Irinotecan (CamptoR) Pharmacokinetics and Metabolism in Patients with Elevated Serum Bilirubin Levels

• Najia Mansoor

  Department of Pharmacology, Faculty of Pharmacy & Pharmaceutical Sciences, University of Karachi, Karachi-75270, Pakistan

• Rafeeq Alam Khan

  Department of Pharmacology, Faculty of Pharmacy & Pharmaceutical Sciences, University of Karachi, Karachi-75270, Pakistan

• Johannes Schueller

  Hospital Rudolfstifung, Department of Internal Medicine and Oncology, Juchgasse 25, A-1030 Vienna, Austria

• Dagmar Ettlinge

  Department of Clinical Pharmacy and Diagnostics, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria

• Philipp Buchner

  Department of Clinical Pharmacy and Diagnostics, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria

• Martin Czejka

  Department of Clinical Pharmacy and Diagnostics, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria

• Tasneem Ahmad

  Pharma Professional Services, A-93 Ettawah Society, Gadap Town, Karachi, Pakistan

 In this study, we have calculated and reported the pharmacokinetics of irinotecan and its active metabolite, SN-38, in patients with increased plasma bilirubin levels. Four patients suffering from metastatic colorectal cancer (CRC) with high bilirubin levels (0.7 to 15 mg/dl) were selected for our study. These patients were being treated by CPT -11 (Irinotecan) in the hospital setup. To all four patients, CPT-11 was administered as a 60 min IV- infusion (180 mg/m², total dose 339 ± 32 mg). Blood samples were collected at 0, 15, 30, 45, 60, 90,120, 180, 240, 300 and 360 minutes after the drug administration. The drug and its pharmacologically active metabolite, SN38 were quantified in these samples by an HPLC method. The blood level profiles were analyzed for their PK behavior by Kinetica® software system. SN 38 levels were found to be decreasing with increasing bilirubin values. The possible rationalizing for lower SN38 levels with elevated bilirubin levels might be some liver impairment which slows the metabolic conversion of irinotecan into SN-38.

Armand JP, Ducreux M, Mahjoubi M, Abigerges D, Bugat R, Chabot G, Herait P, de Forni M, Rougier P. CPT-11 (irinotecan) in the treatment of colorectal cancer; European Journal of Cancer 1995; 31A(7-8): 1283-7. http://dx.doi.org/10.1016/0959-8049(95)00212-2

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

Hare CB, Elion GB, Houghton PJ, et al. Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)- carbonyloxy-camptothecin against pediatric and adult central nervous system tumor xenografts. Cancer Chemother Pharmacol 1997; 39: 187-191.

http://reference.medscape.com/drug/camptosar-irinotecan-342252

Venook AP, Enders Klein C, Fleming G, Hollis D, Leichman CG, Hohl R, Byrd J, Budman D, Vil M. A phase I and pharmacokinetic study of irinotecan in patients with hepatic or renal dysfunction or with prior pelvic radiation: CALGB 9863.

Eklund JW, Mulcahy MF. Oncology Journal, Palliative and Supportive Care July 01, 2005.

Czejka M, Kiss A, Ostermann E, Schueller J, Ahmed M, Mansoor N, Ahmad T. Metabolic Activation and Inactivation of Irinotecan when Combined with the Human Monoclonal Antibody Bevacizumab.

Slatter JG, Schaaf LJ, Sams JP. Pharmacokinetics, metabolism and excretion of irinotecan (CPT-11) following IV- infusion of [14C] CPT-11 in cancer patients. Drug Metab Disp 2000; 28: 423-33.

Czejka M, Schueller J, Hauer K, Ostermann E. Pharmacokinetics and metabolism of CPT-11 combined with capecitabine in patients with advanced colorectal cancer. Anticancer Res 2005; 25: 2985-90.

Jinno H, Tanaka-Kagawa T, Hanioka N, et al. Glucuronidation of 7-Ethyl-10-hydroxycamptothecin (SN-38), an Active Metabolite of Irinotecan (CPT-11), by Human UGT1A1 Variants, G71R, P229Q, and Y486D: Drug Metabolism and Disposition.aspetjournals.org

Gupta E, Wang X, Ramirez J, Rattain MJ. Modulation of glucuronidation of SN-38, the active metabolite of irinotecan, by valproic acid and phenobarbital. Cancer Chemother Pharmacol 1997; 39: 440-444.

Reid JM, Cha S, Buckner JC, Petros WP, Friedman HS, Tourt-Uhlig S, Walker A, Kuhn JG, Prados M, Supko JG, Gilbert MR, Batchelor TT, Schaaf L, Gaylor SK, McGovren JP, Gallo JM. Pharmacokinetics of CPT-11 in glioma patients: Pooled analysis of data from 4 NCI-sponsored trials. Clin Cancer Res 2001; 7(suppl): 373.(abstract 415)

Canal P, Chatelut E, Guichard S. Practical treatment guide for dose individualisation in cancer chemotherapy. Drugs 1998; 56: 1019-38. http://dx.doi.org/10.2165/00003495-199856060-00006

Ciotti M, Basu N, Brangi M, Owens IS. Glucuronidation of 7-ethyl-10-hydroxycamptothecin(SN-38)by the human UDP glucuronosyltransferases encoded at theUGT1 locus. Biochem Biophys Res Commun 1999; 260: 199-202.

Canal P, Chatelut E, Guichard S. Practical treatment guide for dose individualisation in cancer chemotherapy. Drugs 1998; 56: 1019-38. http://dx.doi.org/10.2165/00003495-199856060-00006

Commentary: Oncologic Drugs in Patients with Organ Dysfunction: A Summary Diana Superfin, Andrea A. Iannucci and Angela M. Davies.

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