Metabolic Activation and Inactivation of Irinotecan when Combined with the Human Monoclonal Antibody Bevacizumab

• Martin Czejka

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

• Andreas Kiss

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

• Eva Ostermann

  Department of Internal Medicine / Oncology, Hospital Rudolfstiftung, Boerhaavegasse 13, A-1030 Vienna, Austria

• Johannes Schueller

  Department of Internal Medicine / Oncology, Hospital Rudolfstiftung, Boerhaavegasse 13, A-1030 Vienna, Austria

• Mansoor Ahmed

  Department of Pharmaceutical Chemistry, University of Karachi, Pakistan

• Najia Mansoor

  Department of Pharmacology, University of Karachi, Pakistan

• Tasneem Ahmad

  Pharma Professional Services, Karachi, Pakistan

Purpose: This pharmacokinetic study was designed to investigate whether the co-administration of the monoclonal antibody bevacizumab (BVC) shows potential to modulate the plasma disposition of irinotecan (CPT-11) and its metabolites.

Patients and Methods: Ten patients suffering from advanced colorectal cancer entered this pharmacokinetic study. Patients received CPT-11 as a 60 min i.v. - infusion (180 mg/m2, total dose 339 ± 32 mg) weekly for six weeks. BVC was administered biweekly as an intravenous 90 min infusion containing 5 mg BVC per kg body weight in 100 ml balanced sodium chloride solution. Pre-medication consisted of tropisetrone (3 mg i.v. push) and atropine (0.5 mg i.v.) one hour before CPT-11 infusion. Plasma samples were analysed during / after the first (MONO) and after the third CPT-11 infusion (BVC regimen).

Results: BVC did not alter plasma disposition and pharmacokinetics of the parent compound CPT-11, but in contrary BVC appeared to lower the plasma concentrations of the metabolites SN-38, SN-38gluc and APC.

Conclusion: Overall, our findings indicate that administration of BVC prior to chemotherapy showed no clinically significant impact on the pharmacokinetics and metabolic activation of CPT-11.

Douillard JY, Cunningham D, Roth AD, et al. CPT-11 combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000; 355: 1041-47. http://dx.doi.org/10.1016/S0140-6736(00)02034-1

Saltz LB, Cox JV, Blanke C, et al. CPT-11 plus fluorouracil and leucovorin for metastatic colorectal cancer. CPT-11 Study Group. N Engl J Med 2000; 343: 905-14. http://dx.doi.org/10.1056/NEJM200009283431302

McCormack PL, Keam SJ. Bevacizumab: a review of its use in metastatic colorectal cancer drugs 2008; 68: 487-506.

Motl S. Bevacizumab in combination chemotherapy for colorectal and other cancers. Am J Health-Syst Pharm 2005; 62: 1021-32.

Denlinger CS, Blanchard R, Xu L, et al. Pharmacokinetic analysis of irinotecan plus bevacizumab in patients with advanced solid tumors. Cancer Chemother Pharmacol 2009; 65: 97-105. http://dx.doi.org/10.1007/s00280-009-1008-7

Hurwitz H, Fehrenbacher L, Cartwright T, et al. Bevacizumab (a monoclonal antibody to vascular endothelial growth factor) prolongs survival in first line colorectal cancer (CRC): results of a phase III trial of bevacizumab in combination with bolus IFL (irinotecan, 5-fluorouracil, leucovorin) as first line therapy in subjects with metastatic CRC. Proc Am Soc Clin Oncol 2003; Abstract 3646.

Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New Engl J Med 2004; 350: 2335-42. http://dx.doi.org/10.1056/NEJMoa032691

Kabbinavar FF, Joseph Schulz J, McCleod M, et al. Addition of Bevacizumab to bolus 5-FU/leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 2005; 23: 3697-705. http://dx.doi.org/10.1200/JCO.2005.05.112

Slatter JG, Schaaf LJ, Sams JP. Pharmacokinetics, metabolism and excretion of irinotecan (CPT-11) following i.v. infusion of

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.

Xie R, Mathijssen RH, Sparreboom A, Verweij J, Karlsson MO. Clinical pharma-cokinetics of CPT-11 and its metabolites in relation with diarrhea. Clin Pharmacol Ther 2002; 72: 265-75. http://dx.doi.org/10.1067/mcp.2002.126741

Rivory LP, Bowles RM, Robert J, Pond SM. Conversion of CPT-11 to its active metabolite SN-38 by human liver carboxylesterase. Biochem Pharmacol 1996; 52: 1103-11. http://dx.doi.org/10.1016/0006-2952(96)00457-1

Slatter JG, Su P, Sams JP, Schaaf LJ, Wienkers LC. Bioactivation of the anticancer agent CPT-11 to SN-38 by human hepatic microsomal carboxylesterases and the in-vitro assessment of potential drug interactions. Drug Metab Disp 1997; 25: 1157-64.

Fukuda M, Oka M, Soda H, Terashi K, Kawabata S, Nakatomi K, et al. Phase I study of irinotecan combined with carboplatin in previously untreated solid cancers. Clin Cancer Res 1999; 5: 3963-69.

Yamamoto N, Negoro S, Chikazawa H, Shimizu T, Fukuoka M. Pharmacokinetic interaction of the combination of paclitaxel and irinotecan in vivo and clinical study. Proc Am Soc Clin Oncol 1999; 18: 186a.

Sasaki Y, Ohtsu A, Shimada Y, Ono K, Saijo N. 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 (Bethesda) 1994; 86: 1096-97. http://dx.doi.org/10.1093/jnci/86.14.1096

Killickap S, Abali H, Celik I. Bevacizumab, bleeding, thrombosis and warfarin. J Clin Oncol 2003; 21: 3542-46. http://dx.doi.org/10.1200/JCO.2003.99.046

Czejka M, Gruenberger B, Kiss A, Farkouh A, Schueller J. Pharmacokinetics of irinotecan in combination with biweekly cetuximab in patients with advanced colorectal cancer. Anticancer Res 2010; 30: 2355-60.

Horita Y, Yamada Y, Hirashima Y, Kato K, Naakajima T, Hamaguchi T, Shimana Y. Effects of bevacizumab on plasma concentrations of irinotecan and its metabolites in advanced colorectal cancer patients receiving FOLFIRI with bevacizumab as second line therapy. Cancer Chemother Pharmacol 2010; 65: 467-71. http://dx.doi.org/10.1007/s00280-009-1051-4

Ettlinger D, Mitterhauser M, Wadsak W, Ostermann E, Farkouh A, Schueller J, Czejka M. In-vivo disposition of irinotecan (CPT-11) and its metabolites in combination with the monoclonal antibody cetuximab. Anticancer Res 2006; 26: 1337-42.

Czejka M, Schueller J, Gruenberger B, Farkouh A, Scheithauer W. Plasma disposition of capecitabine and its metabolites 5’DFCR and 5’DFUR in a standard and dose-intensified monotherapy regimen. Cancer Chemother Pharmacol 2011; 67: 613-19. http://dx.doi.org/10.1007/s00280-010-1363-4

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