest 1996; 97: 73–80

    PubMed  CAS  Google Scholar 

  25. Crom WR, Evans WE. Methotrexate. In: Evans WE, Schentag JJ, Jusko WJ, editors. Applied pharmacokinetics-principles of therapeutic drug monitoring. 3rd ed. Vancouver (WA): Applied Therapeutics, Inc., 1992: 29.1–29.42

    Google Scholar 

  26. Christensen ML, Rivera GK, Crom WR, et al. Effect of hydration on methotrexate plasma concentrations in children with acute lymphocytic leukemia. J Clin Oncol 1988; 6: 797–801

    PubMed  CAS  Google Scholar 

  27. Crom WR, Pratt CB, Green AA, et al. The effect of prior cisplatin therapy on the pharmacokinetics of high-dose methotrexate. J Clin Oncol 1984; 22(6): 655–61

    Google Scholar 

  28. Blaney SM, Balis FM, Poplack DG. Current pharmacological treatment approaches to central nervous system leukaemia. Drugs 1991; 41(5): 702–16

    PubMed  CAS  Google Scholar 

  29. Bleyer WA, Poplack DG. Prophylaxis and treatment of leukemia in the central nervous system and other sanctuaries. Sem Oncol 1985; 12(2): 131–48

    CAS  Google Scholar 

  30. Stother DR, Glynn-Barnhart A, Kovnar E, et al. Variability in the disposition of intraventricular methotrexate: a proposal for rational dosing. J Clin Oncol 1989; 7: 1741–7

    Google Scholar 

  31. Bleyer WA, Coccia PF, Sather HN, et al. Reduction in central nervous system leukemia with a pharmacokinetically derived intrathecal methotrexate dosage regimen. J Clin Oncol 1983; 1(5): 317–25

    PubMed  CAS  Google Scholar 

  32. Goldman ID. The characteristics of the membrane transport of aminopterin and the naturally occurring folates. Ann NY Acad Sci 1971; 186: 400–22

    PubMed  CAS  Google Scholar 

  33. Chabner BA, Allegra CJ, Curt GA, et al. Polyglutamation of methotrexate: is methotrexate a prodrug? J Clin Invest 1985; 76: 907–12

    PubMed  CAS  Google Scholar 

  34. Whitehead MV, Rosenblatt DS, Vuchich MJ, et al. Accumulation of methotrexate and methotrexate polyglutamates in lymphoblasts at diagnosis of childhood acute lymphoblastic leukemia: a pilot prognostic factor analysis. Blood 1990; 76(1): 44–9

    PubMed  CAS  Google Scholar 

  35. Kamen BA, Winick NJ. High dose methotrexate therapy: Insecure rationale? Biochem Pharmacol 1988; 37: 2713–5

    PubMed  CAS  Google Scholar 

  36. Kamen BA, Weitman SD. High-dose methotrexate: is it warranted? Pediatr Hematol Oncol 1994; 11: 135–7

    PubMed  CAS  Google Scholar 

  37. Synold TW, Relling MV, Boyett JM, et al. Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia. J Clin Invest 1994; 94(5): 1996–2001

    PubMed  CAS  Google Scholar 

  38. Pui CH. Childhood leukemias. N Engl J Med 1995; 332(24): 1618–30

    PubMed  CAS  Google Scholar 

  39. Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989; 7: 1748–56

    PubMed  CAS  Google Scholar 

  40. Egorin MJ, Van Echo DA, Olman EA, et al. Prospective validation of a pharmacologically based dosing scheme for the cis-diamminedichloroplatinum (II) analogue diamminecyclo-butanedicarboxylatoplatinum. Cancer Res 1985; 45: 6502–6

    PubMed  CAS  Google Scholar 

  41. Newell DR, Pearson DJ, Balmanno K, et al. Carboplatin pharmacokinetics in children: the development of a pediatric dosing formula. J Clin Oncol 1993; 11: 2314–23

    PubMed  CAS  Google Scholar 

  42. Chatelut E, Canal P, Brunner V, et al. Prediction of carboplatin clearance from standard morphological and biological patient characteristics. J Natl Cancer Inst 1995; 87(8): 573–80

    PubMed  CAS  Google Scholar 

  43. Jodrell DI, Egorin MJ, Canetta RM, et al. Relationships between carboplatin exposure and tumor response and toxicity in patients with ovarian cancer. J Clin Oncol 1992; 10(4): 520–8

    PubMed  CAS  Google Scholar 

  44. Horwich A, Dearnaley DP, Nicholls J, et al. Effectiveness of carboplatin, etoposide, and bleomycin combination chemotherapy in good-prognosis metastatic testicular nonseminomatous germ cell tumors. J Clin Oncol 1991; 9(1): 62–9

    PubMed  CAS  Google Scholar 

  45. Grochow LB. Busulfan disposition: the role of therapeutic monitoring in bone marrow transplantation induction regimens. Semin Oncol 1993; 20: 18

    PubMed  CAS  Google Scholar 

  46. Grochow LB, Jones RJ, Brundrett RB, et al. Pharmacokinetics of busulfan: correlation with veno-occlusive disease in patients undergoing bone marrow transplantation. Cancer Chemother Pharmacol 1989; 25: 55–61

    PubMed  CAS  Google Scholar 

  47. Vassal G, Deroussent A, Hartmann O, et al. Dose-dependent neurotoxicity of high-dose bufulfan in children: a clinical and pharmacology study. Cancer Res 1990; 50: 6203–7-

    PubMed  CAS  Google Scholar 

  48. Eisenberger MA, Reyno LM, Jodrell DI, et al. Suramin, an active drug for prostate cancer: interim observations in a phase I trial, [published erratum appears in J Natl Cancer Inst 1994 Apr 20; 86 (8): 639–40]. J Natl Cancer Inst 1993; 85(8): 611–21

    PubMed  CAS  Google Scholar 

  49. La Rocca RV, Meer J, Gilliatt RW, et al. Suramin-induced polyneuropathy. Neurology 1990; 40: 954–60

    PubMed  Google Scholar 

  50. La Rocca RV, Danesi R, Cooper MR, et al. Effect of suramin on human prostate cancer cells in vitro. J Urol 1991; 145: 393–8

    PubMed  Google Scholar 

  51. Cooper MR, Lieberman R, La Rocca RV, et al. Adaptive control with feedback strategies for suramin dosing. Clin Pharmacol Ther 1992; 52(1): 11–23

    PubMed  CAS  Google Scholar 

  52. Eisenberger MA, Sinibaldi VJ, Reyno LM, et al. Phase I and clinical evaluation of a pharmacologically guided regimen of suramin in patients with hormone-refractory prostate cancer. J Clin Oncol 1995; 13(9): 2174–86

    PubMed  CAS  Google Scholar 

  53. Jodrell DI, Reyno LM, Sridhara R, et al. Suramin: development of a population pharmacokinetic model and its use with intermittent short infusions to control plasma drug concentration in patients with prostate cancer. J Clin Oncol 1994; 12(1): 166–75

    PubMed  CAS  Google Scholar 

  54. Kobayashi K, Vokes EE, Vogelzang NJ, et al. Phase I study of suramin given by intermittent infusion without adaptive control in patients with advanced cancer. J Clin Oncol 1995; 13(9): 2196–207

    PubMed  CAS  Google Scholar 

  55. Reyno LM, Egorin MJ, Eisenberger MA, et al. Development and validation of a pharmacokinetically based fixed dosing scheme for suramin. J Clin Oncol 1995; 13: 2187–95

    PubMed  CAS  Google Scholar 

  56. McLeod HL, Relling MV, Liu Q, et al. Polymorphic thiopurine methyltransferase in erythrocytes is indicative of activity in leukemic blasts from children with acute lymphoblastic leukemia. Blood 1995; 85(7): 1897–902

    PubMed  CAS  Google Scholar 

  57. Lennard L, Lilleyman JS. Variable mercaptopurine metabolism and treatment outcome in childhood lymphoblastic leukemia. J Clin Oncol 1989; 7: 1816–23

    PubMed  CAS  Google Scholar 

  58. Lilleyman JS, Lennard L. Mercaptopurine metabolism and risk of relapse in childhood lymphoblastic leukaemia. Lancet 1994; 343(8907): 1188–90

    PubMed  CAS  Google Scholar 

  59. Schmiegelow K, Schroder H, Gustafsson G, et al. Risk of relapse in childhood acute lymphoblastic leukemia is related to RBC methotrexate and mercaptopurine metabolites during maintenance chemotherapy. J Clin Oncol 1995; 13: 345–51

    PubMed  CAS  Google Scholar 

  60. Schmiegelow K, Schroder H, Schmiegelow M. Methotrexate and 6-mercaptopurine maintenance therapy for childhood acute lymphoblastic leukemia: Dose adjustments by white cell counts or by pharmacokinetic parameters? Cancer Chemother Pharmacol 1994; 34: 209–15

    PubMed  CAS  Google Scholar 

  61. Santini J, Milano G, Thyss A, et al. 5-FU therapeutic monitoring with dose adjustment leads to an improved therapeutic index in head and neck cancer. Br J Cancer 1989; 59: 287–90

    PubMed  CAS  Google Scholar 

  62. Yoshida T, Araki E, Ligo M, et al. Clinical significance of monitoring serum levels of 5-fluorouracil by continuous infusion in patients with advanced colonic cancer. Cancer Chemother Pharmacol 1990; 26: 352–4

    PubMed  CAS  Google Scholar 

  63. Milano G, Etienne MC, Thyss RA, et al. Relationship between fluorouracil systemic exposure and tumor response and patient survival. J Clin Oncol 1994; 12: 1291–5

    PubMed  CAS  Google Scholar 

  64. Stewart CF, Arbuck SG, Fleming RA, et al. Changes in the clearance of total and unbound etoposide in patients with liver dysfunction. J Clin Oncol 1990; 8: 1874–9

    PubMed  CAS  Google Scholar 

  65. Pflüger KH, Schmidt L, Merkel M, et al. Drug monitoring of etoposide (VP16-213). Cancer Chemother Pharmacol 1987; 20: 59–66

    PubMed  Google Scholar 

  66. Arbuck SG, Douglass HO, Crom WR, et al. Etoposide pharmacokinetics in patients with normal and abnormal organ function. J Clin Oncol 1986; 4: 1690–5

    PubMed  CAS  Google Scholar 

  67. Stewart CF, Arbuck SG, Fleming RA, et al. Relation of systemic exposure to unbound etoposide and hematologic toxicity. Clin Pharmacol Ther 1991; 50: 385–93

    PubMed  CAS  Google Scholar 

  68. Ratain MJ, Schilsky RL, Choi KE, et al. Adaptive control of etoposide administration: impact of interpatient pharmacodynamic variability. Clin Pharmacol Ther 1989; 45: 226–33

    PubMed  CAS  Google Scholar 

  69. Ratain MJ, Mick R, Schilsky RL, et al. Pharmacologically based dosing of etoposide: a means of safely increasing dose intensity. J Clin Oncol 1991; 9: 1480–6

    PubMed  CAS  Google Scholar 

  70. Relling MV, Nemec J, Schuetz EG, et al. O-Demethylation of epipodophyllotoxin is catalyzed by human cytochrome P450 3A 4. Mol Pharmacol 1994; 45: 352–8

    PubMed  CAS  Google Scholar 

  71. Evans WE, Rodman JH, Relling MV, et al. Differences in teniposide disposition and pharmacodynamics in patients with newly diagnosed and relapsed acute lymphocytic leukemia. J Pharmacol Exp Ther 1991; 260(1): 71–7

    Google Scholar 

  72. Rodman JH, Abromowitch M, Sinkule JA. Clinical pharmacodynamics of continuous infusion teniposide: systemic exposure as a determinant of response in a phase I trial. J Clin Oncol 1987; 7: 1007–14

    Google Scholar 

  73. Tanizawa A, Fujimori A, Fujimori Y, et al. Comparison of topoisomerase I inhibition, DNA damage, and cytotoxicity of camptothecin derivatives presently in clinical trials. J Natl Cancer Inst 1994; 86(11): 836–42

    PubMed  CAS  Google Scholar 

  74. Stewart CF, Baker SD, Heideman RL, et al. Clinical pharmacodynamics of continuous infusion topotecan in children: systemic exposure predicts hematologic toxicity. J Clin Oncol 1994; 12: 1946–54

    PubMed  CAS  Google Scholar 

  75. Grochow LB, Rowinsky EK, Johnson R, et al. Pharmacokinetics and pharmacodynamics of topotecan in patients with advanced cancer. Drug Metab Dispos 1992; 20(5): 706–13

    PubMed  CAS  Google Scholar 

  76. O’Reilly S, Rowinsky EK, Slichenmyer W, et al. Phase I and pharmacologic study of topotecan in patients with impaired renal function. J Clin Oncol 1996; 14: 3062–73

    PubMed  Google Scholar 

  77. Zamboni WC, Heideman RL, Furman WL, et al. Pharmacokinetics of topotecan (TPT) in pediatric patients with normal and altered renal function. Proc Annual Meeting Am Soc Clin Oncol 1996; 15: 18(A371)

    Google Scholar 

  78. 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

    PubMed  Google Scholar 

  79. Zamboni WC, Crom WR, Bowman LC, et al. Interpatient variability in oral (PO) absorption of topotecan (TPT) in children with relapsed solid tumors. Clin Pharmacol Ther. In press

  80. Pommier Y, Leteurtre F, Fesen MR, et al. Cellular determinants of sensitivity and resistant to DNA topoisomerase inhibitors. Cancer Invest 1994; 12: 530–42

    PubMed  CAS  Google Scholar 

  81. Beijen JH, Smith BR, Keijer WJ, et al. High-performance liquid Chromatographie analysis of the new antitumor drug SK&F 104864-A (NSC 609699) in plasma. J Pharm Biomed Anal 1990; 8: 789–94

    Google Scholar 

  82. Mi Z, Malak H, Burke TG. Reduced albumin binding promotes the stability and activity of topotecan in human blood. Biochemistry 1995; 34(42): 13722–8

    PubMed  CAS  Google Scholar 

  83. van Warmerdam LJ, Verweij J, Schellens JH, et al. Pharmacokinetics and pharmacodynamics of topotecan administered daily for 5 days every 3 weeks. Cancer Chemother Pharmacol 1995; 35(3): 237–45

    PubMed  Google Scholar 

  84. Furman WL, Baker SD, Pratt CB, et al. Escalating systemic exposure to topotecan following a 120-hour continuous infusion in children with relapsed acute leukemia. J Clin Oncol 1996; 1(5): 1504–11

    Google Scholar 

  85. Schellens JH, Creemers GJ, Beijnen JH, et al. Bioavailability and harmacokinetics of oral topotecan: a new topoisomeras I inhibitor. Br J Cancer 1996; 73(10): 1268–71

    PubMed  CAS  Google Scholar 

  86. Friedman HS, Houghton PJ, Schold SC, et al. Activity of 9-dimethylaminomethyl-10-hydroxycamptothecin against pediatric and adult central nervous system tumor xenografts. Cancer Chemother Pharmacol 1994; 34(2): 171–4

    PubMed  CAS  Google Scholar 

  87. Houghton PJ, Cheshire PJ, Myers L, et al. Evaluation of 9 -dimethylaminomethyl-10-hydroxycamptothecin against xenografts derived from adult and childhood solid tumors. Cancer Chemother Pharmacol 1992; 31(3): 229–39

    PubMed  CAS  Google Scholar 

  88. Kintzel PE, Dorr RT. Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function. Cancer Treat Rev 1995; 21(1): 33–64

    PubMed  CAS  Google Scholar 

  89. Francis P, Bruno R, Scidman A. Pharmacodynamics of docetaxel (Taxotere Rm) in patients with liver metastases. Proc Am Soc Clin Oncol 1994 Mar; 13: 138

    Google Scholar 

  90. Van de 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: 215–9

    Google Scholar 

  91. 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: 555–61

    PubMed  CAS  Google Scholar 

  92. Dibenedetto SP, Guardabasso V, Ragusa R, et al. 6-Mercaptopurine cumulative dose: a critical factor of maintenance therapy in average risk childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol 1994; 11: 251–8

    PubMed  CAS  Google Scholar 

  93. Gonzalez FJ, Idle JR. Pharmacogenetic phenotyping and genotyping: present status and future potential. Clin Pharmacokinet 1994; 26(1): 59–70

    PubMed  CAS  Google Scholar 

  94. Fleming RA, Milano G, Thyss A, et al. Correlation between dihydropyrimidine dehydrogenase activity in peripheral mononuclear cells and systemic clearance of fluorouracil in cancer patients. Cancer Res 1992; 52: 2899–902

    PubMed  CAS  Google Scholar 

  95. Milano G, Etienne MC. Potential importance of dihydropyrimidine dehydrogenase (DPD) in cancer chemotherapy. Pharmacogenetics 1994; 4(6): 301–6

    PubMed  CAS  Google Scholar 

  96. Harris BE, Song R, Soong SJ, et al. Relationship between dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5-fluorouracil by protracted continuous infusion. Cancer Res 1990; 50: 197–201

    PubMed  CAS  Google Scholar 

  97. Etienne MC, Lagrange JL, Dassonville O, et al. Population study of dihydropyrimidine dehydrogenase in cancer patients. J Clin Oncol 1994; 12: 2248–53

    PubMed  CAS  Google Scholar 

  98. Evans WE, Horner MH, Chu YQ, et al. Altered mercaptopurine metabolism, toxic effects and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J Pediatr 1991; 119: 985–9

    PubMed  CAS  Google Scholar 

  99. Ratain MJ, Mick R, Berezin F, et al. Phase I study of amonafide dosing based on acetylator phenotype. Cancer Res 1993; 53 (10 Suppl.): 2304–8

    PubMed  CAS  Google Scholar 

  100. Ratain MJ, Mick R, Berezin F, et al. Paradoxical relationship between acetylator phenotype and amonafide toxicity. Clin Pharmacol Ther 1991; 50: 573–9

    PubMed  CAS  Google Scholar 

  101. Spatzenegger M, Jaeger W. Clinical importance of hepatic cytochrome P450 in drug metabolism. Drug Metab Rev 1995; 27(3): 397–417

    PubMed  CAS  Google Scholar 

  102. Beaune P. Les cytochromes P450 humains: Applications en pharmacologie. Therapie 1993; 48: 521–6

    PubMed  CAS  Google Scholar 

  103. Watkins PB, Murray SA, Winkelman LG, et al. Erythromycin breat test as an assay of glucocorticoid-induced liver cytochromes P-450: studies in rats and patients. J Clin Invest 1989; 83: 688–97

    PubMed  CAS  Google Scholar 

  104. Watkins PB. Noninvasive tests of CYP3A enzymes. Pharmacogenetics 1994; 4: 171–84

    PubMed  CAS  Google Scholar 

  105. Hrushesky WJM, Bjarnason GA. Circadian cancer therapy. J Clin Oncol 1993; 11: 1403–17

    PubMed  CAS  Google Scholar 

  106. Rivard GE, Infante-Rivard C, Dresse MF, et al. Circadian time-dependent response of childhood lymphoblastic leukemia to chemotherapy: a long-term follow-up study of survival. Chronobiol Int 1993; 10(3): 201–4

    PubMed  CAS  Google Scholar 

  107. Rivard GE, Hoyoux C, Infante-Rivard C, et al. Maintenance chemotherapy for childhood acute lymphoblastic leukaemia: better in the evening. Lancet 1985; II: 1264–6

    Google Scholar 

  108. Smaaland R, Laerum OD, Lote K, et al. DNA synthesis in human bone marrow is circadian stage dependent. Blood 1991; 77(12): 2603–11

    PubMed  CAS  Google Scholar 

  109. Peters GJ, van Groeningen CJ. Clinical relevance of biochemical modulation of 5-fluorouracil. Ann Oncol 1991; 2(7): 469–80

    PubMed  CAS  Google Scholar 

  110. Grem JL, Fischer PH. Enhancement of 5-fluorouracil’s anti-cancer activity by dipyridamole. Pharmacol Ther 1989; 40: 349–71

    PubMed  CAS  Google Scholar 

  111. Kohne CH, Hiddemann W, Schüller J, et al. Failure of orally administered dipyridamole to enhance the antineoplastic activity of fluorouracil in combination with leucovorin in patients with advanced colorectal cancer: a proscpective randomized trial. J Clin Oncol 1995; 13: 1201–8

    PubMed  CAS  Google Scholar 

  112. Masson E, Forrest A, Collins DA. Population pharmacokinetics and pharmacodynamics of fluorouracil administered as a 72-hour intravenous infusion. Annual Meeting of the American College of Clinical Pharmacy; Reno (NE); 1993 Aug

  113. Trump DL, Egorin MJ, Forrest A, et al. Pharmacokinetic and pharmacodynamic analysis of 5-fluorouracil during 72 hour continuous infusion with and without dipyridamole. J Clin Oncol 1991; 9(11): 2027–35

    PubMed  CAS  Google Scholar 

  114. Baccanari DP, Davis ST, Knick VC, et al. 5-Ethynyluracil (776C85): a potent modulator of the pharmacokinetics and antitumor efficacy of 5-fluorouracil. Proc Natl Acad Sci USA 1993; 90: 11064–8

    PubMed  CAS  Google Scholar 

  115. Baker SD, Khor SP, Adjei AA, et al. Pharmacokinetic, oral bioavailability, and safety study of fluorouracil in patients treated with 776C85, an inactivator of dihydropyrimidine dehydrogenase. J Clin Oncol 1996; 14: 3085–96

    PubMed  CAS  Google Scholar 

  116. Ling V. Charles F. Kettering prize: P-glycoprotein and resistance to anticancer drugs. Cancer 1992; 69(10): 2603–9

    PubMed  CAS  Google Scholar 

  117. Wacher VJ, Wu CY, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog 1995; 13(3): 129–34

    PubMed  CAS  Google Scholar 

  118. Lum BL, Gosland MP, Kaubisch S, et al. Molecular targets in oncology: implications of the multidrug resistance gene. Pharmacotherapy 1993; 13(2): 88–109

    PubMed  CAS  Google Scholar 

  119. Lum BL, Kaubisch S, Yahanda AM, et al. Alteration of etoposide pharmacokinetics and pharmacodynamics by cyclosporine in a phase I trial to modulate multidrug resistance. J Clin Oncol 1992; 10: 1635–42

    PubMed  CAS  Google Scholar 

  120. Schuetz EG, Beck WT, Schuetz JD. Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells. Mol Pharmacol 1996; 49: 311–8

    PubMed  CAS  Google Scholar 

  121. Schinkel AH, Smit JJM, van Tellingen O, et al. Disruption of the mouse mdrla P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 1994; 77: 491–502

    PubMed  CAS  Google Scholar 

  122. Schuetz EG, Schinkel AH, Relling MV, et al. P-glycoprotein: a major determinant of rifampicin-inducible expression of cytochrome P4503A in mice and humans. Proc Natl Acad Sci 1996; 93(9): 4001

    PubMed  CAS  Google Scholar 

  123. Slevin ML, Clark PI, Joel SP, et al. A randomized trial to evaluate the effect of schedule on the activity of etoposide in small-cell lung cancer. J Clin Oncol 1989; 7: 1333–40

    PubMed  CAS  Google Scholar 

  124. Johnson DH, Greco FA, Strupp J, et al. Prolonged administration of oral etoposide in patients with relasped or refractory small-cell lung cancer: a phase II trial. J Clin Oncol 1990; 8: 1613–7

    PubMed  CAS  Google Scholar 

  125. Waits TM, Johnson DH, Hainsworth JD, et al. Prolonged administration of oral etoposide in non-small-cell lung cancer: a phase II trial. J Clin Oncol 1992; 10: 292–6

    PubMed  CAS  Google Scholar 

  126. Sonnichsen DS, Ribeiro RC, Luo X, et al. Pharmacokinetics and pharmacodynamics of 21-day continuous oral etoposide in pediatric patients with solid tumors. Clin Pharmacol Ther 1995; 58: 99–107

    PubMed  CAS  Google Scholar 

  127. Gelmon K. The taxoids: paclitaxel and docetaxel. Lancet 1994; 344(8932): 1267–72

    PubMed  CAS  Google Scholar 

  128. Huizing MT, Keung ACF, Rosing H, et al. Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum-pretreated ovarian cancer patients. J Clin Oncol 1993; 11: 2127–35

    PubMed  CAS  Google Scholar 

  129. Cortes JE, Pazdur R. Docetaxel. J Clin Oncol 1995; 13: 2643–55

    PubMed  CAS  Google Scholar 

  130. Bokkerink JP, Bakker MAH, Hulscher TW, et al. Purine de novo synthesis as the basis of synergism of methotrexate and 6-mercaptopurine in human malignant lymphoblasts of different lineages. Biochem Pharmacol 1988; 37(12): 2321–7

    PubMed  CAS  Google Scholar 

  131. Marsh JC, Bertino JR, Katz KH, et al. The influence of drug interval on the effect of methotrexate and fluorouracil in the treatment of advanced colorectal cancer [see comments]. J Clin Oncol 1991; 9(3): 371–80

    PubMed  CAS  Google Scholar 

  132. Ann Holmes F, Madden T, Newman RA, et al. Sequence-Dependent Alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxorubicin in patients with metastatic breast cancer. J Clin Oncol 1996; 14(10): 2713–21

    Google Scholar 

  133. Rowinsky EK, Kaufmann SH, Baker SD, et al. Sequences of topotecan and cisplatin: phase I, pharmacologic, and in vitro studies to examine sequence dependence. J Clin Oncol 1996; 14: 3074–84

    PubMed  CAS  Google Scholar 

  134. Cresteil T, Monsarrat B, Alvinerie P, et al. Taxol metabolism by human liver microsomes: Identification of cytochrome P450 isozymes involved in its biotransformation. Cancer Res 1994; 54: 386–92

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Pharmacy, Laval University, Cité Universitaire, St-Foy, Montreal, Quebec, G1K 7P4, Canada

    Eric Masson

  2. Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA

    William C. Zamboni

  3. Research Center, Laval Hospital, St-Foy, Montreal, Quebec, Canada

    Eric Masson

Authors
  1. Eric Masson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William C. Zamboni
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eric Masson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Masson, E., Zamboni, W.C. Pharmacokinetic Optimisation of Cancer Chemotherapy. Clin-Pharmacokinet 32, 324–343 (1997). https://doi.org/10.2165/00003088-199732040-00005

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-199732040-00005

Keywords

Search

Navigation