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Clinical Pharmacokinetics of Irinotecan

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  • Drug Disposition
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Summary

This article reviews the clinical pharmacokinetics of a water-soluble analogue of camptothecin, irinotecan {CPT-11 or 7-ethyl-10-[4-(1-piperidmo)-1-piperidino]-carbonyloxy-camptothecin}. Irinotecan, and its more potent metabolite SN-38 (7-ethyl-10-hydroxy-camptothecin), interfere with mammalian DNA topoisomerase I and cancer cell death appears to result from DNA strand breaks caused by the formation of cleavable complexes.

The main clinical adverse effects of irinotecan therapy are neutropenia and diarrhoea. Irinotecan has shown activity in leukaemia, lymphoma and the following cancer sites: colorectum, lung, ovary, cervix, pancreas, stomach and breast.

Following the intravenous administration of irinotecan at 100 to 350 mg/m2, mean maximum irinotecan plasma concentrations are within the 1 to 10 mg/L range. Plasma concentrations can be described using a 2- or 3-compartment model with a mean terminal half-life ranging from 5 to 27 hours. The volume of distribution at steady-state (Vss) ranges from 136 to 255 L/m2, and the total body clearance is 8 to 21 L/h/m2.

Irinotecan is 65% bound to plasma proteins. The areas under the plasma concentration-time curve (AUC) of both irinotecan and SN-38 increase proportionally to the administered dose, although interpatient variability is important. SN-38 levels achieved in humans are about 100-fold lower than corresponding irinotecan concentrations, but these concentrations are potentially important as SN-38 is 100- to 1000-fold more cytotoxic than the parent compound.

SN-38 is 95% bound to plasma proteins. Maximum concentrations of SN-38 are reached about 1 hour after the beginning of a short intravenous infusion. SN-38 plasma decay follows closely that of the parent compound with an apparent terminal half-life ranging from 6 to 30 hours. In human plasma at equilibrium, the irinotecan lactone form accounts for 25 to 30% of the total and SN-38 lactone for 50 to 64%.

Irinotecan is extensively metabolised in the liver. The bipiperidinocarbonylxy group of irinotecan is first removed by hydrolysis to yield the corresponding carboxylic acid and SN-38 by carboxyesterase. SN-38 can be converted into SN-38 glucuronide by hepatic UDP-glucuronyltransferase.

Another recently identified metabolite is 7-ethyl-10-[4-N-(5-aminopentanoic acid)-l-piperidino]-carbonyloxy-camptothecin (APC). This metabolite is a weak inhibitor of KB cell growth and a poor inducer of topoisomerase IDNA-cleavable complexes (100-fold less potent than SN-38). Numerous other unidentified metabolites have been detected in bile and urine. The mean 24-hour irinotecan urinary excretion represents 17 to 25% of the administered dose. Recovery of SN-38 and its glucuronide in urine is low and represents 1 to 3% of the irinotecan dose. Cumulative biliary excretion is 25% for irinotecan, 2% for SN-38 glucuronide and about 1% for SN-38.

The pharmacokinetics of irinotecan and SN-38 are not influenced by prior exposure to the parent drug. The AUC of irinotecan and SN-38 correlate significantly with leuco-neutropenia and sometimes with the intensity of diarrhoea. Certain hepatic function parameters have been correlated negatively with irinotecan total body clearance. It was noted that most tumour responses were observed at the highest doses administered in phase I trials, which indicates a dose-response relationship with this drug. In the future, these pharmacokinetic-pharmacodynamic relationships will undoubtedly prove useful in minimising the toxicity and maximise the likelihood of tumour response in patients.

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References

  1. Wall ME, Wani MC, Cook CE, et al. Plant antitumor agents I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata. J Am Chem Soc 1966; 88: 3888–90

    CAS  Google Scholar 

  2. Potmesil M. Camptothecins: from bench research to hospital wards. Cancer Res 1994; 54: 1431–9

    PubMed  CAS  Google Scholar 

  3. Wall ME, Wani MC. Camptothecin and analogs: from discovery to clinic. In: Potmesil M, Pinedo H, editors. Camptothecins: new anticancer agents. Boca Raton (FL): CRC Press, Inc., 1995: 21–41

    Google Scholar 

  4. Wall ME, Wani MC. Camptothecin: discovery to clinic. Ann N Y Acad Sci 1996; 803: 1–12

    PubMed  CAS  Google Scholar 

  5. Hsiang YH, Liu LF. Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res 1988; 48: 1722–6

    PubMed  CAS  Google Scholar 

  6. Jaxel C, Kohn K, Wani MC, et al. Structure-activity study of the actions of camptothecin derivatives on mammalian toopoisomerase I. Evidence for a specific receptor site and for a relation to antitumor activity. Cancer Res 1989; 49: 1465–9

    PubMed  CAS  Google Scholar 

  7. Hsiang YH, Liu LF, Wall ME, et al. DNA topoisomerase I mediated DNA cleavage and cytotoxicity of camptothecin analogues. Cancer Res 1989; 49: 4835–9

    Google Scholar 

  8. Giovanella BC, Stehlin JS, Wall ME, et al. DNA topoisomerase I-targeted chemotherapy of human colon cancer in xenografts. Science 1989; 246: 1046–8

    PubMed  CAS  Google Scholar 

  9. Potmesil M, Hsiang YH, Liu LF, et al. Resistance of human leukemic and normal lymphocytes to drug-induced DNA cleavage and low levels of DNA topoisomerase II. Cancer Res 1988; 48: 3537–43

    PubMed  CAS  Google Scholar 

  10. Kunimoto T, Nitta K, Tanaka T, et al. Antitumor activity of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxy-ca mptothecin, a novel water-soluble derivative of camptothecin, against murine tumors. Cancer Res 1987; 47: 5944–7

    PubMed  CAS  Google Scholar 

  11. Kingsbury WD, Boehm JC, Jakas DR, et al. Synthesis of water-soluble (aminoalkyl) camptothecin analogues: inhibition of topoisomerase I and antitumor activity. J Med Chem 1991; 34: 98–107

    PubMed  CAS  Google Scholar 

  12. Wani MC, Nicholas AW, Wall ME. Plant antitumor agents: 23. Synthesis and antileukemic activity of camptothecin analogues. J Med Chem 1986; 29: 2358–63

    PubMed  CAS  Google Scholar 

  13. Hertzberg RP, Caranfa MJ, Hecht S. On the mechanism of topoisomerase I inhibition by camptothecin: evidence for binding to an enzyme-DNA complex. Biochemistry 1989; 28: 4629–38

    PubMed  CAS  Google Scholar 

  14. Kessel D, Bosmann HB, Lohr K. Camptothecin effects on DNA synthesis in murine leukemia cells. Biochem Biophys Acta 1972; 269: 210–6

    PubMed  CAS  Google Scholar 

  15. Wang JC. DNA topoisomerases. Annu Rev Biochem 1985; 54: 665–97

    PubMed  CAS  Google Scholar 

  16. Liu LF. DNA topoisomerase poisons as antitumor drugs. Annu Rev Biochem 1989; 58: 351–75

    PubMed  CAS  Google Scholar 

  17. Kawato Y, Aonuma M, Hirota Y, et al. Intracellular roles of SN-38, a metabolite of the camptothecin derivative, CPT-11, in the antitumor effect of CPT-11. Cancer Res 1991; 51: 4187–91

    PubMed  CAS  Google Scholar 

  18. Ogasawara H, Nishio K, Kanzawa F, et al. Intracellular carboxylesterase activity is a determinant of cellular sensitivity to the antineoplastic agent KW-2189 in cell lines resistant to cisplatin and CPT-11. Jpn J Cancer Res 1995; 86: 124–9

    PubMed  CAS  Google Scholar 

  19. Jansen WJ, Zwaer B, Hulscher ST, et al. CPT-11 in human colon cancer cell lines and xenografts: characterization of cellular sensitivity determinants. Int J Cancer 1997; 70: 335–40

    PubMed  CAS  Google Scholar 

  20. Suzuki A, Kato M. Chemotherapeutic agent CPT-11 induces the new expression of the apoptosis initiator to the cytoplasm. Exp Cell Res 1996; 227: 154–9

    PubMed  CAS  Google Scholar 

  21. Woessner RD, Eng WK, Hofmann FA, et al. Camptothecin hyper-resistant P388 cells: drug-dependent reduction in topoisomerase I content. Oncol Res 1992; 4: 481–8

    PubMed  CAS  Google Scholar 

  22. Gupta RS, Gupta R, Eng B, et al. Camptothecin-resistant mutants of Chinese hamster ovary cells containing a resistant form of topoisomerase I. Cancer Res 1988; 48: 6404–10

    PubMed  CAS  Google Scholar 

  23. Kanzawa F, Sugimoto Y, Minato K, et al. Establishment of a camptothecin analogue (CPT-11)-resistant cell line of human small cell lung cancer: characterization and mechanism of resistance. Cancer Res 1990; 50: 5919–24

    PubMed  CAS  Google Scholar 

  24. Sugimoto Y, Tsukahara S, Oh-Hara T, et al. Decreased expression of DNA topoisomerase I in camptothecin-resistant tumor cell lines as determined by a monoclonal antibody. Cancer Res 1990; 50: 6925–30

    PubMed  CAS  Google Scholar 

  25. Tamura H, Kohchi C, Yamada R. Molecular cloning of a cDNA of a camptothecin-resistant human DNA topoisomerase I and identification of mutation sites. Nucleic Acids Res 1991; 51: 1129–36

    Google Scholar 

  26. Goldwasser F, Bae I, Valenti M, et al. Topoisomerase I-related parameters and camptothecin activity in the colon carcinoma cell lines from the National Cancer Institute anticancer screen. Cancer Res 1995; 55: 2116–21

    PubMed  CAS  Google Scholar 

  27. Chen AY, Yu C, Potmesil M, et al. Camptothecin overcomes MDR1-mediated resistance in human KB carcinoma cells. Cancer Res 1991; 51: 6039–44

    PubMed  CAS  Google Scholar 

  28. Takeda S, Shimazoe T, Kuga H, et al. Camptothecin analog (CPT-11)-sensitive human pancreatic tumor cell line QGP-1N shows resistance to SN-38, an active metabolite of CPT-11. Biochem Biophys Res Commun 1992; 188: 70–7

    PubMed  CAS  Google Scholar 

  29. Onishi Y, Oguro M, Kizaki H. A lymphoma cell line resistant to 4-piperidinopiperidine was less sensitive to CPT-11. Cancer Chemother Pharmacol 1997; 39: 473–8

    PubMed  CAS  Google Scholar 

  30. Kawato Y, Furuta T, Aonuma M, et al. Antitumor activity of a camptothecin derivative, CPT-11, against human tumor xenografts in nude mice. Cancer Chemother Pharmacol 1991; 28: 192–8

    PubMed  CAS  Google Scholar 

  31. Bissery MC, Vrignaud P, Lavelle F, et al. Experimental antitumor activity and pharmacokinetics of the camptothecin analog irinotecan (CPT-11) in mice. Anti-Cancer Drugs 1996; 7: 437–60

    PubMed  CAS  Google Scholar 

  32. Tanizawa A, Fujimori A, Fugimori 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: 836–42

    PubMed  CAS  Google Scholar 

  33. Lavelle F, Bissery MC, André S, et al. Preclinical evaluation of CPT-11 and its active metabolite SN-38. Semin Oncol 1996; 3(1 Suppl.): 11–20

    Google Scholar 

  34. Houghton PJ, Cheshire PJ, Hallman JC, et al. Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin against human tumor xenografts: lack of cross-resistance in vivo in tumors with acquired resistance to the topoisomerase I inhibitor 9-dimethylaminomethyl-10-hydroxycamptothecin. Cancer Res 1993; 53: 2823–9

    PubMed  CAS  Google Scholar 

  35. Vassal G, Terrier-Lacombe MJ, Bissery MC, et al. Therapeutic activity of CPT-11, a DNA-topoisomerase I inhibitor, against peripheral primitive neuroectodermal tumour and neuroblastoma xenografts. Br J Cancer 1996; 74: 537–45

    PubMed  CAS  Google Scholar 

  36. Komuro H, Li P, Tsuchida Y, et al. Effects of CPT-11 (a unique DNA topoisomerase I inhibitor) on a highly malignant xenotransplanted neuroblastoma. Med Pediatr Oncol 1994; 23: 487–92

    PubMed  CAS  Google Scholar 

  37. Hare CB, Elion GB, Houghton PJ, et al. Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-l-piperidino)-carboxyloxy-camptothecin against pediatric and adult central nervous system tumor xenografts. Cancer Chemother Pharmacol 1997; 38: 187–91

    Google Scholar 

  38. Tsuruo T, Matsuzaki T, Matsushita M, et al. Antitumor effect of CPT-11, a new derivative of camptothecin, against pleiotropic drug-resistant tumors in vitro and in vivo. Cancer Chemother Pharmacol 1988; 21: 71–4

    PubMed  CAS  Google Scholar 

  39. Taguchi T, Wakui A, Hasegawa K. Phase I clinical study of CPT-11: Research Group of CPT-11. Jpn J Cancer Chemother 1990; 17: 115–20

    CAS  Google Scholar 

  40. Negoro S, Fukuoka M, Masuda N, et al. Phase I study of weekly intravenous infusion of CPT-11, a new derivative of camptothecin, in the treatment of advance non-small cell lung cancer. J Natl Cancer Inst 1991; 83: 1164–8

    PubMed  CAS  Google Scholar 

  41. Ohe Y, Sasaki Y, Shinkai T, et al. Phase I study and pharmacokinetics of CPT-11 with 5-day continuous infusion. J Natl Cancer Inst 1992; 84: 972–4

    PubMed  CAS  Google Scholar 

  42. Rothenberg ML, Kuhn JG, Burris III HA, et al. Phase I and pharmacokinetic trial of weekly CPT-11. J Clin Oncol 1993; 11: 2194–204

    PubMed  CAS  Google Scholar 

  43. Rowinsky EK, Grochow LB, Ettinger DS, et al. Phase I and pharmacological study of the novel topoisomerase I inhibitor 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyl-oxyca mptothecin (CPT-11) administered as a ninety-minute infusion every 3 weeks. Cancer Res 1994; 54: 427–36

    PubMed  CAS  Google Scholar 

  44. Catimel G, Chabot GG, Guastalla JP, et al. Phase I and pharmacokinetic study of irinotecan (CPT-11) administered daily for three consecutive days every three weeks in patients with advanced solid tumors. Ann Oncol 1995; 6: 133–40

    PubMed  CAS  Google Scholar 

  45. de Forni M, Bugat R, Chabot GG, et al. Phase I and pharmacokinetic study of the camptothecin derivative irinotecan administered on a weekly schedule in cancer patients. Cancer Res 1994; 54: 4347–54

    PubMed  Google Scholar 

  46. Abigerges D, Chabot GG, Armand JP, et al. Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients. J Clin Oncol 1995; 13: 210–21

    PubMed  CAS  Google Scholar 

  47. Gandia D, Abigerges D, Armand JP, et al. CPT-11-Induced cholinergic effects in cancer patients [letter]. J Clin Oncol 1993; 11: 196–7

    PubMed  CAS  Google Scholar 

  48. Merrouche Y, Extra JM, Abigerges D, et al. High dose-intensity of irinotecan administered every 3 weeks in advanced cancer patients: a feasibility study. J Clin Oncol 1997; 15: 1080–6

    PubMed  CAS  Google Scholar 

  49. Hagipantelli R, Saliba F, Misset JL, et al. Pathophysiology and therapy of irinotecan (CPT-11) induced delayed onset diarrhoea: a prospective assessment [abstract]. Proc Am Soc Clin Oncol 1995; 14: 464

    Google Scholar 

  50. Sakata Y, Suzuki, H, Kamataki T. Preventive effect of TJ-14, a kampo medicine, on diarrhoea induced by irinotecan hydrochloride [in Japanese]. Jpn J Cancer Chemother (Gan To Kagaku Ryoho) 1994; 21: 1241–4

    CAS  Google Scholar 

  51. Takasuna K, Hagiwara T, Hirohashi M, et al. Involvement of -glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor camptothecin derivative irinotecan hydrochloride (CPT-11) in rats. Cancer Res 1996; 56: 3752–7

    PubMed  CAS  Google Scholar 

  52. Boisseau M, Guichard S, Canal P, et al. Irinotecan (CPT-11): current status and perspectives. Expert Opin Investig Drugs 1996; 5: 613–26

    CAS  Google Scholar 

  53. Rothenberg ML. CPT-11: an original spectrum of clinical activity. Semin Oncol 1996; 23 (1 Suppl. 3): 21–6

    PubMed  CAS  Google Scholar 

  54. Armand JP, Ducreux M, Mahjoubi M, et al. CPT-11 (irinotecan) in the treatment of colorectal cancer. Eur J Cancer 1995; 31 A: 1283–7

    Google Scholar 

  55. Shimada Y, Yoshino M, Wakui A, et al. Phase II study of CPT-11, a new camptothecin derivative, in metastatic colorectal cancer: CPT-11 Gastrointestinal Cancer Study Group. J Clin Oncol 1993; 11: 909–13

    PubMed  CAS  Google Scholar 

  56. Conti JA, Kemeny NE, Saltz LB, et al. Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 1996; 14: 709–15

    PubMed  CAS  Google Scholar 

  57. Shimada Y, Rougier P, Pitot H. Efficacy of CPT-11 (irinotecan) as a single agent in metastatic colorectal cancer. Eur J Can 1996; 3(32A Suppl.): S13–7

    Google Scholar 

  58. Rothenberg ML, Eckardt JR, BurrisIII HA, et al. Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 1996; 14: 1128–35

    PubMed  CAS  Google Scholar 

  59. Rougier P, Bugat R, Douillard JY, et al. Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 1997; 15: 251–60

    PubMed  CAS  Google Scholar 

  60. Fukuoka M, Nitani H, Suzuki A, et al. A phase II study of CPT-11, a new derivative of camptothecin, for previously untreated non-small cell lung cancer. J Clin Oncol 1992; 10: 16–20

    PubMed  CAS  Google Scholar 

  61. Masuda N, Fukuoka M, Kusunoki Y, et al. CPT-11: a new derivative of camptothecin for the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol 1992; 10: 1225–9

    PubMed  CAS  Google Scholar 

  62. Masuda N, Fukuoka M, Takada M, et al. CPT-11 in combination with cisplatin for advanced non-small-cell lung cancer. J Clin Oncol 1992; 10: 1775–80

    PubMed  CAS  Google Scholar 

  63. Chevallier B, Lhomme C, Dieras V, et al. Phase II trial of CPT-11 in advanced cervical carcinoma [abstract]. Proc Am Soc Clin Oncol 1995; 14: 267

    Google Scholar 

  64. Potkul RK, Price VT, Bailey H, et al. Irinotecan (CPT-11) in advanced squamous cell carcinoma of the cervix (Phase II) [abstract]. Proc Am Soc Clin Oncol 1995; 14: 279

    Google Scholar 

  65. Verschraegen CF, Levy T, Kudelka AP, et al. Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix. J Clin Oncol 1997; 15: 625–31

    PubMed  CAS  Google Scholar 

  66. Sakata Y, Shimada Y, Yoshino M, et al. A late phase II study of CPT-11, irinotecan hydrochloride, in patients with advanced pancreatic cancer [in Japanese]. Gan To Kagaku Ryoho 1994; 21: 1039–46

    PubMed  CAS  Google Scholar 

  67. Wagener DJ, Verdonk HE, Dirix LY, et al. Phase II trial of CPT-11 in patients with advanced pancreatic cancer, an EORTC early clinical trials group study. Ann Oncol 1995; 6: 129–32

    PubMed  CAS  Google Scholar 

  68. Futatsuki K, Wakui A, Nakao I, et al. A late Phase II study of irinotecan hydrochloride (CPT-11) in advanced gastric cancer: CPT-11 Gastrointestinal Cancer Study Group [in Japanese]. Gan To Kagaku Ryoho 1994; 21: 1033–8

    PubMed  CAS  Google Scholar 

  69. Bonneterre J, Pion JM, Adenis A, et al. A Phase II study of a new camtothecin analog CPT-11 in previously treated advanced breast cancer patients [abstract]. Proc Am Soc Clin Oncol 1993; 12: 94

    Google Scholar 

  70. Taguchi T, Tominaga T, Ogawa M, et al. A late phase II study of CPT-11 (irinotecan) in advanced breast cancer, CPT-11 Study Group on Breast Cancer [in Japanese]. Jpn J Cancer Chemother (Gan To Kagaku Ryoho) 1994; 21: 1017–24

    CAS  Google Scholar 

  71. Ohno R, Okada K, Masaoka T, et al. An early phase II study of CPT-11: a new derivative of camptothecin for the treatment of leukemia and lymphoma. J Clin Oncol 1990; 8: 1907–12

    PubMed  CAS  Google Scholar 

  72. Tsuda H, Takatsuki K, Ohno R, et al. Treatment of adult T-cell leukaemia-lymphoma with irinotecan hydrochloride (CPT-11): CPT-11 Study Group on Hematological Malignancy. Br J Cancer 1994; 70: 771–4

    PubMed  CAS  Google Scholar 

  73. Kaneda N, Nagata H, Furuta T, et al. Metabolism and pharmacokinetics of the camptothecin analogue CPT-11 in the mouse. Cancer Res 1990; 50: 1715–20

    PubMed  CAS  Google Scholar 

  74. Barilero I, Gandia D, Armand JP, et al. Simultaneous determination of the camptothecin analogue CPT-11 and its active metabolite SN-38 by high-performance liquid chromatography: application to plasma pharmacokinetic studies in cancer patients. J Chromatogr Biomed Appl 1992; 575: 275–80

    CAS  Google Scholar 

  75. Akimoto K, Goto A, Ohya K. Selective and sensitive determination of lactone and hydroxy acid forms of camptothecin and two derivatives (CPT-11 and SN-38) by high-performance liquid chromatography with fluorescence detection. J Chromatogr 1991; 588: 165–70

    CAS  Google Scholar 

  76. Rivory LP, Robert J. Reversed-phase high-performance liquid chromatographic method for the simultaneous quantitation of the carboxylate and lactone forms of the camptothecin derivative irinotecan, CPT-11, and its metabolite SN-38 in plasma. J Chromatogr Biomed Appl 1994; 661: 133–41

    CAS  Google Scholar 

  77. Warner DL, Burke TG. Simple and versatile high-performance liquid chromatographic method for the simultaneous quantitation of the lactone and carboxylate forms of camptothecin anticancer drugs. J Chromatogr B Biomed Appl 1997; 691: 161–71

    CAS  Google Scholar 

  78. Sumiyoshi H, Fujiwara Y, Ohune T, et al. High-performance liquid chromatographic determination of irinotecan (CPT-11) and its active metabolite (SN-38) in human plasma. J Chromatogr B Biomed Appl 1995; 670: 309–16

    PubMed  CAS  Google Scholar 

  79. Sasaki Y, Yoshida Y, Sudoh K, et al. Pharmacological correlation between total drug concentration and lactones of CPT-11 and SN-38 in patients treated with CPT-11. Jpn J Cancer Res 1995; 86: 111–6

    PubMed  CAS  Google Scholar 

  80. Sasaki Y, Hakusui H, Mizuno S, et al. A pharmacokinetic and pharmacodynamic analysis of CPT-11 and its active metabolite SN-38. Jpn J Cancer Res 1995; 86: 101–10

    PubMed  CAS  Google Scholar 

  81. Rivory LP, Chatelut E, Canal P, et al. Kinetics of the in vivo interconversion of the carboxylate and lactone forms of irinotecan (CPT-11) and of its metabolite SN-38 in patients. Cancer Res 1994; 54: 6330–3

    PubMed  CAS  Google Scholar 

  82. Tsuji T, Kaneda N, Kado K, et al. CPT-11 converting enzyme from rat serum: purification and some properties. J Pharmacobiodyn 1991; 14: 341–9

    PubMed  CAS  Google Scholar 

  83. Satoh T, Hosokawa M, Atsumi R, et al. Metabolic activation of CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino)carbonyl-oxy camptothecin, a novel antitumor agent, by carboxyesterase. Biol Pharm Bull 1994; 17: 662–4

    PubMed  CAS  Google Scholar 

  84. Rivory LP, Bowles MR, Robert J, et al. Conversion of irinotecan (CPT-11) to its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), by human liver carboxy-esterase. Biochem Pharmacol 1996; 52: 1103–11

    PubMed  CAS  Google Scholar 

  85. Chabot GG, Abigerges D, Catimel G, et al. Population pharma-cokinetics and pharmacodynamics of irinotecan (CPT-11) and active metabolite SN-38 during phase I trials. Ann Oncol 1995; 6: 141–51

    PubMed  CAS  Google Scholar 

  86. Rivory LP, Robert J. Identification and kinetics of a beta-glucuronide metabolite of SN-38 in human plasma after administration of the camptothecin derivative irinotecan. Cancer Chemother Pharmacol 1995; 36: 176–9

    PubMed  CAS  Google Scholar 

  87. Haaz MC, Rivory L, Jantet S, et al. Glucuronidation of SN-38, the active metabolite of irinotecan, by human hepatic microsomes. Pharmacol Toxicol 1997; 80: 91–6

    PubMed  CAS  Google Scholar 

  88. Gupta E, Lestingi TM, Mick R, et al. Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhoea. Cancer Res 1994; 54: 3723–5

    PubMed  CAS  Google Scholar 

  89. Rivory LP, Riou JF, Haaz MC, et al. Identification and properties of a major plasma metabolite of irinotecan (CPT-11) isolated from the plasma of patients. Cancer Res 1996; 56: 3689–94

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  91. Masuda N, Fukuoka M, Kudoh S, et al. Phase I and pharmacologic study of irinotecan in combination with cisplatin for advanced lung cancer. Br J Cancer 1993; 68: 777–82

    PubMed  CAS  Google Scholar 

  92. Masuda N, Fukuoka M, Kudoh S, et al. Phase I and pharmacologic study of irinotecan and etoposide with recombinant human granulocyte colony-stimulating factor support for advanced lung cancer. J Clin Oncol 1994; 12: 1833–41

    PubMed  CAS  Google Scholar 

  93. Canal P, Gay C, Dezeuze A, et al. Pharmacokinetics and pharmacodynamics of irinotecan during a phase II clinical trial in colorectal cancer. J Clin Oncol 1996; 14: 2688–95

    PubMed  CAS  Google Scholar 

  94. Rivory LP, Haaz MC, Canal P, et al. Pharmacokinetic inter-relationships of irinotecan (CPT-11) and its three major plasma metabolites in patients enrolled in phase I-II trials. Clin Cancer Res 1997; 3: 1261–6

    PubMed  CAS  Google Scholar 

  95. Iyer L, King C, Tephly T, et al. UGT isoform 1.1 (UGT*1.1) glucuronidates SN-38, the active metabolite of irinotecan [abstract 707]. Proc Am Soc Clin Oncol 1997; 16: 201a

    Google Scholar 

  96. Data on file Rhône-Poulenc Rorer, S.A Antony, France

  97. Burke TG, Mi Z. The structural basis of camptothecin interacions with human serum albumin: impact on drug stability. J Med Chem 1994; 37: 40–6

    PubMed  CAS  Google Scholar 

  98. Burris H, Dietz A, Eckardt J, et al. A Phase I trial to evaluate orally administered irinotecan HC1 (CPT-11) given daily X 5 every 3 weeks in patients with refractory malignancies [abstract]. Proc Am Soc Clin Oncol 1996; 15: 489

    Google Scholar 

  99. Lokiec F, Canal P, Gay C, et al. Pharmacokinetics of irinotecan and its metabolites in human blood, bile, and urine. Cancer Chemother Pharmacol 1995; 36: 79–82

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  101. Gupta E, Mick R, Ramirez J, et al. Pharmacokinetic and pharmacodynamic evaluation of the topoisomerase inhibitor irinotecan in cancer patients. J Clin Oncol 1997; 15: 1502–10

    PubMed  CAS  Google Scholar 

  102. Gupta E, Wang X, Ramirez J, et al. Modulation of glucuronidation of SN-38, the active metabolite of irinotecan, by valproic acid and phenobarbital. Cancer Chemother Pharmacol 1997; 39: 440–4

    PubMed  CAS  Google Scholar 

  103. Gupta E, Safa AR, Wang X, et al. Pharmacokinetic modulation of irinotecan and metabolites by cyclosporin A. Cancer Res 1996; 56: 1309–14

    PubMed  CAS  Google Scholar 

  104. Sasaki Y, Ohtsu A, Shimada Y, et al. Simultaneous administration of CPT-11 and fluorouracil: alteration of the pharmacokinetics of CPT-11 and SN-38 in patients with advanced colorectal cancer. J Natl Cancer Inst 1994; 86: 1096–8

    PubMed  CAS  Google Scholar 

  105. Grossin F, Barbault H, Benhammouda A, et al. A phase I pharmacokinetics study of concomitant CPT-11 and 5FU combination [abstract 1156]. Proc Am Assoc Cancer Res 1996; 37: 168

    Google Scholar 

  106. Saltz LB, Kanowitz J, Kemeny NE, et al. Phase I clinical and pharmacokinetic study of irinotecan, fluorouracil, and leucovorin in patients with advanced solid tumors. J Clin Oncol 1996; 14: 2959–67

    PubMed  CAS  Google Scholar 

  107. Karato A, Sasaki Y, Shiraishi J, et al. Pharmacokinetic study in the dose escalation study of CPT-11 and VP-16 [abstract]. Proc Am Assoc Cancer Res 1993; 34: 2325

    Google Scholar 

  108. Couteau C, Lokiec F, Vernillet L, et al. Phase I dose-finding and pharmacokinetic (PK) study of docetaxel (D) in combination with irinotecan (I) in advanced solid tumors [abstract 709]. Proc Am Soc Clin Oncol 1997; 16: 202a

    Google Scholar 

  109. Kudoh S, Fukuoka M, Masuda N, et al. Relationship between the pharmacokinetics of irinotecan and diarrhoea during combination chemotherapy with cisplatin. Jpn J Cancer Res 1995; 86: 406–13

    PubMed  CAS  Google Scholar 

  110. Mick R, Gupta E, Vokes EE, et al. Limited-sampling models for irinotecan pharmacokinetics-pharmacodynamics: prediction of biliary index and intestinal toxicity. J Clin Oncol 1996; 14: 2012–9

    PubMed  CAS  Google Scholar 

  111. Chabot GG. Limited sampling models for simultaneous estimation of the pharmacokinetics of irinotecan and its active metabolite SN-38. Cancer Chemother Pharmacol 1995; 36: 463–72

    PubMed  CAS  Google Scholar 

  112. Nakashima H, Lieberman, R, Karato A, et al. Efficient sampling strategies for forecasting pharmacokinetic parameters of irinotecan (CPT-11): implication for area under the concentration-time curve monitoring. Ther Drug Monit 1995; 17: 221–9

    PubMed  CAS  Google Scholar 

  113. Sasaki Y, Mizuno S, Fujii H, et al. A limited sampling model for estimating pharmacokinetics of CPT-11 and its metabolite SN-38. Jpn J Cancer Res 1995; 86: 117–23

    PubMed  CAS  Google Scholar 

  114. Yamamoto N, Ramura T, Karato A, et al. CPT-11: population pharmacokinetic model and estimation of pharmacokinetics using the Bayesian method in patients with lung cancer. Jpn J Cancer Res 1994; 85: 972–7

    PubMed  CAS  Google Scholar 

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  1. Pharmacology Laboratory (URA 147 CNRS), Gustave-Roussy Institute, 39 rue Camille-Desmoulins, F-94805, Villejuif, France

    Guy G. Chabot

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Chabot, G.G. Clinical Pharmacokinetics of Irinotecan. Clin. Pharmacokinet. 33, 245–259 (1997). https://doi.org/10.2165/00003088-199733040-00001

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