Therapeutical Drug Monitoring of Anticancer Drugs

  • L. K. Paalzow
Part of the ESO Monographs book series (ESO MONOGRAPHS)


The idea of using plasma concentrations as a quantitative approach to therapeutical decision making emanates from an intent to reduce toxicity and improve drug efficacy, and to allow a more objective assessment of pharmacological therapy. Since its introduction in the early 1960s, it has developed as one of the most expanding components of diagnostic laboratory medicine today [1,2]. It has become especially useful for drugs with low therapeutical indices and for drugs with therapeutical effects that are difficult to evaluate. Maintaining plasma drug concentrations within a defined therapeutical range has been shown to improve efficacy, and reduce toxicity for therapy with several groups of drugs such as antiasthmatic, antiarrhytmic, antibacterial and antirheumatic drugs [2]. In the past, answers to many of the therapeutical questions regarding these drugs were obtained by trial and error, and pharmacotherapy was generally based on the selection of a dose, dosing interval, route of administration followed by observations of the response of the patient.


Anticancer Drug Therapeutical Drug Monitoring Antineoplastic Agent Total Plasma Clearance Plasma Concentration Measurement 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    McLeod SM: Therapeutic drug monitoring: what is its role in modern practise? Annals of the Royal College of Physicians and Surgeons of Canada 1986 19: 35–39Google Scholar
  2. 2.
    Holford NHG: Therapeutic drug monitoring. In: Avery GS ed Drug treatment. Sydney 1988 pp 194–222Google Scholar
  3. 3.
    Moore MJ, Erlichman C: Therapeutic drug monitoring in oncology: Problems and potential in antineoplastic therapy. Clin Pharmacokin 1987 13:205–227CrossRefGoogle Scholar
  4. 4.
    Rowland M, Tozer TN: Clinical Pharmacokinetics. Lea & Febiger, Philadelphia 1989Google Scholar
  5. 5.
    Vozeh S: Cost-effectiveness of therapeutic drug monitoring. Clin Pharmacokinet 1987 13: 131–140PubMedCrossRefGoogle Scholar
  6. 6.
    Paalzow LK: How physiological and pathophysiological factors influence the pharmacokinetics and analgesic effect of opiates in cancer patients. In: Domellöf L ed Drug Delivery in Cancer Treatment I. Springer-Verlag, Berlin Heidelberg 1987 pp 18–27Google Scholar
  7. 7.
    Paalzow LK: Pharmacokinetic aspects of drug-drug and drug-plastic interactions with anticancer drugs. In: Domellöf L ed Drug Delivery in Cancer Treatment H. Springer-Verlag, Berlin Heidelberg 1989 pp 15–26CrossRefGoogle Scholar
  8. 8.
    Pawls G: Effect of human renal and hepatic disease on the pharmacokinetics of anticancer drugs. Cancer Treat Rev 1982 9: 85–124Google Scholar
  9. 9.
    Kaplan BS, Gault MH, Knaack J: Nephropathy as a consequence of neoplasms or their treatment. In: Klastersky et al eds Medical complications in Cancer Patients. Raven Press, New York 1981 pp 135–153Google Scholar
  10. 10.
    Schilsky R: Renal and metabolic toxicities of cancer chemotherapy. Seminars in Oncology 1982 9: 75–83PubMedGoogle Scholar
  11. 11.
    Crom WR, Pratt CB, Green AA, Champion JE, Crom DB, Stewart CF and Evans WE: The effect of prior cisplatin therapy on the pharmacokinetics of high dose methrotrexate. J Clin Oncol 1984 2 No. 6Google Scholar
  12. 12.
    Zimm S, Collins JM, O’Neill D, Chabner BA, Poplack DG: Inhibition of first-pass metabolism in cancer chemotherapy: Interaction of 6-mercaptopurine and allopurinol. Clin Pharmacol Ther 1983 34: 810–817PubMedCrossRefGoogle Scholar
  13. 13.
    Poplack DG, Balis FM and Zimm S: The pharmacology of orally administered chemotherapy. Cancer 1986 Suppl July 15:473–480CrossRefGoogle Scholar
  14. 14.
    Finn C, Sadee W: Determination of 5-fluorouracil NSC-19893 plasma levels in rats and man by isotope dilution-mass fragmentography. Cancer Chemother Rep 1975 59: 279–286Google Scholar
  15. 15.
    Balis FM, Holcenberg JS, Bleyer WA: Clinical pharmacokinetics of commonly used anticancer drugs. Clin Pharmacokin 1983 8: 202–232CrossRefGoogle Scholar
  16. 16.
    Christophidis N, Vajda FJE, Lucus J, Drummer O, Moon WJ, Louis WJ: Fluorouracil therapy in patients with carcinoma of the large bowel: a pharmacokinetic comparison of various rates and routes of administration. Clin Pharmacokin 1978 3: 330–336CrossRefGoogle Scholar
  17. 17.
    Ehrsson H, Eksborg S, Österborg A, Mellerstedt H, Lindfors A: Oral melphalan pharmacokinetics in relation to dose and days of treatment. Med Oncol & Tumour Pharmacother 1989 6: 151–154Google Scholar
  18. 18.
    Tattersall MHN, Jarman M, Newlands ES et al: Pharmacokinetics of melphalan following oral or intravenous adminstration in patients with malignant disease. EurJ Cancer 1978 14: 507–513CrossRefGoogle Scholar
  19. 19.
    Harvey VJ, Slevin ML, Joel SP et al: Variable bioavailability following repeated oral doses of etoposide. Eur J Cancer Clin Oncol 1985 21: 1315–1319PubMedCrossRefGoogle Scholar
  20. 20.
    Smythe RD, Pfeffer M, Scaizo A, Comis RL: Bioavailability and pharmacokinetics of etoposide VP-16. Seminars in Oncology 1985 12: 48–51Google Scholar
  21. 21.
    D’Incalci M, Boils G, Mangioni C et al: Variable oral absorption of hexamethylmelamine in man. Cancer Treat Rep 1978 62:2117–2119PubMedGoogle Scholar
  22. 22.
    Ehrsson H, Wallin I, Nilsson SO, Johansson B: Pharmacokinetics of chlorambucil in man after administration of the free drug and its prednisolone ester. EurJ Clin Pharmacol 1983 24: 251–253CrossRefGoogle Scholar
  23. 23.
    Balis FM, Savitch JL, Bleyer WA: Pharmacokinetics of oral methotrexate in children. Cancer Res 1983 43: 2342–2345PubMedGoogle Scholar
  24. 24.
    Campbell MA, Perrier DG, Dorr RT, Alberts DS, Finley PR: Methotrexate: Bioavailability and pharmacokinetics. Cancer Treat Rep 1985 69: 833–838PubMedGoogle Scholar
  25. 25.
    Smith DK, Omura GA, Ostroy F: Clinical pharmacology of intermediate dose oral methotrexate. Cancer Chemot Pharmacol 1980 4: 117–120Google Scholar
  26. 26.
    EORTC: Pharmacokinetically guided dose escalation in phase I clinical trials. Commentary and proposed guidelines. Eur J Cancer Clin Oncol 1987 23: 1083–1087CrossRefGoogle Scholar
  27. 27.
    Beal SL, Sheiner LB: The NONMEM system. American Statistician 1980 34: 178CrossRefGoogle Scholar
  28. 28.
    Sheiner LB, Rosenberg BG, Marathe VV: Estimation of population characteristics of pharmacokinetic parameters from routine clinical data. J Pharmacokin Biopharm 1977 5: 445–480CrossRefGoogle Scholar
  29. 29.
    Grasela TH, Sheiner LB, Rambeck B, Boenigk HE, Dunlop A, Mullen PW, Wadsworth J, Richens A, lshizaki T, Chiba K, Miura H, Minagawa K, Blain PG, Mucklow JC, Bacon CT, Rawlins M: Steady-state pharmacokinetics of phenytoin from routinely collected patient data. Clin Pharmacokin 1983 8: 355–364CrossRefGoogle Scholar
  30. 30.
    Grasela TH, Sheiner LB: Population pharmacokinetics of procainamide from routine clinical data. Clin Pharmacokin 1984 9: 545CrossRefGoogle Scholar
  31. 31.
    Mungall DR, Ludden TM, Marshall J, Hawkins DW, Talbert RL, Crawford MH: Population pharmacokinetics of racemic warfarin in adult patients. J Pharmacokin Biopharm 1985 13: 213CrossRefGoogle Scholar
  32. 32.
    Frei Ill E, Canellos GP: Dose: a critical factor in cancer chemotherapy. Am J Med 1989 69: 585–594CrossRefGoogle Scholar
  33. 33.
    Bruce WR, Meeker BE, Valeriote FA. Comparison of the sensitivity of normal hematopoietic and transplanted lymphoma colony forming cells to chemotherapeutic agents administered in vivo. J Nat Cancer Inst 1966 36: 233–245Google Scholar
  34. 34.
    Frei Ill E, Blum RH, Pitman SW et al: High dose methotrexate with leucovorin rescue. Am J Med 1980 68: 370–376CrossRefGoogle Scholar
  35. 35.
    Pinedo HM, Zaharko DS, Bull JM et al: The reversal of methotrexate cytotoxicity to mouse bone marrow cells by leucovorin and nucleotides. Cancer Res 1977 36: 4418–4424Google Scholar
  36. 36.
    Pinedo HM, Chabner BA: Role of drug concentration, duration of exposure and endogenous metabolites in determining methotrexate cytotoxicity. Cancer Treat Rep 1977 61: 709–715PubMedGoogle Scholar
  37. 37.
    Stoller RG, Hande KR, Jacobs SA et al: Use of plasma pharmacokinetics to predict and prevent methotrexate toxicity. N Engl J Med 1977 297: 630–634PubMedCrossRefGoogle Scholar
  38. 38.
    Keefe DA, Capizzi RI, Rudnick SA: Methotrexate cytotoxicity for L5178Y/Asn-lymphoblaste: relationship of dose and duration of exposure to tumour cell viability. Cancer Res 1982 42: 1641–1645PubMedGoogle Scholar
  39. 39.
    Evans WE, Pratt CB, Taylor RH, Barker LF, Crom WR: Pharmacokinetic monitoring of high dose methotrexate. Cancer Chemother Pharmacol 1979 3: 161–166PubMedCrossRefGoogle Scholar
  40. 40.
    Isacoff WH, Morrison PF, Aroesty J, Willis KL, Block JB, Lincoln TL: Pharmacokinetics of high-dose methotrexate with citrovorum factor rescue. Cancer Treat Rep 1977 61: 1665–1674PubMedGoogle Scholar
  41. 41.
    Reich SDI, Gonczy C: Mathematical modeling-guide to high-dose methotrexate infusion therapy. Cancer Chemother Pharmacol 1979 3: 25–31PubMedGoogle Scholar
  42. 42.
    Kerr IG, Jolivet J, Collins JM, Drake JC, Chabner BA: Test dose for predicting high-dose methotrexate infusions. Clin Pharmacol Ther 1983 33: 44–51PubMedCrossRefGoogle Scholar
  43. 43.
    Evans WE, Crom WR, Yalowich J: Methotrexate. In: Evans et al eds Applied Pharmacokinetics, Applied Therapeutics, Spokane 1986 pp 1009–1056Google Scholar
  44. 44.
    Au JLS, Rustum YM, Ledesma EJ et al: Clinical pharmacological studies of concurrent infusion of 5fluorouracil and thymidine in treatment of colorectal carcinomas. Cancer Res 1982 42: 2930–2937PubMedGoogle Scholar
  45. 45.
    Goldberg JA, Kerr DJ, Willmott N et al: Pharmacokinetics and pharmacodynamics of locoregional 5-fluorouracil 5-FU in advanced colorectal liver metastases. Br J Cancer 1988 57: 186–189PubMedCrossRefGoogle Scholar
  46. 46.
    Milano G, Roman P, Khater R et al: Dose versus pharmacokinetics for predicting tolerance to 5-day continuous infusion of 5-FU. tat J Cancer 1988 41: 537–541Google Scholar
  47. 47.
    Evans EW, Relling MV: Clinical pharmacokineticspharmacodynamics of anticancer drugs. Clin Pharmacokin 1989 16: 327–336CrossRefGoogle Scholar
  48. 48.
    Rodman JH, Abromowitch M, Sinkule JA, Rivera GK, Evans WE: Clinical pharmacodynamics of continuous infusion teniposide: systemic exposure as a determinant of response in a Phase I trial. J Clin Oncol 1987 5: 1007–1014PubMedGoogle Scholar
  49. 49.
    Egorin MJ, Van Echo SJ, Tipping EA et al: Pharmacokinetics and dosage reduction of carboplatin in patients with impaired renal function. Cancer Res 1984 44: 5432–5438PubMedGoogle Scholar
  50. 50.
    Vozeh S, Steimer JL: Feedback control methods for drug dosage optimisation: concepts, classification, and clinical application. Clin Pharmacokin 1985 10: 457–476CrossRefGoogle Scholar
  51. 51.
    Peck CC, Rodman JH: Analysis of clinical pharmacokinetic data for individualizing drug dosage regimens. Applied Therapeutics Spokane 1986 pp 55–82Google Scholar
  52. 52.
    Sheiner LB, Rosenberg B, Marathe VV: Estimation of population characteristics of pharmacokinetic parameters from routine clinical data. J Pharmacokin Biopharm 1977 5: 445–479CrossRefGoogle Scholar
  53. 53.
    Sheiner L, Rosenberg B, Melmon K: Modeling of individual pharmacokinetics for computer-aided drug dosage. Comput Biomed Res 1972 5: 441–459CrossRefGoogle Scholar
  54. 54.
    Whiting B, Kelman AW, Bryson SM, Derkx FHM, Thomson AH, Fotheringham GH, Joel SE: Clinical pharmacokinetics: a comprehensive system for therapeutic drug monitoring and prescribing. Br Med J 1984 288: 541CrossRefGoogle Scholar
  55. 55.
    Vozeh S, Berger M, Wenk M, Ritz R, Follath F: Rapid prediction of individual dosage requirements for lignocaine. Clin Pharmacokin 1984 9: 354–363CrossRefGoogle Scholar
  56. 56.
    Burton ME, Vasko MR, Brater DC: Comparison of drug dosing methods. Clin Pharmacokin 1985 10: 1CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1990

Authors and Affiliations

  • L. K. Paalzow
    • 1
  1. 1.Department of Biopharmaceutics and PharmacokineticsUniversity of UppsalaUppsalaSweden

Personalised recommendations