Abstract
Prescribing chemotherapy is a difficult task, because of drug resistance, which prevents all tumors to respond to a given protocol and because of drug toxicity, which is generally unavoidable but which must be limited to acceptable levels. The therapeutic window of anticancer drugs is very narrow and clinicians have to try to optimize the individual doses and schedules of the drugs to be administered. They can rely upon simple anthropometric features, such as body weight or surface area; they can also take into account the physiological status of the patient: age, liver and kidney function, genetic characteristics of drug metabolism, etc. The best way for dose adaptation lies in the establishment of pharmacokinetic/pharmacodynamic relationships, i.e., between the behavior of a drug in the body and its efficacy and toxicity. When it is established that the optimal effect of a drug is related to a given parameter, such as the area under the curve plotting plasma concentration vs. time (AUC), it becomes possible to administer the drug with the dose allowing to obtain the target parameter value. Individual dose adaptation can be achieved thanks to the study of the pharmacokinetics of a test dose preceding that of the therapeutic dose, or by the measure of drug plasma levels, either at steady state during a protracted infusion, or from cycle to cycle during repetitive protocols. Population analysis now allows the adaptation of anticancer drug dosing from a minimum knowledge of individual pharmacokinetic features, together with other characteristics of the patients such as age, gender or physiological functions.
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References
Grochow LB, Ames MM: A clinician’s guide to chemotherapy. Pharmacokinetics and pharmacodynamics. Williams & Wilkins, Baltimore, 1998.
Ratain MJ, Schilsky RL, Conley BA, Egorin MJ: Pharmacodynamics in cancer therapy. J Clin Oncol 8:1739–1753, 1990.
Reilly JJ, Workman P: Normalisation of anticancer drug dosage using body weight and surface area is it worthwhile ? A review of theoretical and practical considerations. Cancer Chemother Pharmacol 32:411–418, 1993.
Ratain MJ: Body-surface area as a basis for dosing anticancer agents: science, myth, or habit? J Clin Oncol 16:2297–2298, 1998.
Twelves CJ, Dobbs NA, Gillies HC, et al: Doxorubicin pharmacokinetics: the effect of abnormal liver biochemistry tests. Cancer Chemother Pharmacol 42:229–234, 1998.
Chatelut E, Canal P, Brunner V et al: Prediction of carboplatin clearance from standard morphological and biological patient characteristics. J Nat Cancer Inst 87:573–580, 1995.
Stewart LF, Arbuck SG, Fleming RA et al: Changes in the clearance of total and unbound etoposide in patients with liver dysfunction. J Clin Oncol 8:1874–1879, 1990.
Evans WE, Homer M, Chu YQ et al: Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J Pediat 119:985–989, 1991.
Diasio RB, Beavers TE, Carpenter JT: Familial deficiency of dihydropyrimidine dehydrogenase: biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity. J Clin Invest 81:47–51, 1988.
Iyer L, King CD, Whitington PF et al: Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 101:847–854, 1998.
Ratain MJ, Mick R, Berezin F et al: Paradoxical relationship between acetylator phenotype and amonafide toxicity. Clin Pharmacol Ther 50:573–579, 1991.
Egorin MJ: Cancer pharmacology in the elderly. Semin Oncol 20:43–49, 1993.
Kantarjian HM, Estey EH, Plunkett W et al: Phase I-II clinical and pharmacologic studies of high-dose cytosine arabinoside in refractory leukemia. Am J Med 81:387–394, 1986.
Evans WE, Cram WR, Abromowitch M et al: Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia. Identification of a relation between concentration and effect. N Engl J Med 314:471–477, 1986.
Graf N, Winkler K, Betlemovic M, et al: Methotrexate pharmacokinetics and prognosis in osteosarcoma. J Clin Oncol 12:1443–1451, 1994.
Milano G, Etienne MC, Renee N et al: Relationship between fluorouracil systemic exposure and tumor response and patient survival. J Clin Oncol 12:1291–1295, 1994.
Gamelin E, Danquechin-Dorval EM, Dumesnil YF et al: Relationship between 5-fluorouracil dose intensity and therapeutic response in patients with advanced colorectal cancer receiving infusional therapy containing 5-FU. Cancer 77:441–451, 1996.
Robert J, Iliadis A, Hoerni B, et al: Pharmacokinetics of adriamycin in breast cancer. Eur J Cancer Clin Oncol 18:739–745, 1982.
Preisler HD, Gessner T, Azarnia N et al: Relationship between plasma adriamycin levels and the outcome of remission induction therapy for acute nonlymphocytic leukemia. Cancer Chemother Pharmacol 12:125–130, 1984.
Hu OYP, Chang SP, Jame JN, Chen KY: Pharmacokinetic and pharmacodynamic studies with 4’-epidoxorubicin in nasopharyngeal carcinoma patients. Cancer Chemother Pharmacol 24:332–337, 1989.
Vermorken JB, van der Wijgh WJF, Klein I et al: Pharmacokinetics of free and total platinum species after rapid and prolonged infusions of cisplatin. Clin Pharmacol Ther 39:136–144, 1986.
Desoize B, Maréchal F, Millard H and Cattan A: Correlation of clinical pharmacokinetic parameters of cisplatin with efficacy and toxicity. Biomed Pharmacother 45:203–205, 1991.
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 10:520–528, 1992.
Desoize B, Maréchal F and Cattan A: Clinical pharmacokinetics of etoposide during 120-h continuous infusion in solid tumors. Br J Cancer 62:840–841, 1990.
Rodman JH, Abromowitch M, Sinkule JA, et al: Clinical pharmacodynamics of continuous infusion of teniposide. J Clin Oncol 5:1007–1014, 1987.
Ayash LJ, Wright JE, Tretyakov O, et al: Cyclophosphamide pharmacokinetics: correlation with cardiac toxicity and tumor response. J Clin Oncol 10:995–1000, 1992.
Lu K, Yap HY, Loo TL: Clinical pharmacokinetics of vinblastine by continuous intravenous infusion. Cancer Res 43:1405–1408, 1983.
Stoller RG, Hande KR, Jacobs SA, et al: Use of plasma pharmacokinetics to predict and prevent methotrexate toxicity. N Engl J Med 297:630–634, 1977.
Santini J, Milano G, Thyss A et al: 5-FU therapeutic monitoring with dose adjustment leads to improved therapeutic index in head and neck cancer. Br J Cancer 59:287–290, 1989.
Lennard L, Lilleyman JS: Variable mercaptopurine metabolism and treatment outcome in childhood lymphoblastic leukemia. J Clin Oncol 7:1816–1823, 1989.
Ackland SP, Ratain MJ, Vogelzang NJ, et al: Pharmacokinetics and pharmacodynamics of long-term continuous infusion doxorubicin. Clin Pharmacol Ther 45:340–347, 1989.
Jakobsen P, Bastolt L, Dalmark M et al: A randomized study of epirubicin at four different levels in advanced breast cancer. Feasibility of myelotoxicity prediction through single blood sample measurement. Cancer Chemother Pharmacol 28:465–469, 1991.
Robert J, Monnier A, Poutignat N, et al: A pharmacokinetic and pharmacokinetic study of the new anthracycline pirarubicin in breast cancer patients. Cancer Chemother Pharmacol 29:75–79, 1991.
Canal P, Attal M, Chatelut E et al: Plasma and cellular pharmacokinetics of mitoxantrone in high-dose chemotherapeutic regimen for refractory lymphomas. Cancer Res 53:4850–4854, 1993.
Gregg RW, Molepo JM, Monpetit VJ, et al: Cisplatin neurotoxicity: the relationship between dosage, time, and platinum concentration in neurologic tissues and morphologic evidence of toxicity. J Clin Oncol 10:795–803, 1992.
Kelsen DP, Alcock N and Young CW: Cisplatin nephrotoxicity: correlation with plasma concentrations. Am J Clin Oncol 8:77–80, 1985.
Newell DR, Siddik ZH, Gumbrell LA, et al. Plasma free platinum pharmacokinetics in patients treated with high-dose carboplatin. Eur J Cancer Clin Oncol 23:1387–1399, 1987.
Bennett CL, Sinkule JA, Schilsky RL, et al: Phase I clinical and pharmacological study of 72-h continuous infusion of etoposide in patients with advanced cancer. Cancer Res 47:1952–1956, 1987.
Ratain MJ Mick R, Schilsky RL, et al: Pharmacologically based dosing of etoposide: a means of safety increasing dose intensity. J Clin Oncol 9:1480–1486, 1991.
Ratain MJ, Vogelzang NJ: Phase I and pharmacological study of vinblastine by prolonged continuous infusion. Cancer Res 46:4827–4830, 1986.
Desai ZR, van den Berg HW, Bridges JM, et al: Can severe vincristine neurotoxicity be prevented Cancer Chemother Pharmacol 8:211–214, 1982.
Gianni L, Kearns CM, Giani A, et al: Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetics/pharmacodynamics relationships in humans. J Clin Oncol 13:180–190, 1995.
Bruno R, Hille D, Riva A et al: Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer. J Clin Oncol 16:187–196, 1998.
Chabot GG, Abigerges D, Catimel G, et al: Population pharmacokinetics and pharmacodynamics of irinotecan (CPT-11) and active metabolite SN-38 during phase I trials. Ann Oncol 6:141–151, 1995.
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 35:237–245, 1995.
Ratain MJ, Vogelzang NJ: Experimental rationale for continuous infusion therapy. In: Cancer chemotherapy by infusion (Ed: Lokich J) Precept Press, Chicago, 1987, pp. 12–34.
Monjanel S, Imbert AM, Favre R, et al: High-dose methotrexate: preliminary evaluation of a pharmacokinetic approach. Cancer Chemother Pharmacol 3:189–196, 1979.
Favre R, Monjanel S, Alfonsi M, et al: High-dose methotrexate: a clinical and pharmacokinetic evaluation. Cancer Chemother Pharmacol 9:156–160, 1982.
Tranchand B, Poin YD, Minuit MP, et al: High-dose melphalan dosage adjustment: possibility of using a test-dose. Cancer Chemother Rep 23:95–100, 1982.
Desoize B, Dumont P, Manot L, et al: Comparison of two dose prediction models for cisplatin. Anticancer Res 14:2285–2290, 1994.
Gamelin E, Boisdron-Celle M, Delva R, et al: Long-term weekly treatment of colorectal metastatic cancer with fluorouracil and leucovorin: results of a multicentric prospective trial of fluorouracil dosage optimization by pharmacokinetic monitoring in 152 patients. J Clin Oncol 16:1470–1478, 1998.
Iliadis A, Bachir-Rao M, Bruno R, Favre R: Bayesian estimation and prediction of clearance in high-dose methotrexate infusions. J Pharmacokin Biopharm 13:101–115, 1985.
Bressolle F, Ray P, Jacquet JM, et al: Bayesian estimation of doxorubicin pharmacokinetic parameters. Cancer Chemother Pharmacol 29:53–60, 1991.
Wade JR, Kelman AW, Kerr DJ, et al: Variability in the pharmacokinetics of epirubicin. Cancer Chemother Pharmacol 29:391–395, 1992.
Guillet P, Monjanel S, Nicoara A, et al: A Bayesian dosing method for carboplatin given by continuous infusion for 120 h. Cancer Chempother Pharmacol 40:143–149, 1997.
Evène E, Chatelut E, Tranchand B et al: Estimation Bayésienne des paramètres pharmacocinétiques de l’étoposide. Bull Cancer 84:699–703, 1997.
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Canal, P., Gamelin, E., Vassal, G. et al. Benefits of pharmacological knowledge in the design and monitoring of cancer chemotherapy. Pathol. Oncol. Res. 4, 171–178 (1998). https://doi.org/10.1007/BF02905246
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DOI: https://doi.org/10.1007/BF02905246